Th17 cell differentiation and pathogenicity depend on metabolic reprogramming inducing shifts toward glycolysis. Here, we show that the pyruvate kinase M2 (PKM2), a glycolytic enzyme required for ...cancer cell proliferation and tumor progression, is a key factor mediating Th17 cell differentiation and autoimmune inflammation. We found that PKM2 is highly expressed throughout the differentiation of Th17 cells in vitro and during experimental autoimmune encephalomyelitis (EAE) development. Strikingly, PKM2 is not required for the metabolic reprogramming and proliferative capacity of Th17 cells. However, T cell-specific PKM2 deletion impairs Th17 cell differentiation and ameliorates symptoms of EAE by decreasing Th17 cell-mediated inflammation and demyelination. Mechanistically, PKM2 translocates into the nucleus and interacts with STAT3, enhancing its activation and thereby increasing Th17 cell differentiation. Thus, PKM2 acts as a critical nonmetabolic regulator that fine-tunes Th17 cell differentiation and function in autoimmune-mediated inflammation.
Background and Purpose
Rheumatoid arthritis (RA) is a chronic autoimmune disease that can cause bone erosion due to increased osteoclastogenesis. Neutrophils involvement in osteoclastogenesis remains ...uncertain. Given that neutrophil extracellular traps (NETs) can act as inflammatory mediators in rheumatoid arthritis, we investigated the role of NETs in stimulating bone loss by potentiating osteoclastogenesis during arthritis.
Experimental Approach
The level of NETs in synovial fluid from arthritis patients was assessed. Bone loss was evaluated by histology and micro‐CT in antigen‐induced arthritis (AIA)‐induced WT mice treated with DNase or in Padi4‐deficient mice (Padi4flox/flox LysMCRE). The size and function of osteoclasts and the levels of RANKL and osteoprotegerin (OPG) released by osteoblasts that were incubated with NETs were measured. The expression of osteoclastogenic marker genes and protein levels were evaluated by qPCR and western blotting. To assess the participation of TLR4 and TLR9 in osteoclastogenesis, cells from Tlr4−/− and Tlr9−/− mice were cultured with NETs.
Key Results
Rheumatoid arthritis patients had higher levels of NETs in synovial fluid than osteoarthritis patients, which correlated with increased levels of RANKL/OPG. Moreover, patients with bone erosion had higher levels of NETs. Inhibiting NETs with DNase or Padi4 deletion alleviated bone loss in arthritic mice. Consistently, NETs enhanced RANKL‐induced osteoclastogenesis that was dependent on TLR4 and TLR9 and increased osteoclast resorptive functions in vitro. In addition, NETs stimulated the release of RANKL and inhibited osteoprotegerin in osteoblasts, favouring osteoclastogenesis.
Conclusions and Implications
Inhibiting NETs could be an alternative strategy to reduce bone erosion in arthritis patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
PI3K activation plays a central role in the development of pulmonary inflammation and tissue remodeling. PI3K inhibitors may thus offer an improved therapeutic opportunity to treat non-resolving lung ...inflammation but their action is limited by unwanted on-target systemic toxicity. Here we present CL27c, a prodrug pan-PI3K inhibitor designed for local therapy, and investigate whether inhaled CL27c is effective in asthma and pulmonary fibrosis. Mice inhaling CL27c show reduced insulin-evoked Akt phosphorylation in lungs, but no change in other tissues and no increase in blood glycaemia, in line with a local action. In murine models of acute or glucocorticoid-resistant neutrophilic asthma, inhaled CL27c reduces inflammation and improves lung function. Finally, inhaled CL27c administered in a therapeutic setting protects from bleomycin-induced lung fibrosis, ultimately leading to significantly improved survival. Therefore, local delivery of a pan-PI3K inhibitor prodrug reduces systemic on-target side effects but effectively treats asthma and irreversible pulmonary fibrosis.
