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Lamin A/C is involved in macrophage activation and premature aging, also known as progeria. As the resident macrophage in brain, overactivation of microglia causes brain inflammation, promoting aging and brain disease. In this study, we investigated the role of Lamin A/C in microglial activation and its impact on progeria using Lmna-/- mice, primary microglia, Lmna knockout (Lmna-KO) and Lmna-knockdown (Lmna-KD) BV2 cell lines. We found that the microglial activation signatures, including cell proliferation, morphology changes, and proinflammatory cytokine secretion (IL-1ß, IL-6, and TNF-α), were significantly suppressed in all Lamin A/C-deficient models when stimulated with LPS. TMT-based quantitative proteomic and bioinformatic analysis were further applied to explore the mechanism of Lamin A/C-regulated microglia activation from the proteome level. The results revealed that immune response and phagocytosis were impaired in Lmna-/- microglia. Stat1 was identified as the hub protein in the mechanism by which Lamin A/C regulates microglial activation. Additionally, DNA replication, chromatin organization, and mRNA processing were also altered by Lamin A/C, with Ki67 fulfilling the main hub function. Lamin A/C is a mechanosensitive protein and, the immune- and proliferation-related biological processes are also regulated by mechanotransduction. We speculate that Lamin A/C-mediated mechanotransduction is required for microglial activation. Our study proposes a novel mechanism for microglial activation mediated by Lamin A/C.
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Lamina Tipo A , Progeria , Animales , Ratones , Proliferación Celular , Activación de Macrófagos , Mecanotransducción Celular , Microglía , Fagocitosis , ProteómicaRESUMEN
Systemic sclerosis (SSc) poses a significant challenge in autoimmunology, characterized by the development of debilitating fibrosis of skin and internal organs. The pivotal role of dysregulated T cells, notably the skewed polarization toward Th2 cells, has been implicated in the vascular damage and progressive fibrosis observed in SSc. In this study, we explored the underlying mechanisms by which cannabinoid receptor 2 (CB2) highly selective agonist HU-308 restores the imbalance of T cells to alleviate SSc. Using a bleomycin-induced SSc (BLM-SSc) mouse model, we demonstrated that HU-308 effectively attenuates skin and lung fibrosis by specifically activating CB2 on CD4+ T cells to inhibit the polarization of Th2 cells in BLM-SSc mice, which was validated by Cnr2-specific-deficient mice. Different from classical signaling downstream of G protein-coupled receptors (GPCRs), HU-308 facilitates the expression of SOCS3 protein and subsequently impedes the IL2/STAT5 signaling pathway during Th2 differentiation. The deficiency of SOCS3 partially mitigated the impact of HU-308. Analysis of a cohort comprising 80 SSc patients and 82 healthy controls revealed an abnormal elevation in the Th2/Th1 ratio in SSc patients. The proportion of Th2 cells showed a significant positive correlation with mRSS score and positivity of anti-Scl-70. Administration of HU-308 to PBMCs and peripheral CD4+ T cells from SSc patients led to the upregulation of SOCS3, which effectively suppressed the aberrantly activated STAT5 signaling pathway and the proportion of CD4+IL4+ T cells. In conclusion, our findings unveil a novel mechanism by which the CB2 agonist HU-308 ameliorates fibrosis in SSc by targeting and reducing Th2 responses. These insights provide a foundation for future therapeutic approaches in SSc by modulating Th2 responses.
