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Non-decameric NLRP3 reveals a TGN/MTOC-distal pathway of inflammasome activation.

The NLRP3 inflammasome contributes to a wide range of conditions from infections to Alzheimer's disease. NLRP3 forms an inactive decameric cage, that upon interaction with the trans-Golgi network (TGN) and microtubule organization center (MTOC), leads to inflammasome activation, yet whether non-decamer NLRP3 species form functional inflammasomes remains unclear. Here, we design a NLRP3 exon 3 deletion variant that forms low molecular weight NLRP3 assemblies. Spatially and dynamically highly resolved microscopy in THP-1 and human macrophages shows that nigericin, a K+-dependent NLRP3 stimulus, …

Hypothermia protects against ventilator-induced lung injury by limiting IL-1β release and NETs formation.

Although mechanical ventilation is a critical intervention for acute respiratory distress syndrome (ARDS), it can trigger an IL-1β-associate … d NETs formation. We also observed that LPS-primed macrophages, when stimulated at 32°C with ATP or nigericin, release less IL-1β associated with reduced GSDMD cleavage. Thus, hypothermia is an important modulating factor in the NLRP3 inflammasome activation, IL-1β release and NETs formation, preventing LPS-HVV-induced acute respiratory failure.

Discovery of Potent, Specific, and Orally Available NLRP3 Inflammasome Inhibitors Based on Pyridazine Scaffolds for the Treatment of Septic Shock and Peritonitis.

The NLRP3 inflammasome is a multiprotein complex that is a component of the innate immune system, involved in the production of pro-inflammatory cytokines. Its abnormal activation is associated with many inflammatory diseases. In this study, we designed and synthesized a series of NLRP3 inflammasome inhibitors based on pyridazine scaffolds. Among them, P33 exhibited significant inhibitory effects against nigericin-induced IL-1β release in THP-1 cells, BMDMs, and PBMCs, with IC50 values of 2.7, 15.3, and 2.9 nM, respectively. Mechanism studies indicated that P33 directly binds to NLRP3 protein …

Discovery of pterostilbene analogs as novel NLRP3 inflammasome inhibitors for potential treatment of DSS-induced colitis in mice.

The pterostilbene skeleton is a promising chemical scaffold that exerts anti-inflammatory, anti-depressant, and anti-tumor effects. In this study, we aim to reduce in vivo and in vitro toxicity of compound 32 (preliminary work) and maintain its biological activity. A series of novel pterostilbene derivatives (D1-D43) were designed and synthesized, and their anti-inflammatory activities were screened. All compounds were screened to evaluate their inhibitory effect on LPS/Nigericin-induced IL-1β production and pyroptosis. The structure-activity relationships was deduced, and finally 1-((E)-4-(2-…

Tanshinones inhibit NLRP3 inflammasome activation by alleviating mitochondrial damage to protect against septic and gouty inflammation.

Tanshinones, the active ingredients derived from the roots of Salvia miltiorrhiza, have been widely used as traditional medicinal herbs for … otanshinone I) reduced mitochondrial reactive-oxygen species production in lipopolysaccharide (LPS)/nigericin-stimulated macrophages and correlated with altered mitochondrial membrane potentials, mitochondria complexes activities, and adenosine triphosphate and protonated-nicotinamide adenine dinucleotide production. The tanshinones may confer mitochondrial …

Altered MICOS Morphology and Mitochondrial Ion Homeostasis Contribute to Poly(GR) Toxicity Associated with C9-ALS/FTD.

Amyotrophic lateral sclerosis (ALS) manifests pathological changes in motor neurons and various other cell types. Compared to motor neurons, … ts. Genetic manipulation of MICOS components or pharmacological restoration of ion homeostasis with nigericin effectively rescue the mitochondrial pathology and disease phenotypes in both systems. These results implicate MICOS-regulated ion homeostasis in C9-ALS pathogenesis and suggest potential new therapeutic strategies.

Chloroquine enhances TRAIL-mediated apoptosis through up-regulation of DR5 by stabilization of mRNA and protein in cancer cells.

