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Polymethoxyflavones (PMFs) are a type of uncommon dietary flavonoids, characterized by more than one methoxy group, which exist in limited plant species, like Citrus species and Kaempferia parviflora. In addition, different PMFs, such as nobiletin, sinensetin, tangeretin, and casticin, have been isolated from these natural sources. PMFs have received increasing attention due to their multiple bioactivities, such as antioxidant, anti-inflammatory, anti-cancer, metabolic regulatory, immunoregulatory, neuroprotective, and skin protective effects. These bioactivities of PMFs should be associated with the regulation of critical molecular targets and the interaction with gut microbiota. In order to provide a comprehensive and updated review of PMFs, their natural sources, refined extraction, biosynthesis, metabolism, and bioactivities are summarised and discussed, with the emphasis on the molecular mechanisms of PMFs on regulating different chronic diseases. Overall, PMFs may be promising flavonoids to the forefront of nutraceuticals for the prevention and/or treatment of certain human chronic diseases.

Background: The process of the globally aging population has been accelerating, leading to an increasing social burden. As people age, the musculoskeletal system will gradually go through a series of degenerative and loss of function and eventually develop age-related musculoskeletal diseases, like sarcopenia, osteoporosis, and osteoarthritis. On the other hand, several studies have shown that polyunsaturated fatty acids (PUFAs) possess various important physiological functions on the health of muscles, bones, and joints. Objective: This narrative review paper provides a summary of the literature about the effects and mechanisms of PUFAs on age-related musculoskeletal diseases for the prevention and management of these diseases. Methods: Web of Science, PubMed, Science Direct, and Scopus databases have been searched to select the relevant literature on epidemiological, cellular, and animal experiments and clinical evidence in recent decades with keywords “polyunsaturated fatty acids”, “PUFAs”, “omega-3”, “omega-6”, “musculoskeletal diseases”, “sarcopenia”, “osteoporosis”, “osteoarthritis”, and so on. Results: PUFAs could prevent and treat age-related musculoskeletal diseases (sarcopenia, osteoporosis, and osteoarthritis) by reducing oxidative stress and inflammation and controlling the growth, differentiation, apoptosis, and autophagy of cells. This review paper provides comprehensive evidence of PUFAs on age-related musculoskeletal diseases, which will be helpful for exploitation into functional foods and drugs for their prevention and treatment. Conclusions: PUFAs could play an important role in the prevention and treatment of sarcopenia, osteoporosis, and osteoarthritis.

Aging and age-related diseases are serious public health issues that are receiving growing attention from researchers. Lutein has a critical function in the prevention and management of these issues. Possible mechanisms mainly include suppressing inflammation and oxidative stress, regulating cell activity, and modulating the levels of toxic substances. In this narrative review paper, we sum up the most current developments in the study of the effects of lutein on aging and five age-related diseases (age-related macular degeneration, cataracts, Alzheimer’s disease, Parkinson’s disease, and osteoporosis), and fundamental mechanisms are reviewed. The bioavailability of lutein and the strategies to improve its bioavailability are discussed. This piece of work can bring a clearer comprehension of the protective effects of lutein against aging and age-related diseases and can be also helpful for developing lutein as functional food and dietary supplements for these age-related diseases.