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Diferenciación Celular , Modelos Animales de Enfermedad , Receptor Cannabinoide CB2 , Esclerodermia Sistémica , Transducción de Señal , Proteína 3 Supresora de la Señalización de Citocinas , Células Th2 , Animales , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/patología , Células Th2/inmunología , Ratones , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/metabolismo , Diferenciación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Humanos , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Femenino , Quinasas Janus/metabolismo , Masculino , Ratones Noqueados , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Bleomicina , Agonistas de Receptores de Cannabinoides/farmacología , Agonistas de Receptores de Cannabinoides/uso terapéutico , Persona de Mediana EdadRESUMEN
BACKGROUND: Gastric mucosal injury caused by ethanol is a common gastrointestinal disease. Quinoa (Chenopodium quinoa Willd.), as a nutrient-rich grain, plays a significant role in preventing and treating gastric mucosal damage. The present study aimed to explore the protective effect of quinoa on alcohol-induced gastric mucosal damage and its possible mechanism. RESULTS: The ethanol-induced gastric mucosal injury rat model was used for in vivo experiments and H2 O2 -induced GES-1 cells for in vitro experiments to elucidate the protective effect of quinoa. The results show that quinoa water extract can increase the superoxide dismutase level and decrease the malondialdehyde level in vitro and in vivo. Furthermore, quinoa also reduced the bleeding point and bleeding area in rats with ethanol-induced gastric mucosal injury and improved gastric histopathological changes. H2 O2 significantly increased the levels of inflammatory factors in GES-1 cells, which were markedly ameliorated by quinoa water extract. Likewise, quinoa water extract regulated the protein expression levels of Nrf2, Keap1, HO-1, p-IKK, and p-NF-κB through Nrf2 and nuclear factor-κB signaling pathways, reducing the production of oxidative stress and inflammation, thereby repairing the damaged gastric mucosa. CONCLUSION: The findings of this study demonstrated that quinoa shows protective effect against ethanol-induced gastric mucosal injury through its anti-inflammatory and anti-oxidant effects. We propose that our research will provide a reference for quinoa as a functional food. © 2022 Society of Chemical Industry.
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Chenopodium quinoa , Úlcera Gástrica , Ratas , Animales , Chenopodium quinoa/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Mucosa Gástrica/metabolismo , Etanol/metabolismo , Estrés Oxidativo , FN-kappa B/metabolismo , Agua/metabolismo , Úlcera Gástrica/inducido químicamenteRESUMEN
BACKGROUND & AIMS: The metabolic features and function of intratumoral regulatory T cells (Tregs) are ambiguous in colorectal cancer. Tumor-infiltrating Tregs are reprogrammed to exhibit high glucose-depleting properties and adapt to the glucose-restricted microenvironment. The glucose-responsive transcription factor MondoA is highly expressed in Tregs. However, the role of MondoA in colorectal cancer-infiltrating Tregs in response to glucose limitation remains to be elucidated. METHODS: We performed studies using mice, in which MondoA was conditionally deleted in Tregs, and human colorectal cancer tissues. Seahorse and other metabolic assays were used to assess Treg metabolism. To study the role of Tregs in antitumor immunity, we used a subcutaneous MC38 colorectal cancer model and induced colitis-associated colorectal cancer in mice by azoxymethane and dextran sodium sulfate. RESULTS: Our analysis of single-cell RNA sequencing data of patients with colorectal cancer revealed that intratumoral Tregs featured low activity of the MondoA-thioredoxin-interacting protein (TXNIP) axis and increased glucose uptake. Although MondoA-deficient Tregs were less immune suppressive and selectively promoted T-helper (Th) cell type 1 (Th1) responses in a subcutaneous MC38 tumor model, Treg-specific MondoA knockout mice were more susceptible to azoxymethane-DSS-induced colorectal cancer. Mechanistically, suppression of the MondoA-TXNIP axis promoted glucose uptake and glycolysis, induced hyperglycolytic Th17-like Tregs, which facilitated Th17 inflammation, promoted interleukin 17A-induced of CD8+ T-cell exhaustion, and drove colorectal carcinogenesis. Blockade of interleukin 17A reduced tumor progression and minimized the susceptibility of MondoA-deficient mice to colorectal carcinogenesis. CONCLUSIONS: The MondoA-TXNIP axis is a critical metabolic regulator of Treg identity and function in the colorectal cancer microenvironment and a promising target for cancer therapy.