Raffia, a natural lignocellulosic fiber (NLF) extracted from the leaf of the Raphia vinifera palm tree was a long time introduced to the Amazon region. A thermochemical and structural evaluation of ...the raffia fiber fabric was conducted in the current study. Characterization of the fabric fibers was done using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), lignocellulosic analysis and scanning electron microscopy (SEM). The thermogravimetric analysis showed a loss of moisture at 52.0 °C and the beginning of degradation at 245 °C. During DSC analysis, three peaks were detected: one endothermic peak at 56 °C and two exothermic peaks at 298 and 336 °C, which were linked to the materials in the fibers. The FTIR showed bands indicating molecular vibrations of functional groups present in the constituents of the NLF, like cellulose, hemicellulose, and lignin. Moreover, the raffia fiber fabric exhibited a CI of 66.04% and an MFA of 7.24° as shown in the XRD pattern. The moisture content of the raffia fabric was measured at 9.47%. The density of the raffia fabric was measured at 0.95 g/cm³. Furthermore, it has been discovered a chemical composition with 25% lignin, 14% hemicellulose, and 52% cellulose. Moreover, SEM images revealed that the raffia fiber fabric displays surface porosity throughout its entirety. Given the results mentioned above, raffia fabric fibers show great promise for use in engineering applications, as their properties are comparable to those of other NLF composites used in polymer reinforcement.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aldosterone excess aggravates endothelial dysfunction in diabetes and hypertension by promoting the increased generation of reactive oxygen species, inflammation, and insulin resistance. Aldosterone ...activates the molecular platform inflammasome in immune system cells and contributes to vascular dysfunction induced by the mineralocorticoid hormone. It is unclear as to whether the NLRP3 inflammasome associated with the mineralocorticoid receptor contributes to vascular dysfunction in diabetic conditions. Here, we tested the hypothesis that an excess of aldosterone induces vascular dysfunction in type 2 diabetes, via the activation of mineralocorticoid receptors (MR) and assembly of the NLRP3 inflammasome. Mesenteric resistance arteries from control (db/m) and diabetic (db/db) mice treated with vehicle, spironolactone (MR antagonist) or an NLRP3 selective inhibitor (MCC950) were used to determine whether NLRP3 contributes to diabetes-associated vascular dysfunction. Db/db mice exhibited increased vascular expression/activation of caspase-1 and IL-1β, increased plasma IL-1β levels, active caspase-1 in peritoneal macrophages, and reduced acetylcholine (ACh) vasodilation, compared to db/m mice. Treatment of db/db mice with spironolactone and MCC950 decreased plasma IL-1β and partly restored ACh vasodilation. Spironolactone also reduced active caspase-1-positive macrophages in db/db mice, events that contribute to diabetes-associated vascular changes. These data clearly indicate that MR and NLRP3 activation contribute to diabetes-associated vascular dysfunction and pro-inflammatory phenotype.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A tese de doutorado “Saberes e fazeres de mulheres camponesas e quilombolas nas agriculturas: produzindo formas de resistências e existências”, desenvolvida por Renata Borges Kempf, foi eleita a ...melhor tese defendida na área de Ciências Ambientais pela décima oitava edição do Prêmio CAPES de Tese - 2023. O trabalho, orientado pela Professora Doutora Carolina dos Anjos de Borba e coorientado pelas Professoras Doutora Josiane Carine Wedig e Doutora Nata Duvvury (Irlanda), foi defendido pela referida pesquisadora no Programa de Pós-graduação em Meio Ambiente e Desenvolvimento, no Setor de Ciências Agrárias da Universidade Federal do Paraná (UFPR), em Curitiba - Paraná, em 18 de novembro de 2022.
