FOXP3+ regulatory T cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity.

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.

Lamin A/C mediates microglial activation by modulating cell proliferation and immune response.

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.

Mindfulness training modifies attentional bias to facial emotion and emotional symptoms.

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.

Coffee Silverskin Cellulose-Based Composite Film with Natural Pigments for Food Packaging: Physicochemical and Sensory Abilities.

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.

Extracellular Vesicles Play a Central Role in Cerebral Venous Disease-Associated Brain Atrophy.

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.

Effects of curcumin, phycocyanin, or modified lycopene colorants on the physicochemical and sensory properties of whey protein-cellulose nanocrystal packaging films.

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.

The protective effect of quinoa on the gastric mucosal injury induced by absolute ethanol.

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.

Physicochemical and Sensory Properties Colored Whey Protein-Cellulose Nanocrystal Edible Films after Freeze-Thaw Treatment.

Balancing physicochemical properties and sensory properties is one of the key points in expanding edible packaging applications. The work consisted of two parts, one was to investigate the effects of cellulose nanocrystals (CNC) on the packaging-related properties of whey protein isolate films with natural colorants (curcumin, phycocyanin, and lycopene) under freeze-thaw (FT) conditions; the other was to test oral tactility and visual sensory properties of the edible films and their overall acceptability in packed ice cream. FT treatment reduced the mechanical strength and moisture content and increased the water vapor permeability of the films, as water-phase transformation not only disrupted hydrogen bonds but also the film network structure through physical stress. The oral tactility produced by CNC and the visual effect produced by colorants could affect participants' preference for edible films. This study provides a good reference for the consumer-driven product development of packaged low-temperature products.

Chemical constituents and pharmacological activities of medicinal plants from Rosa genus.

The genus Rosa (Rosaceae family) includes about 200 species spread in the world, and this genus shows unique advantages in medicine and food. To date, several scholars concentrated on compounds belonging to flavonoids, triterpenes, tannins, polysaccharide, phenolic acids, fatty acids, organic acids, carotenoids, and vitamins. Pharmacological effects such as antineoplastic and anti-cancer properties, anti-inflammatory, antioxidant, liver protection, regulate blood sugar, antimicrobial activity, antiviral activity, as well as nervous system protection and cardiovascular protection were wildly reported. This article reviews the chemical constituents, pharmacological effects, applications and safety evaluations of Rosa plants, which provides a reference for the comprehensive utilization of medicine and food resources and gives a scientific basis for the development of medicinal plants of the genus Rosa.

Regulatory effect of traditional Chinese medicines on signaling pathways of process from chronic atrophic gastritis to gastric cancer.

Chronic atrophic gastritis (CAG), a common disease of digestive system, is an extremely important cause of gastric cancer (GC). The occurrence and development of CAG involves the abnormality of multiple signaling pathways. Traditional Chinese medicines (TCMs) has the advantages of mild action, multi-target and small adverse reaction, etc., which broadens the way for the treatment of the disease, and TCMs can play a therapeutic role by regulating multiple signaling pathways. In this review, based on the related experiments of TCMs and Chinese herbal compounds in recent years, the related literatures were searched and 10 kinds of signaling pathways involved were summarized, in order to provide a reference for further research on reversing or delaying the progress of CAG and preventing gastric cancer.

Neobavaisoflavone inhibits allergic inflammatory responses by suppressing mast cell activation.

Neobavaisoflavone (NBIF), a monomolecular compound extracted from Psoralea corylifolia (Leguminosae), is commonly used in traditional Chinese medicine for multiple purposes. NBIF is known to exert anti-fungal and anti-tumor effects, and promote bone formation. Whether NBIF exhibits anti-allergic effects by regulating mast cell activation remains unclear. Therefore, we designed this study to investigate the anti-allergic effects of NBIF on IgE/Ag-induced mouse bone marrow-derived mast cells and ovalbumin-induced asthma, and the passive systemic anaphylaxis (PSA) reaction in mice. Our results showed that NBIF suppresses the production of leukotriene C4, prostaglandin D2 and inflammatory cytokines, and decreases the degranulation of BMMCs stimulated by IgE/Ag. A thorough investigation ascertained that NBIF suppresses the phosphorylation of mitogen-activated protein kinases, and represses the nuclear factor-κB-related signaling pathway. In addition, the oral administration of NBIF in mice inhibited the IgE-induced PSA reaction in a dose-dependent manner. Overall, we provide new insights into how NBIF regulates the IgE/Ag-mediated signaling pathways. Moreover, our investigation promotes the potential use of NBIF in treating allergy and asthma.

Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics.