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Proteínas Portadoras/metabolismo , Neoplasias Asociadas a Colitis/metabolismo , Neoplasias Colorrectales/metabolismo , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos T Reguladores/metabolismo , Tiorredoxinas/metabolismo , Microambiente Tumoral , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Proteínas Portadoras/genética , Línea Celular Tumoral , Neoplasias Asociadas a Colitis/genética , Neoplasias Asociadas a Colitis/inmunología , Neoplasias Asociadas a Colitis/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , Glucólisis , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Células Th17/metabolismo , Tiorredoxinas/genéticaRESUMEN
Regulatory T (Treg) cells and T helper type 17 (Th17) cells play important roles in adaptive immune responses, antagonizing each other in immune disorders. Th17/Treg balance is critical to maintaining the immune homeostasis of human bodies and is tightly regulated under healthy conditions. The transcription factors that are required for driving Th17 and Treg cell lineages differentiation respectively, RORγt and FOXP3 are tightly regulated under different tissue microenvironment, especially the transcriptional induction, posttranslational modifications, and dynamic enzymatic cofactors binding. The imbalance caused by alteration of the quantity or properties of RORγt+ Th17 or FOXP3+ Treg can contribute to inflammatory disorders in humans. Restoring Th17/Treg balance by modifying the enzymatic activities of RORγt and FOXP3 binding partners may be therapeutically applied to treat severe immune disorders. In this review, we focus on the transcriptional and posttranslational regulations of Th17/Treg balance, immune disorders caused by Th17/Treg imbalance, and new therapeutic strategies for restoring immune homeostasis.
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Factores de Transcripción Forkhead/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Inmunidad Adaptativa/genética , Inmunidad Adaptativa/inmunología , Factores de Transcripción Forkhead/genética , Humanos , Inflamación/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Procesamiento Proteico-Postraduccional/genética , Linfocitos T Reguladores/citología , Células Th17/citología , Transcripción Genética/genéticaRESUMEN
IL-10 is critical for Foxp3+ regulatory T cell (Tregs)-mediated immune suppression, but how to efficiently upregulate IL-10 production in Tregs remains unclear. In this article, we show that human IL-10+ FOXP3+-induced regulatory T cell (iTreg) generation can be dramatically promoted by inhibiting GSK3 activity. IL-10+ FOXP3+ iTregs induced by GSK3 inhibition exhibit classical features of immune-suppressive T cells. We further demonstrate that IL-10+ iTregs exhibit enhanced suppressive function in both IL-10-dependent and -independent manners. The enhanced suppressive function of IL-10+ Tregs is not due to a single factor such as IL-10, although IL-10 may mediate this enhanced suppressive function to some extent. Mechanistically, the increased transcriptional activity of IL-10 promoter and the enhanced expression of C-Maf and BLIMP1 coordinately facilitate IL-10 expression in human iTregs under GSK3 inhibition. Our study provides a new strategy to generate human immune-suppressive IL-10+ FOXP3+ Tregs for immunotherapies.
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Glucógeno Sintasa Quinasa 3/metabolismo , Interleucina-10/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Células Cultivadas , Factores de Transcripción Forkhead/metabolismo , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/genética , Xenoinjertos , Humanos , Tolerancia Inmunológica , Indoles/farmacología , Interleucina-10/genética , Activación de Linfocitos , Maleimidas/farmacología , Ratones , Ratones Noqueados , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-maf/genética , Activación TranscripcionalRESUMEN
Enzyme-like metal-organic frameworks (MOFs) are currently one type of starring material in the fields of artificial enzymes and analytical sensing. However, there has been little progress in making use of the MOF structures based on the catalytically active metal center with multiple valences. Herein, we report a mixed-valence Ce-MOF (Ce-BPyDC) that can exhibit both oxidase-like and peroxidase-like activities. Ce-BPyDC was synthesized by a facile hydrothermal method, which preserves the rare coexistence of Ce(III) and Ce(IV) in the MOF structure. The enzymatic studies demonstrated the enzyme-like activities of Ce-BPyDC follow the Michaelis-Menten kinetics and are strongly dependent on temperature, pH, and reaction time. Ce-BPyDC was also revealed to exert high catalytic activity that could transcend horseradish peroxidase and other MOF nanozymes, due to the redox-active Ce(III)/Ce(IV) cycles inside. Furthermore, the simple synthesis, high nanozyme activity, and great stability of Ce-BPyDC motivated us to establish a colorimetric biosensing platform using 3,3',5,5'-tetramethylbenzidine as a color reagent. Adopting this strategy, we established a visual, sensitive, and selective colorimetric method for ascorbic acid (AA) detection, for which the linear interval and limit of detection were 1-20 and 0.28 µM, respectively. The successful AA detection in real juice samples implies the promising use of such mixed-valence MOF nanozymes in food and biomedical samples.