BackgroundAlthough oxidative stress is involved in the pathophysiological process of chronic rhinosinusitis with nasal polyps (CRSwNP), the specific underlying mechanism is still unclear. Whether antioxidant therapy can treat CRSwNP needs further investigation.MethodsImmunohistochemistry, immunofluorescence, western blotting and quantitative polymerase chain reaction (qPCR) analyses were performed to detect the distribution and expression of oxidants and antioxidants in nasal polyp tissues. qPCR revealed correlations between oxidase, antioxidant enzymes and inflammatory cytokine levels in CRSwNP patients. Human nasal epithelial cells (HNEpCs) and primary macrophages were cultured to track the cellular origin of oxidative stress in nasal polyps(NPs) and to determine whether crocin can reduce cellular inflammation by increasing the cellular antioxidant capacity.ResultsThe expression of NOS2, NOX1, HO-1 and SOD2 was increased in nasal epithelial cells and macrophages derived from nasal polyp tissue. Oxidase levels were positively correlated with those of inflammatory cytokines (IL-5 and IL-6). Conversely, the levels of antioxidant enzymes were negatively correlated with those of IL-13 and IFN-γ. Crocin inhibited M1 and M2 macrophage polarization as well as the expression of NOS2 and NOX1 and improved the antioxidant capacity of M2 macrophages. Moreover, crocin enhanced the ability of antioxidants to reduce inflammation via the KEAP1/NRF2/HO-1 pathway in HNEpCs treated with SEB or LPS. Additionally, we observed the antioxidant and anti-inflammatory effects of crocin in nasal explants.ConclusionOxidative stress plays an important role in the development of CRSwNP by promoting various types of inflammation. The oxidative stress of nasal polyps comes from epithelial cells and macrophages. Antioxidant therapy may be a promising strategy for treating CRSwNP.

Liver injury induced by alcohol is a serious global health problem. Several tea-like plants are widely used as beverages, which are drunk like tea. In this study, the hepatoprotective effects of eight tea-like plant extracts with the intake of 200 mg/kg.bw/day were investigated and compared using a C57BL/6J mouse model of acute alcohol exposure, including sweet tea, vine tea, Rabdosia serra kudo, broadleaf holly leaf, mulberry leaf, bamboo leaf, Camellia nitidissima, and Akebia trifoliata peels. The results showed that the eight tea-like plants had hepatoprotective effects to different degrees against acute alcohol exposure via enhancing the activities of alcoholic metabolism enzymes, ameliorating oxidative stress and inflammation in the liver, as well as regulating gut microbiota. In particular, sweet tea, bamboo leaf, mulberry leaf, and Camellia nitidissima increased the activities of alcohol dehydrogenase or aldehyde dehydrogenase. Among these tea-like plants, sweet tea and Camellia nitidissima had the greatest hepatoprotective effects, and their bioactive compounds were determined by high-performance liquid chromatography. Chlorogenic acid, rutin, and ellagic acid were identified in sweet tea, and epicatechin, rutin, and ellagic acid were identified in Camellia nitidissima, which could contribute to their hepatoprotective action. These tea-like plants could be drunk or developed into functional food against alcoholic liver injury, especially sweet tea and Camellia nitidissima. In the future, the effects of sweet tea and Camellia nitidissima on chronic alcoholic liver diseases should be further investigated.

As an excellent food raw material with abundant nutrients, daylily (Hemerocallis citrina Baroni) exhibits promising research and application potential. This article summarizes the major nutrients of daylily and finds that dry daylily is a healthy food with low fat, high protein and rich minerals. In addition, due to the bioactive components, daylily has a variety of biological activities beneficial to human health. On this basis, it also reviews the fresh-keeping storage and drying technologies of daylily, and it indicates that the quality of daylily could be improved via the pretreatment of fresh daylily and the drying and packaging of dry daylily. Finally, it introduces the applications and research direction of daylily in the food industry. This review will provide theoretical basis for the research of bioactive components in daylily, preservation and processing technologies, developments of related functional foods, and other industry applications.

The role of iron (Fe) in soil organic matter (SOM) stabilization and decomposition in paddy soils has recently gained attention, but the underlying mechanisms during flooding and drying periods remain elusive. As the depth water layer is maintained in the fallow season, there will be more soluble Fe than during the wet and drainage seasons and the availability of oxygen (O2) will be different. To assess the influence of soluble Fe on SOM mineralization during flooding, an incubation experiment was designed under oxic and anoxic flooding conditions, with and without Fe(III) addition. The results showed that Fe(III) addition significantly (p

Several mechanisms have been associated with transcriptional and post-transcriptional regulation of PD-L1 in cancer. Here the authors show that a RNA binding protein, DENR, positively regulates the translation of JAK2 and induces PD-L1 expression in tumor cells, associated with immune evasion.