Psoriasis is a chronic inflammatory skin disorder driven by the IL-23/type 3 immune response. However, molecular mechanisms sustaining the chronicity of inflammation and psoriatic lesions remain ...elusive. Combining systematic analyses of several transcriptomic datasets, we delineated gene signatures across human psoriatic skin, identifying S100A9 as one of the most up-regulated genes, which was confirmed in lesioned skin from patients with psoriasis and preclinical psoriasiform skin inflammation models. Genetic ablation or pharmacologic inhibition of S100A9 alleviated Aldara-induced skin inflammation. By single-cell mapping of human psoriatic skin and bone marrow chimeric mice experiments, we identified keratinocytes as the major source of S100A9. Mechanistically, S100A9 induced IL-23 production by dendritic cells, driving the IL-23/type 3 immunity in psoriasiform skin inflammation. In addition, the cutaneous IL-23/IL-17 axis induced epidermal S100A9 expression in human and experimental psoriasis. Thus, we showed an autoregulatory circuit between keratinocyte-derived S100A9 and IL-23/type 3 immunity during psoriasiform inflammation, identifying a crucial function of S100A9 in the chronification of psoriasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
In this study, we investigated the modulatory effects of PI3Kγ on IL-17A expression and the progression of experimental periodontitis in vivo.
Methods
Ligature-induced periodontitis was ...developed around the first molar of mice. Animals were treated with anti-mouse IL-17A or IPI-549 (PI3Kγ inhibitor). In addition, PI3Kγ-deficient mice (PI3Kγ
−/−
) were used in the study. Alveolar bone loss was measured and real-time PCR of
Il17a
and
Rankl
genes was performed. A bioinformatics analysis was carried out using the Gene Set Enrichment Analysis computational tool.
Results
Nine days after ligature placement, alveolar bone loss scores were significantly increased, with upregulation of
Il17a
and
Rankl
genes in the gingival tissues. Treatment with anti-mouse IL-17A (100 µg/mice) significantly attenuated alveolar bone loss. Mice with ligature-induced periodontitis treated with IPI-549 (3 mg/kg) or PI3Kγ
−/−
mice showed reduced alveolar bone loss and downregulation of
Il17a and Rankl
gene expression in the gingival tissues. Consistent with this, the bioinformatics analysis showed upregulation of
IL17F
,
IL17A
,
IL17D
, and
STAT3
genes, as well as greater activation of IL-17 and PI3KCI pathways (upregulation of
PIK3CG
gene) in the gingival tissue of patients with periodontitis.
Conclusion
PI3Kγ plays an important role in modulating IL-17A expression and alveolar bone loss in vivo and can be considered a promising pathway for the management of periodontal disease and the development of new therapies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Brazilian sawdust samples (
Caryocar spp.;
Manilkara spp.; and
Tabebuia spp.) have been used for Pb(II) ions adsorption from water at 25
°C. The series of adsorption isotherms were adjusted to a ...modified Langmuir equation from data obtained by suspending the sawdust with Pb(NO
3)
2 solutions, which gave the maximum number of moles adsorbed as 89.10
±
8.28; 145.04
±
12.43 and 95.31
±
8.28
mg
g
−1 for
Caryocar spp.;
Manilkara spp.; and
Tabebuia spp., respectively. Thermodynamic data of interactions were studied by the calorimetric titration of Pb(II) in aqueous solution. Gibbs free energies were negative for all systems and the adsorption interactions presented the following exothermic enthalpic values: −1.99
±
0.11; −3.20
±
0.21 and −2.27
±
0.11
kJ
mol
−1 for
Caryocar spp.;
Manilkara spp.; and
Tabebuia spp., respectively. All liquid/solid interface adsorptions were entalpically and entropically driven. These sawdust samples were applied to remove Pb(II) from wastewater of a battery industry of Brasilia, DF, Brazil, which presented a Pb(II) concentration of 2.66
mg
L
−1. The Pb(II) concentration in this wastewater was reduced to 2.49; 0.45 and 0.47
mg
L
−1 by application of
Caryocar spp.;
Manilkara spp.; and
Tabebuia spp., respectively.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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