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Técnicas Biosensibles , Cerio/química , Colorimetría , Estructuras Metalorgánicas/química , Ácido Ascórbico/análisis , Catálisis , Concentración de Iones de Hidrógeno , Estructuras Metalorgánicas/síntesis química , TemperaturaRESUMEN
The authors describe a fluorometric method for the quantification of tannic acid (TA). MoO3-x quantum dots (QDs) can selectively capture TA via the formation of an organic molybdate complex. This causes an electron transfer effect and an inner filter effect to result in synergistic quenching of the fluorescence of the QDs. TA can be detected via this effect with a linear response in the of 0.1-10 µM concentration range and a lower detection limit of 30 nM within 1 min. The use of such QDs as a quenchable fluorescent probe warrants good selectivity even in the presence of relatively high concentration of potentially interferents and makes the method suitable for real sample analysis. Graphical abstract Tannic acid can be rapidly and selectively detected in food using a MoO3-x quantum dots based fluorometric assay.
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BACKGROUND: Fragarianilgerrensis Schlecht. medicine compound (FN-MC) is a kind of Chinese herbs' compound consisted of Fragarianilgerrensis Schlecht. and Centella asiatica (L.) Urban. The study was to investigate the hypolipidemia effect of FN-MC in a hypolipidemic rat model. METHODS: Male SD rats were randomly divided into five groups: normal-fat diet (NFD) group, high-fat diet (HFD) group, FN-MC (2 g/Kg) group, FN-MC (4 g/Kg) group and simvastatin (PDC) group. After FN-MC treatment, body weight, food intake, serum and hepatic biochemistry parameters of rats were measured and the pathological changes of liver and its cells were observed by optical microscope and transmission electron microscopy. RESULTS: The results showed that FN-MC significantly decreased the levels of serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C), apolipoprotein B (ApoB) and hepatic malondialdehyde (MDA), while increased serum high-density lipoprotein (HDL-C), apolipoprotein A1 (ApoA1) and hepatic Superoxide Dismutase (SOD). FN-MC also improved the structure of liver and decreased the lipid drops in the cytoplasm significantly. In addition, FN-MC significantly decreased the weight gain and had no significant effects on food intake. CONCLUSIONS: The study suggested that FN-MC exhibited strong ability to improve the dyslipidemia and prevent hepatic fatty deposition in rats fed with high-fat diet. Meanwhile, FN-MC exerted anti-obesity and antioxidant properties. HIGHLIGHTS: Fragarianilgerrensis Schlecht. medicine compound possesses a hypolipidemic effect on hyperlipidemic rat model Fragarianilgerrensis Schlecht. medicine compound administration improves the antioxidant capacity of rats Fragarianilgerrensis Schlecht. medicine compound prevents hepatic fatty deposition.
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Centella/química , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/administración & dosificación , Triterpenos/administración & dosificación , Animales , Antioxidantes/administración & dosificación , Antioxidantes/química , HDL-Colesterol/sangre , Modelos Animales de Enfermedad , Humanos , Hiperlipidemias/metabolismo , Hiperlipidemias/patología , Hipolipemiantes/química , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Hígado/metabolismo , Extractos Vegetales , Ratas , Simvastatina/administración & dosificación , Triglicéridos/sangreRESUMEN
A method is described for the rapid fluorometric determination of dopamine (DA) by using molybdenum disulfide quantum dots (MoS2 QDs) that were fabricated via an ammonium hydroxide etching method. The probe has a fluorescence (with excitation/emission peaks at 267/380 nm) that is quenched by DA with high selectivity over various interferences. This is attributed to a reaction that occurs between DA and the molybdate ions in pH 9 solutions of MoS2 QDs. The formation of organic molybdate complexes and of dopamine-quinone results in strong quenching of the fluorescence of the QDs which is due to both electron transfer and an inner filter effect. Under the optimum conditions, the assay works in the 0.1-100 µM DA concentration range, with two linear ranges and a 10 nM detection limit. The method was applied to the determination of DA in spiked artificial urine samples, where it gave recoveries ranging from 97.6 to 102.2%, demonstrating that the method a promising tool for rapid and selective detection of DA. Graphical abstract MoS2 QDs are facilely synthesized via the etching effect of ammonium hydroxide for highly selective fluorometric detection of dopamine.
