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A series of stimuli-responsive fluorescent hydrogels were successfully synthesized via micelle radical copolymerization of hydrophilic acrylamide (AM), hydrophobic chromophore terpyridine-based monomer (TPY), and N-isopropylacrylamide (NIPAM). These hydrogels presented blue emissions (423-440 nm) under room temperature, which is caused by the π-π* transition of the conjugated structures. Once the ambient temperature was increased to 55 °C, the fluorescence color changed from blue (430 nm) to pink (575 nm) within 10 min, subsequently to yellow (535 nm), and eventually back to pink. The thermal-responsive properties are attributed to the transition of the TPY units from unimer to dimer aggregation via the intermolecular charge transfer complex at high temperatures. The hydrogels showed pH-responsive properties. The emission peak of the hydrogel exhibited a blue shift of ~54 nm from neuter conditions to acidic conditions, while a 6 nm red shift to an alkaline environment was observed. The hydrogels demonstrated an obvious change in fluorescence intensity and wavelength upon adding different metal ions, which is caused by the coordination between the terpyridine units incorporated on the backbones and the metal ions. As a consequence, the hydrogels presented a sharp quenching fluorescence interaction with Fe2+, Fe3+, Cu2+, Hg2+, Ni2+, and Co2+, while it exhibited an enhanced fluorescence intensity interaction with Sn2+, Cd2+, and Zn2+. The microstructural, mechanical, and rheological properties of these luminescent hydrogels have been systematically investigated.
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Follicular helper T (TFH) cells are essential for inducing germinal center (GC) reactions to mediate humoral adaptive immunity in tumors; however, the mechanisms underlying TFH-cell differentiation remain unclear. In this study, we found that the metabolism sensor sirtuin 3 (SIRT3) is critical for TFH-cell differentiation and GC formation during tumor development and viral infection. SIRT3 deficiency in CD4+ T cells intrinsically enhanced TFH-cell differentiation and GC reactions during tumor development and viral infection. Mechanistically, damaged oxidative phosphorylation (OXPHOS) compensatively triggered the NAD+-glycolysis pathway to provide a cellular energy supply, which was necessary for SIRT3 deficiency-induced TFH-cell differentiation. Blocking NAD+ synthesis-glycolysis signaling or recovering OXPHOS activities reversed the TFH-cell differentiation induced by SIRT3 deficiency. Moreover, the mTOR and hypoxia-inducible factor 1α (HIF1α) signaling axis was found to be responsible for TFH-cell differentiation induced by SIRT3 deficiency. HIF1α directly interacted with and regulated the activity of the transcription factor Bcl6. Thus, our findings identify a cellular energy compensatory mechanism, regulated by the mitochondrial sensor SIRT3, that triggers NAD+-dependent glycolysis during mitochondrial OXPHOS injuries and an mTOR-HIF1α-Bcl6 pathway to reprogram TFH-cell differentiation. These data have implications for future cancer immunotherapy research targeting SIRT3 in T cells.
Asunto(s)
Diferenciación Celular , Centro Germinal , Fosforilación Oxidativa , Sirtuina 3 , Sirtuina 3/metabolismo , Diferenciación Celular/inmunología , Animales , Ratones , Centro Germinal/inmunología , Centro Germinal/metabolismo , Glucólisis , Células T Auxiliares Foliculares/inmunología , Células T Auxiliares Foliculares/metabolismo , Transducción de Señal , Humanos , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones Noqueados , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/genética , Ratones Endogámicos C57BL , Serina-Treonina Quinasas TOR/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
Although myeloid-derived suppressor cells (MDSCs) are critical for allograft survival, their regulatory mechanism remains unclear. Herein, our results showed that metabolism sensor sirtuin 2 (SIRT2) negatively regulates the functions of MDSCs in inducing allogeneic skin graft rejection. Genetic deletion of SIRT2 in myeloid cells (Sirt2Δmye) increased the number of CD11b+Gr1+ MDSCs in bone marrow, spleens, draining lymph nodes, and allografts, inhibited the production of proinflammatory cytokine tumor necrosis factor É, enhanced the production of anti-inflammatory cytokine interleukin 10, and potentiated the suppressive activation of MDSCs in prolonging allograft skin survival. C-X-C motif chemokine receptor 2 is critical for mediating the recruitment and cytokine production of MDSCs induced by SIRT2. Mechanistically, Sirt2Δmye enhanced NAD+ levels, succinate dehydrogenase subunit A (SDHA) activities, and oxidative phosphorylation (OXPHOS) levels in MDSCs after transplantation. Pharmacologically blocking nicotinamide phosphoribosyltransferase effectively reverses the production of cytokines and suppressive activities of MDSC induced by Sirt2Δmye. Blocking OXPHOS with knockdown of SDHA or pharmacological blocking of SDHA significantly restores Sirt2Δmye-mediated stronger MDSC suppressive activity and inflammatory factor productions. Thus, our findings identify a previously unrecognized interplay between NAD+ and SDH-mediated OXPHOS metabolic pathways in regulating MDSC functions induced by the metabolic sensor SIRT2 in allogeneic transplantation.