Abstract Proppants are being increasingly used in hydraulic fracturing, which keep the fractures open. Progress has been made in developing hollow proppants that can be transported to the far end of the fractures to improve propped fracture conductivity. Two primary mechanisms by which proppants are damaged under closure stress are embedment and crushing, leading to a remarkable reduction in fracture conductivity. In this study, finite element model (FEM), considering rock plasticity, was used to study the embedment and crushing of a hollow proppant. After comparison with the existing model and experimental data, the proposed FEM was employed to conduct sensitivity studies. The effects of the following parameters on embedment and crushing were analyzed: closure stress, distance coefficient, Young's modulus of rock and proppant, proppant size, and hollow structure. The results show that the most sensitive environmental factor is the distance coefficient, followed by closure stress and Young's modulus of rock. The embedment depth increases approximately linearly with the proppant size, and proppants with different sizes have similar crushing rates. The hollow structure has little effect on proppant embedment but significantly affects proppant crushing. Based on the data normalization method, the optimal ratio of hollow radius to proppant radius was designed to be 0.7. These results can guide the preparation of hollow proppants.

Ricin is a highly toxic ribosome-inactivating lectin derived from castor beans. To date, no antidote is available to treat ricin-poisoned patients, and the development of a safe and effective antidote is urgently needed. First, ricin was prepared and used to construct a mouse model and a rhesus monkey model of ricin intoxication. Second, pepsin-digested F(ab′) 2 fragments of serum IgG from horses injected with Freund’s-adjuvanted purified ricin were prepared. Third, the protective efficacy was evaluated in mouse and rhesus monkey models of lethal ricin intoxication. The purity quotient of the prepared ricin and F(ab′) 2 fragments exceeded 90% and 85% in the mouse and monkey models, respectively. The LD 50 of ricin in mice and rhesus monkeys was 2.7 and 9 μg/kg, respectively. A quantity of 6.25 and 1.85 mg/kg F(ab′) 2 was sufficient to treat lethal ricin intoxication in the mice and rhesus monkeys, respectively. Finally, the effect of this therapeutic antibody on peripheral blood immune cells was examined by analysis of peripheral blood immune cells through single cell sequencing. The underlying mechanism was found to involve restraining neutrophil activation, proliferation, and differentiation. Purified F(ab′) 2 fragments administered with needle-free devices fully protect mice and rhesus monkeys against lethal doses of ricin intoxication.

In recent years, the [2.2]paracyclophane (PCP) ring has attracted extensive attention due to its features of providing not only chirality and electron-donating ability but also steric hindrance, which reduces intermolecular π–π stacking interactions and thereby improves the fluorescence properties of dyes. To date, some circularly polarized luminescence (CPL)-active small organic molecules based on the PCP skeleton have been reviewed; however, the application of the PCP ring in improving the photophysical properties of fluorescent dyes is still limited, and new molecular design strategies are still required. This review summarizes and promotes the application of PCP in fluorescent dye design, fluorescence detection, and CPL modulation. We expect that this review will provide readers with a comprehensive understanding of the PCP skeleton and lead to further improvement in fluorescent dye design.

Abstract Background Little is known about the changes in allergen sensitization in China secondary to the environmental variations over the past decade. We aimed at investigating the variations in sensitization among asthma and/or rhinitis patients in China between 2008 and 2018. Methods This study analyzed cross‐sectional data from national surveys conducted in China in 2008 and 2018. After finishing the questionnaire, participants underwent serum specific IgE measurements. A total of 2322 and 2798 patients were enrolled in 2008 and 2018, respectively. The significance of differences in sensitization rates among four regions of China were assessed. Correlation analysis was used to identify the associations of sensitization with climate change and planting of Artemisia desertorum between the two surveys. Results Compared with 2008, the general sensitization rate to mites significantly increased in 2018, which ranked highest among all tested allergens. Sensitization to pollens, especially Artemisia vulgaris, showed the greatest increase in the north. The annual mean temperature, rainfall and relative humidity in all four regions, and the Artemisia desertorum coverage in the northeastern area, increased significantly in 2018 as compared with 2008. From 2008 to 2018, an increase in Dermatophagoides pteronyssinus sensitization was significantly associated with an increase in relative humidity (r = 0.54, p = 0.037). The increase in A. vulgaris sensitization was significantly associated with the increase in the A. desertorum planting area (r = 0.67, p = 0.006) and with a decrease in rainfall (r = −0.59, p = 0.021). Conclusions House dust mites remain the most important allergen in Chinese individuals with asthma and/or rhinitis. Pollen sensitization dramatically increased in northern China. Increases in sensitization to dust mites and Artemisia were related to the increases in humidity and planting area of A. desertorum.