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Objective: Rosa odorata var. gigantea is a popular medicinal plant. Some studies have demonstrated that ethanolic extract of the fruits of R. odorata var. gigantea (FOE) has gastroprotective properties. The aim of this study was to investigate the gastroprotective activity of FOE on water immersion restrained stress (WIRS)-induced gastric mucosal injury in a rat model and elucidate the possible molecular mechanisms involved. Methods: A rat stress ulcer model was established in this study using WIRS. After rats were treated with FOE orally for 7 d, the effect of FOE treatment was analyzed by hematoxylin and eosin (H&E) staining, and the changes of inflammatory factors, oxidative stress factors, and gastric-specific regulatory factors and pepsin in the blood and gastric tissues of rats were examined by ELISA assay. Molecular mechanism of FOE was investigated by immunohistochemical assay and Western blot. Results: Compared with the WIRS group, FOE could diminish both the macroscopic and microscopic pathological morphology of gastric mucosa. FOE significantly preserved the antioxidants glutathione peroxidase (GSH-PX), superoxide dismutase (SOD) and catalase (CAT) contents; anti-inflammatory cytokines interleukin-10 (IL-10) and prostaglandin E2 (PGE2) levels as well as regulatory factors tumor necrosis factor-α (TGF-α) and somatostatin (SS) contents, while decreasing malondialdehyde (MDA), nitric oxide synthase (iNOS), tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), gastrin (GAS) and endothelin (ET) levels. Moreover, FOE distinctly upregulated the expression of Nrf2, HO-1, Bcl2 and proliferating cell nuclear antigen (PCNA). In addition, FOE activated the expression of p-EGFR and downregulated the expression of NF-κB, Bax, Cleaved-caspase-3, Cyto-C and Cleaved-PARP1, thus promoting gastric mucosal cell survival. Conclusion: The current work demonstrated that FOE exerted a gastroprotective activity against gastric mucosal injury induced by WIRS. The underlying mechanism might be associated with the improvement of anti-inflammatory, anti-oxidation and anti-apoptosis systems.
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Currently, the low cost and effective purification toward heavy metal ions in wastewater has garnered global attention. Herein, we used hydrothermal method to prepare highly dispersed calcium silicate hydrate in fluorite tailings. And the stacking thickness of calcium silicate hydrate layered morphology was less than 5 nm. For high concentration Cu2+ purification investigation in wastewater, we found that the equilibrium adsorption capacity reached 797.92 mg/g via the CSH with 3:2 Ca/Si molar ratio, be 1.43-21.8 times than that of reported data. Therein, the metal-metal exchange and deposition are the primary pathways for Cu2+ adsorption, and electrostatic attraction is the secondary pathway. And the relative â¼100 % removal rate of high-concentration Ni2+ and Cr3+ ions were confirmed via CSH prepared from different tailings. This method offers a cost-effective way to utilize tailings for preparing highly efficient adsorbents toward HMIs removal in wastewater.
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In this work, the metabolomics, physicochemical and in vitro digestion properties of black beans influenced by different calcium ion solutions (0, 0.5 %, 1 %, and 2 %) were explored. The addition of calcium ions had a significant effect on the metabolic processing of black beans, including 16 differential metabolites and 4 metabolic pathways related to the cell wall. From the results of FT-IR and ICP-OES, it was confirmed that calcium ions can interact with COO- in non-methylated galacturonic acid in pectin to form calcium carboxylate strengthening the middle lamellae of the cell wall. Based on this mechanism, the soaked beans with an intact and dense cell structure were verified by the analyses of SEM and CLSM. Compared with other soaked beans, BB-2 exhibited lower cell permeability with electrical conductivity value decreased to 0.60 µs·cm-1. Additionally, BB-2 demonstrated slower digestion properties with digestion rate coefficient at 0.0020 min-1 and digestion extent only at 30.83 %, which is attributed to its increasingly compact cell wall and densely cellular matrix. This study illustrates the effect of calcium ions on the cellular structure of black beans, providing an effective process method for low glycemic index diets.