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Células Supresoras de Origen Mieloide , Animales , Ratones , Sirtuina 2/metabolismo , Sirtuina 2/farmacología , NAD/metabolismo , NAD/farmacología , Trasplante Homólogo , Citocinas/metabolismo , Aloinjertos , Ratones Endogámicos C57BLRESUMEN
As one of the most important components of the innate immune system, neutrophils are always at the forefront of the response to diseases. The immune functions of neutrophils include phagocytosis, degranulation, production of reactive oxygen species, and the production of neutrophil extracellular traps (NETs). NETs are composed of deconcentrated chromatin DNA, histones, myeloperoxidase (MPO) and neutrophil elastase (NE), playing an important role in the resistance to some pathogenic microbial invasions. Until recent years, when NETs were found to play a critical role in cancer. NETs play bidirectional regulation both positive and negative roles in the development and progression of cancer. Targeted NETs may provide new therapeutic strategies for the treatment of cancer. However, the molecular and cellular regulatory mechanisms underlying the formation and role of NET in cancer remain unclear. This review just summarizes the recent progress in regulatory mechanisms about the formation of NETs and their role in cancers.
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Trampas Extracelulares , Neoplasias , Neutrófilos , HistonasRESUMEN
Follicular regulatory T (Tfr) cells are a novel and unique subset of effector regulatory T (Treg) cells that are located in germinal centers (GCs). Tfr cells express transcription profiles that are characteristic of both follicular helper T (Tfh) cells and Treg cells and negatively regulate GC reactions, including Tfh cell activation and cytokine production, class switch recombination and B cell activation. Evidence also shows that Tfr cells have specific characteristics in different local immune microenvironments. This review focuses on the regulation of Tfr cell differentiation and function in unique local immune microenvironments, including the intestine and tumor.
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Intestinos , Linfocitos T Reguladores , Microambiente Tumoral , Centro Germinal , Intestinos/citología , Intestinos/inmunología , Linfocitos T Colaboradores-InductoresRESUMEN
The polyacrylamide weak gel is an effective system to block a high-permeability layer, realize water control, and enhance oil recovery. However, its application is limited by poor temperature resistance and high polymer dosage. In this paper, an inorganic-organic composite cross-linking agent was synthesized by using Cr(III) and phenolic resin. The composite cross-linking agent can cross-link low concentrations of polyacrylamide to obtain a high-temperature-resistant weak gel system in oilfield sewage. By adjusting the ratio of Cr(III), phenolic resin, and polyacrylamide, an optimum formula MF-7 can be obtained according to the gel strength. Results from evaluation experiments show that the strength of MF-7 can reach H grade even at polyacrylamide concentrations as low as 0.3%. The temperature resistance of the weak gel system is up to 100 °C, and no syneresis occurs after 330 h at 95 °C. Scanning electron microscopy (SEM) results show that MF-7 has a three-dimensional network structure with spherical nodes. The spherical node is composed of polyacrylamide, and its structure size is completely matched with the hydrodynamic radius of the used polyacrylamide. When combined with the network structure formed by Cr(III), the dense cross-linking network structure with nodes can greatly improve the strength and thermal stability of the gel system. The higher the molecular weight of the polyacrylamide used, the higher the strength of the gel obtained. Overall, the composite cross-linking agent can synergistically improve the mechanical properties of the gel, and this weak gel system formed by oilfield sewage is more economical and tolerant.
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In this study, we evaluate the influence of hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethane (DDT) on bacterial communities of sediment core from an estuary formed during the period of 1960-2011. Canonical correspondence analysis showed that o,p'-DDT, o,p'-DDD (mitotane), and depth had important influences on bacterial community distributions (p<0.05). Furthermore, our results found variance explained by all variables was 82.9%, while that by o,p'-DDD was 24.4%, and that of o,p'-DDT was 9.8%, indicating that o,p'-DDD had a greater influence on sediment-dwelling bacteria than o,p'-DDT. Also, bacterial diversity was affected and the Shannon index was significantly negatively correlated with total HCHs (r=-0.579, p<0.05) and total DDTs (r=-0.607, p<0.01), respectively. Furthermore, our results showed that Flavobacteria and Clostridia content can be considered an indicator of pollution of HCHs and DDTs in sediment core samples.