Chloroquine (CQ), an anti-malarial drug, has immune-modulating activity and lysosomotropic activity. In this study, we investigated CQ sensi … down of Cbl markedly enhanced DR5 up-regulation. Other lysosomal inhibitors, including monensin and nigericin, also up-regulated DR5 and sensitized TRAIL-mediated apoptosis. Therefore, this study demonstrates that lysosomal inhibition by CQ may sensitize TRAIL-mediated apoptosis in human renal cancer Caki cells via DR5 up-regulation.

Monensin, a polyether ionophore antibiotic, overcomes TRAIL resistance in glioma cells via endoplasmic reticulum stress, DR5 upregulation and c-FLIP downregulation.

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is preferentially cytotoxic to cancer cells over normal cells. However, many … mediated downregulation of c-FLIP. Interestingly, other polyether antibiotics, such as salinomycin, nigericin, narasin and lasalocid A, also stimulated TRAIL-mediated apoptosis in glioma cells via ER stress, CHOP-mediated DR5 upregulation and c-FLIP downregulation. Taken together, these results suggest that combined treatment of glioma cells with TRAIL and …

Ionic dependence of adenosine uptake into cultured astrocytes.

Adenosine uptake in cultured astrocytes is dependent on various ions and energy metabolism. The Na(+)-gradient plays an important role, since nigericin, ouabain, amiloride and substitution of Na+ with choline inhibited adenosine uptake. The proton-gradient was of importance, since carbonylcyanide m-chlorophenylhydrozone (CCCP) and omeprazole also inhibited adenosine uptake. Furthermore, adenosine uptake was dependent on Cl- anion. Substitution of Cl- with isethionate, as well as DIDS or furosemide inhibited adenosine uptake. Adenosine uptake was also sensitive to Ca2+ gradient, removal of extr…

Populations of photoinactivated photosystem II reaction centers characterized by chlorophyll a fluorescence lifetime in vivo.

Photosystem (PS) II centers, which split water into oxygen, protons, and electrons during photosynthesis, require light but are paradoxically inactivated by it. Prolonged light exposure concomitantly decreased both the functional fraction of PSII reaction centers and the integral PSII chlorophyll (Chl) a fluorescence lifetime in leaf segments of Capsicum annuum L. Acceleration of photoinactivation of PSII by a pretreatment with the inhibitors/uncoupler lincomycin, DTT, or nigericin further reduced PSII Chl a fluorescence lifetimes. A global analysis of fluorescence lifetime distributions revea…

Characterization of the Saccharomyces cerevisiae cytosine transporter using energizable plasma membrane vesicles.

The purine-cytosine permease is a carrier localized in the plasma membrane of the yeast Saccharomyces cerevisiae. The energetics of cytosine … the purine-cytosine permease is able to catalyze a secondary active transport of cytosine. By using nigericin and valinomycin, the DeltapH component of the proton-motive force is shown to be the only force driving nucleobase accumulation. Moreover, transport measurements done at two pH values have shown that alkalinization of intravesicular pH leads to a si …

NLRP3 inflammasome activation and pyroptosis are dispensable for tau pathology.

BACKGROUND: Neuroinflammation is widely recognized as a key factor in the pathogenesis of Alzheimer's disease (AD), alongside ß-amyloid depo … pic brain slice cultures from P301S transgenic mice were treated with lipopolysaccharide (LPS) plus nigericin as a positive control or exposed to tau seeds (K18) to evaluate NLRP3 inflammasome activation. The effect of tau seeding on NLRP3 activity was further examined using Meso Scale Discovery (MSD) assays to measure IL1β secretion levels in the presence …

Phenylphosphonate transport by Helicobacter pylori.

BACKGROUND: Helicobacter pylori can utilize phenylphosphonate as a sole source of phosphorus, and it is able to transport the phosphonate N- … ze. The effects of various inhibitors were investigated: iodoacetamide, amiloride, valinomycin, and nigericin reduced the rate of phenylphosphonate transport; sodium azide and sodium cyanide increased the transport rate; and monensin had no effect. CONCLUSIONS: The kinetics and properties of H. pylori phenylphosphonate transport were characterized, and the …

D-Gluconate transport in Arthrobacter pyridinolis. Metabolic trapping of a protonated solute.