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Calcio , Pared Celular , Metabolómica , Pectinas , Pectinas/farmacología , Pectinas/química , Pectinas/metabolismo , Pared Celular/metabolismo , Pared Celular/química , Calcio/metabolismo , Digestión/efectos de los fármacos , Iones , Phaseolus/química , Fabaceae/química , Fenómenos Químicos , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
BACKGROUND: Ischemic stroke is a common neurovascular disorder with high morbidity and mortality. However, the underlying mechanism of stereotactically intracerebral transplantation of human neural stem cell (hNSC) is not well elucidated. MATERIALS AND METHODS: Four days after ischemic stroke induced by Rose Bengal photo-thrombosis, 7 cynomolgus monkeys were transplanted with hNSCs or vehicles stereotactically and followed up for 84 days. Behavioral assessments, magnetic resonance imaging, blood tests, and pathological analysis were performed before and after treatment. The proteome profiles of the left and right precentral gyrus and hippocampus were evaluated. Extracellular vesicle micro-RNA (miRNA) from the peripheral blood was extracted and analyzed. RESULTS: hNSC transplantation reduced the remaining infarcted lesion volume of cynomolgus monkeys with ischemic stroke without remarkable side effects. Proteomic analyses indicated that hNSC transplantation promoted GABAergic and glutamatergic neurogenesis, and restored the mitochondrial electron transport chain function in the ischemic infarcted left precentral gyrus or hippocampus. Immunohistochemical staining and qRT-PCT confirmed the promoting effects on neurogenesis and revealed that hNSCs attenuated post-infarct inflammatory responses by suppressing resident glia activation and mediating peripheral immune cell infiltration. Consistently, miRNA-sequencing revealed the miRNAs which were related to these pathways were down-regulated after hNSC transplantation. CONCLUSIONS: This study indicates that hNSCs can be effectively and safely used to treat ischemic stroke by promoting neurogenesis, regulating post-infarct inflammatory responses, and restoring mitochondrial function in both the infarct region and hippocampus.
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Aryl hydrocarbon receptor (AhR) is a key transcription factor that modulates the differentiation of T helper 17 (Th17) cells. How AhR is regulated at the post-translational level in Th17 cells remains largely unclear. Here we identify USP21 as a newly defined deubiquitinase of AhR. We demonstrate that USP21 interacts with and stabilizes AhR by removing the K48-linked polyubiquitin chains from AhR. Interestingly, USP21 inhibits the transcriptional activity of AhR in a deubiquitinating-dependent manner. USP21 deubiquitinates AhR at the K432 residue, and the maintenance of ubiquitination on this site is required for the intact transcriptional activity of AhR. Moreover, the deficiency of USP21 promotes the differentiation of Th17 cells both in vitro and in vivo. Consistently, adoptive transfer of USP21 deficient naïve CD4+ T cells elicits more severe colitis in Rag1-/- recipients. Therefore, our study reveals a novel mechanism in which USP21 deubiquitinates AhR and negatively regulates the differentiation of Th17 cells.
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Targeting tumor-infiltrating regulatory T cells (Tregs) is an efficient way to evoke an anti-tumor immune response. However, how Tregs maintain their fragility and stability remains largely unknown. IFITM3 and STAT1 are interferon-induced genes that play a positive role in the progression of tumors. Here, we showed that IFITM3-deficient Tregs blunted tumor growth by strengthening the tumor-killing response and displayed the Th1-like Treg phenotype with higher secretion of IFNγ. Mechanistically, depletion of IFITM3 enhances the translation and phosphorylation of STAT1. On the contrary, the decreased IFITM3 expression in STAT1-deficient Tregs indicates that STAT1 conversely regulates the expression of IFITM3 to form a feedback loop. Blocking the inflammatory cytokine IFNγ or directly depleting STAT1-IFITM3 axis phenocopies the restored suppressive function of tumor-infiltrating Tregs in the tumor model. Overall, our study demonstrates that the perturbation of tumor-infiltrating Tregs through the IFNγ-IFITM3-STAT1 feedback loop is essential for anti-tumor immunity and constitutes a targetable vulnerability of cancer immunotherapy.