Regulatory T (Treg) cells are critical for maintaining immune homeostasis and preventing autoimmunity. Here, we show that the non-oxidative pentose phosphate pathway (PPP) regulates Treg function to prevent autoimmunity. Deletion of transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in Treg cells causes a fatal autoimmune disease in mice, with impaired Treg suppressive capability despite regular Treg numbers and normal Foxp3 expression levels. Mechanistically, reduced glycolysis and enhanced oxidative stress induced by TKT deficiency triggers excessive fatty acid and amino acid catabolism, resulting in uncontrolled oxidative phosphorylation and impaired mitochondrial fitness. Reduced α-KG levels as a result of reductive TCA cycle activity leads to DNA hypermethylation, thereby limiting functional gene expression and suppressive activity of TKT-deficient Treg cells. We also find that TKT levels are frequently downregulated in Treg cells of people with autoimmune disorders. Our study identifies the non-oxidative PPP as an integrator of metabolic and epigenetic processes that control Treg function.

An Automated Room Temperature Flip-Chip Mounting Process for Hybrid Printed Electronics.

Printing technology and mounting technology enable the novel field of hybrid printed electronics. To establish a hybrid printed system, one challenge is that the applied mounting process meets the requirements of functional inks and substrates. One of the most common requirements is low process temperature. Many functional inks and substrates cannot withstand the high temperatures required by traditional mounting processes. In this work, a standardized interconnection and an automated bump-less flip-chip mounting process using a room temperature curing conductive adhesive are realised. With the proposed process, the conductive adhesive selected for the standardized interconnection can be dispensed uniformly, despite its increase of viscosity already during pot time. Electrical and mechanical performance of the interconnection are characterized by four terminal resistance measurement and shear test. The herein proposed automated process allows for fabrication of hybrid printed devices in larger batch sizes than manual assembly processes used beforehand and thus, more comprehensive evaluation of device parameters. This is successfully demonstrated in a first application, a novel hybrid printed security device. The room temperature mounting process eliminates any potentially damaging thermal influence on the performance of the printed circuits that might result from other assembly techniques like soldering.

Comparison of Self-Report Questionnaire and Eye Tracking Method in the Visual Preference Study of a Youth-Beverage Model.

This study compares the characteristics of a self-report questionnaire (SRQ) and eye tracking (ET) based on a simple human-beverage visual cognition model. The young participants were mainly defined by their gender and body mass index (BMI). The beverage samples consisted of milk, coffee, cup, and coaster. SRQs allow the participants to clearly express their overall cognition of the samples in the form of vocabulary, while ET captures their hidden thinking process. The analysis, using a random forest (RF) classifier, found that participant parameters (gender and BMI) played a more important role for SRQ, while ET was related to beverage parameters (color and shape). This work reiterates that these two methods have their advantages and complement each other in food sensory analysis.

Stability and surface properties of selenium nanoparticles coated with chitosan and sodium carboxymethyl cellulose.

The effect of polysaccharide coatings on the stability and release characteristics of selenium nanoparticles (SeNPs) was evaluated by comparing the characteristics of chitosan-coated SeNPs (CS-SeNPs) and sodium carboxymethyl cellulose-coated SeNPs (CMC-SeNPs). The release characteristics of SeNPs were investigated in storage conditions, gastrointestinal conditions, and free radical systems. CMC-SeNPs formed dimers or trimers, whereas CS-SeNPs were monodispersed but formed large aggregates in a pH range of 7.4-8.25. Upon 50 days of storage at 30 °C, both CMC-SeNPs and CS-SeNPs were converted to Se4+. SeNPs exhibited a lower release rate in simulated gastrointestinal conditions than in free radical systems. SeNPs release in ABTS and superoxide anion free radical systems followed the first-order and Korsmeyer-Peppas models, respectively, indicating that SeNP release is mainly governed by dissolution mechanisms. Additional studies are needed to examine the potential environmental effects and biological activity of the Se4+ released from SeNPs.

Effectiveness of the fruit of Rosa odorata sweet var. gigantea (Coll. et Hemsl.) Rehd. et Wils in the protection and the healing of ethanol-induced rat gastric mucosa ulcer based on Nrf2/NF-κB pathway regulation.