D-Gluconate uptake was studied in whole cells of Arthrobacter pyridinolis; the uptake activity was inducible, mutable and showed saturation … port. Rather, the rate of D-gluconate uptake metabolism: (a) treatment of cells with valinomycin or nigericin, under conditions in which there was a loss of intracellular potassium, inhibited both D-gluconate uptake and the metabolism of pre-accumulated D-gluconate; (b) the effects of cyanide and azide on D-gluconate uptake were much more severe at pH 6.5 t …

Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca2+ axis.

BACKGROUND: Microglia pyroptosis-mediated neuroinflammation is thought to be the crucial pathogenesis of sepsis-associated encephalopathy (S … gation perforation (CLP) to induce SAE. Primary mouse microglia and BV2 cells were treated with LPS/nigericin in vitro. Behavioral tests were performed to evaluate cognitive function. Nissl staining and transmission electron microscopy were used to assess histological and structural lesions. ELISA and qPCR were carried out to detect neuroinflammation. Weste …

Activation of the NLRP3 inflammasome in osteoclasts is suppressed by a Tmem178-dependent mechanism that restricts Ca2+ influx.

Activation of the NLRP3 inflammasome can drive bone resorption by osteoclasts in various inflammatory conditions. Here, we identified Tmem178, a protein that restrains Ca2+ fluxes by limiting SOCE activation, as an inhibitor of NLRP3 inflammasome activation and the bone-resorbing activity of osteoclasts. We found that NLRP3 abundance gradually decreased during osteoclastogenesis but was restored by treatment with the bacterial product LPS. LPS and the NLRP3 activator nigericin stimulated this inflammasome in macrophages, as expected, but not in osteoclasts or their lineage-committed precursors…

Сипонимод препятствует микроглиальной воспламенительной активации.

Сипонимод — первый пероральный препарат, утвержденный для активного вторичного прогрессивного склероза. Он выступает в качестве функционального антагониста рецептора 1 (S1P1) фосфата (S1P1) через интернализацию S1P1, а также служит агонистом S1P5; однако детальные механизмы его терапевтического воздействия на глиальные клетки еще не определены. В этом исследовании мы изучили антивоспалительный механизм сипонимона в микроглии. Предварительная обработка либо сипонимодом, либо антагонистом S1P1 W146 значительно остановила производство интерлейкина-1β в активированном микроглии, стимулируемом липо

Совпадение в аннотации оригинала
Siponimod is the first oral drug approved for active secondary progressive multiple sclerosis. It acts as a functional antagonist of sphingo … sed the production of interleukin-1β in activated microglia stimulated with lipopolysaccharide plus nigericin, an inflammasome activator. Furthermore, siponimod treatment reduced the protein levels of cleaved caspase-1 and inhibited the formation of aggregates of apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC …

Genome Editing of Human Primary Keratinocytes by CRISPR/Cas9 Reveals an Essential Role of the NLRP1 Inflammasome in UVB Sensing.

By forming a protective barrier, epidermal keratinocytes represent the first line of defense against environmental insults. UVB radiation of … eratinocytes. Moreover, NLRP1 but not NLRP3 was required for inflammasome activation in response to nigericin, a potassium ionophore and well-established NLRP3 activator in immune cells. Because the CRISPR/Cas9-targeted cells retained their full differentiation capacity, genome editing of human primary keratinocytes might be useful for numerous research and …

Kinetic characterization of cytochrome c oxidase from Bacillus subtilis.

Bacillus subtilis aa3-type cytochrome c oxidase is capable of oxidizing cytochrome c from different origins. The kinetic properties of the e … holipid composition, protein/lipid ratios and also on the external pH. The action of the ionophores nigericin and valinomycin, at various pH values, on the enzyme activity and proton-permeability measurements of the membranes indicate that both components of the proton-motive force, the membrane potential and the pH gradient, can in principle regulate enzym …