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Neoplasias , Linfocitos T Reguladores , Humanos , Retroalimentación , Neoplasias/genética , Neoplasias/terapia , Citocinas/metabolismo , Factores de Transcripción Forkhead/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Unión al ARN/metabolismo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismoRESUMEN
To promote a circular economy, the use of agricultural by-products as food packaging material has steadily increased. However, designing food packaging films that meet consumers' preferences and requirements is still a challenge. In this work, cellulose extracted from coffee silverskin (a by-product of coffee roasting) and chitosan were combined with different natural pigments (curcumin, phycocyanin, and lycopene) to generate a variety of composite films with different colors for food packaging. The physicochemical and sensory properties of the films were evaluated. The cellulose/chitosan film showed favorable mechanical properties and water sensitivity. Addition of natural pigments resulted in different film colors, and significantly affected the optical properties and improved the UV-barrier, swelling degree, and water vapor permeability (WVP), but there were also slight decreases in the mechanical properties. The various colored films can influence the perceived features and evoke different emotions from consumers, resulting in films receiving different attraction and liking scores. This work provides a comprehensive evaluation strategy for coffee silverskin cellulose-based composite films with incorporated pigments, and a new perspective on the consideration of the hedonic ratings of consumers regarding bio-based films when designing food packaging.
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To utilize natural hydrophobic/hydrophilic colorants to manufacture good quality and attractive packaging films, we investigated the effects of natural colorants (curcumin, phycocyanin, modified lycopene, and their mixed colorants) on the physicochemical and sensory properties of whey protein isolate-cellulose nanocrystal packaging film. Owing to the improvement in hydrophobicity and spatial density, moisture content (MC) and water vapor permeability (WVP) of films containing curcumin were reduced by 16.91% and 8.49%, respectively, in contrast to that, MC and WVP increased by 10.75% and 4.09%, respectively, in film containing modified lycopene. Mechanical testing, infrared spectra, and X-ray diffraction revealed the retention of structural properties of protein matrix. Rate-All-That-Apply evaluation indicated that films containing colorants enriched tactile and visual sensory characteristics. The eye tracking testing of packed foods showed that preferential attraction depends on the color of the food itself. Thus, a consumer-oriented multi-colored packaging film with good performance was achieved.
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Curcumina , Nanopartículas , Celulosa/química , Proteína de Suero de Leche/química , Curcumina/química , Ficocianina , Licopeno , Embalaje de AlimentosRESUMEN
BACKGROUND: Mindfulness training has been shown to improve emotional symptoms such as anxiety and depressive symptoms. However, its cognitive-behavioral mechanism is still unclear. The present study aimed to investigate the effect of mindfulness training on attention to emotional faces and its role in the improvement in emotional symptoms. METHODS: Eighty participants were recruited and randomly divided into a training group (n = 40) that received eight weeks of mindfulness training and a control group (n = 40) that attended a mindfulness lecture. Before training (T1), immediately after training (T2), and three months after training (T3), all participants were asked to complete the Self-Rating Depression Scale (SDS) and the Self-Rating Anxiety Scale (SAS) to assess their emotional symptoms and a modified dot-probe task to measure their attention to emotional faces. RESULTS: Mindfulness training significantly reduced anxiety and depressive symptoms at both T2 and T3. After training, the attentional bias toward happy faces increased, while the attentional bias toward sad faces decreased in the training group compared with the control group. Mediation analysis showed that the improvement in attentional bias toward sad faces partially mediated the effect of mindfulness training on depression at T2. LIMITATIONS: Our participants were not a clinical sample (i.e., were not diagnosed with emotional disorders), and the time course of attention components was difficult to examine in the present study. CONCLUSIONS: Mindfulness training can stably reduce anxious and depressive symptoms. However, it may have a temporary effect on attentional bias toward facial emotions, which plays a limited role in improving emotional symptoms.
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Cerebral venous abnormalities, distinct from traditional arterial diseases, have been linked to brain atrophy in a previous community-based cohort study, specifically in relation to the reduction of deep medullary veins (r-DMVs). To better understand the properties and biological functions of serum extracellular vesicles (EVs) in cerebral venous disease-associated brain atrophy, EVs are extracted from the serum of both participants with r-DMV and normal controls and analyzed their proteomic profiles using Tandem Mass Tag label quantitation analysis. Phenotypic experiments showed that EVs from individuals with r-DMVs are able to disrupt the normal functions of neurons, endothelial cells, and smooth muscle cells, and induce A1 reactive astrocytes. Additionally, this study provided a comprehensive characterization of the proteomic profile of DMV EVs and found that the collagen hydroxyproline is upregulated, while complement C3 is downregulated in the r-DMV group, suggesting that r-DMV may not be a simple pathological phenomenon and highlighting the potential involvement of EVs in the progression of brain atrophy in r-DMVs which has implications for the development of future therapeutic strategies.