ETHNOPHARMACOLOGICAL RELEVANCE: Rosa odorata Sweet var. gigantea (Coll. et Hemsl.) Rehd. et Wils (Rosaceae), is also known as "GU-GONG-GUO", the root of which has been recognized as common ethnodrug from the Yi nationality for treating inflammatory bowel disease. The aim of the present study was to investigate the preventive and curative effects of extract from the fruits of Rosa odorata Sweet var. gigantea (Coll.et Hemsl.) Rehd. et Wils (FOE) in vitro and in vivo as well as elucidate the potential mechanisms of the action involved. MATERIALS AND METHODS: Male Wistar rats were applied to ethanol-induced gastric ulcer model. They were divided into six groups: control, model (GU), positive (Magnesium aluminate chewable tablets, 125 mg/kg), FOE low (125 mg/kg), middle (250 mg/kg) and high (500 mg/kg) doses groups. Histopathology observation of gastric tissues was detected by hematoxylin and eosin (H&E) staining. The expression of Nrf2, HO-1, Keap1, NF-κB p65 and IKKα/ß in gastric tissues were evaluated by immunohistochemistry (IHC). The levels of cytokines in serum and tissues were measured by Enzyme-linked immunosorbent assay (ELISA). The expression of Nrf2, HO-1, Keap1, NF-κB p65, IKKα/ß, PCNA and COX2 proteins were ulteriorly assessed by Western blotting to elucidate the molecular mechanism of FOE's protective effect on gastric ulcer. RESULTS: MTT detection showed that LPS reduced RAW264.7 cell survival, and FOE blocked the inhibition of RAW264.7 cell growth induced by LPS. When RAW264.7 cells were treated with both FOE (100 µg mL-1) and LPS (5 µg mL-1) for 24 h, compared with the model group, the level of NO, TNF-α, IL-6, IL-1ß and MDA significantly decreased, and the activity of SOD was significantly reduced. Obvious pathological injuries in the GU model group were observed, which was improved after treatments with FOE. The contents of pro-inflammatory factors in serum and tissues were decreased by 25% whereas prostaglandin E2 (PGE2) and epidermal growth factor (EGF) were increased by 30% in a dose-dependent manner after FOE (500 mg/kg) treatments. In addition to the promotion effects of superoxide dismutase (SOD), FOE (500 mg/kg) also attenuated the levels of nitric oxide (NO) and malondialdehyde (MDA) by 20%. Likewise, the expression of NF-κB p65, IKKα/ß and Keap1 were suppressed after treatments with FOE whereas Nrf2 and HO-1 showed the opposite trend, which mechanisms were found to be associated with Nrf2/NF-κB signaling pathways. CONCLUSION: The study demonstrated that FOE is able to protect against GU via inhibiting NF-κB signaling pathway and activating Nrf2 signaling pathway, which might provide a stronger theoretical basis for the treatment of GU.

Transcriptional and posttranslational regulation of Th17/Treg balance in health and disease.

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.

hnRNPA1 enhances FOXP3 stability to promote the differentiation and functions of regulatory T cells.

Regulatory T cells (Tregs) are indispensable for the maintenance of immunological self-tolerance and homeostasis. Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is required for optimal Treg induction. Here, we reveal that human-induced Tregs (iTregs) lacking hnRNPA1 show reduced expression of the transcription factor FOXP3, increased ubiquitination level of FOXP3, and impaired suppressive abilities. Human naïve CD4 T cells with hnRNPA1 knockdown show a decreased Treg differentiation ratio. hnRNPA1 could interact with FOXP3 as well as with the E3 ligase Stub1. The phosphorylation at hnRNPA1 S199 could increase both interactions. The overexpression of FOXP3 in Tregs containing shhnRNPA1 could not recover the phenotype caused by hnRNPA1 knockdown. Therefore, there might be multiple essential pathways regulated by hnRNPA1 in Tregs. In conclusion, we present a new role of hnRNPA1 in promoting Treg function, indicating it as a promising target for tumor therapies.

USP4 is pathogenic in allergic airway inflammation by inhibiting regulatory T cell response.

AIMS: Asthma is characterized by chronic inflammation and airway hyperresponsiveness (AHR). It is controllable, but not curable. Ubiquitin-specific peptidase 4 (USP4) has been verified as a regulator of regulatory T (Treg) cells and Th17 cells in vitro. In this study, we aim to investigate whether USP4 could serve as a therapeutic target for asthma. MAIN METHODS: Age-matched USP4 wild-type and knockout mice received an intraperitoneal injection of 100 µg ovalbumin (OVA) mixed in 2 mg aluminum hydroxide in 1 × PBS on days 0, 7 and 14. On days 21 to 27, the mice were challenged with aerosolized 1% OVA in 1 × PBS for 30 min. Tissue histology, ELISA and flow cytometry were applied 24 h after the last OVA challenge. KEY FINDINGS: USP4 deficiency protected mice from OVA-induced AHR and decreased the production of several inflammatory cytokines in T cells in vivo. Compared to the lung cells isolated from WT mice, Usp4-/- lung cells decreased secretion of IL-4, IL-13 and IL-17A upon stimulation in vitro. Meanwhile, the percentage of CD4+Foxp3+ Treg cells was elevated, with more CCR6+Foxp3+ Treg cells accumulating in the lungs of OVA-challenged USP4 deficient mice than in their wild-type counterparts. Treatment with the USP4 inhibitor, Vialinin A, reduced inflammatory cell infiltration in the lungs of OVA-challenged mice in vivo. SIGNIFICANCE: We found USP4 deficiency contributes to attenuated airway inflammation and AHR in allergen-induced murine asthma, and Vialinin A treatment alleviates asthma pathogenesis and may serve as a promising therapeutic target for asthma.