Smallpox, a severe infectious disease caused by the smallpox virus, causes a death rate as high as 30% within 15-20 days after infection. Therefore, development of anti-Smallpox product as a strategic reserve is urgently needed. We prepared and tested pepsin-digested F(ab′) 2 fragments of serum IgG from horses. Transmission electron microscopy indicated that the purified virus showed morphology consistent with VVTT. The titer was above 1.0 × 10 7 PFU/mL. The purity of the antigen exceeded 90%, according to HPLC. After purification and cleavage, the yield of the purified product F(ab′) 2 was approximately 1.3%, its purity exceeded 90%, and the neutralizing antibody titer exceeded 1:3200. F(ab′) 2 fragments had good preventive and therapeutic effects in mice at antibody doses of 5.2 mg/mL and 2.6 mg/mL. The viral loads of the drug-treated mice were suppressed to varying degrees, and the higher dose groups (5.2 and 2.6 mg/mL) showed a 2-3 fold lower viral load than that in the control group. A process for producing equine immunoglobulin F(ab′) 2 against VVTT was established. The prepared horse anti-smallpox immunoglobulin product had good neutralizing antibody effects on VVTT. The highly purified preparation may serve as a potential candidate for smallpox treatment.

Global temperature is projected to increase, which impacts the ecological process in northern mid- and high-latitude ecosystems, but the winter temperature change in ecosystems is among the least understood. Rice paddy represents a significant contributor to global anthropogenic CH _4 emissions and has a strong climate forcing feedback; however, the legacy effects of warming winter on CH _4 emissions in the subsequent growing season remain uncertain. Here, we conducted field and incubation experiments to determine the effects of winter soil temperature changes on CH _4 emissions in the subsequent growing season. First, in the 3 year field experiment, we continuously measured CH _4 emissions from the rice cropping system. The winter soil temperature and its variation showed significant differences over the 3 years. In the warming-winter year, the rice paddy accumulated less NH _4 ^+ –N and more dissolved organic carbon (DOC) in the soil during winter, resulting in high CH _4 emissions. Second, we incubated the paddy soils without flooding at three temperatures (5 °C, 15 °C, and 25 °C) for 4 weeks to simulate warming winter, and subsequently incubated at same temperature (25 °C) under submerged conditions for 4 weeks to simulate growing season. The result was consistent with field experiment, increased soil temperature significantly increased soil DOC content and decreased NH _4 ^+ –N content in ‘winter season’. The CH _4 emissions in the subsequent ‘growing season’ increased by 190% and 468% when previous incubation temperature increased 10 °C and 20 °C. We showed strong and clear links between warming winter and CH _4 emissions in the subsequent growing season for the first time, suggesting that CH _4 related processes respond not only to warming during the growing season but also in the previous winter. Our findings indicate that nonuniform global warming causes a disproportionate increase in climate forcing feedback to emit more CH _4 .

Escherichia coli ( E. coli ) is one of the most common pathogens causing clinical mastitis in cattle, but no vaccine is available to prevent this disease in China. Therefore, development of an E. coli vaccine against bovine clinical mastitis is urgently needed. The candidate vaccine (Ch-O111-1) and challenge (LZ06) strains were screened from milk samples of cows with clinical mastitis. To extend the cross-protection of the Ch-O111-1 strain, we deleted the galE gene fragment of the Ch-O111-1 strain through homologous recombination between the Ch-O111-1 strain and pCVD442/ΔgalE plasmid, which was identified through conventional methods, including PCR, SDS-PAGE and sequencing. The Ch-O111-1/ΔgalE (Z9) strain was characterized by extensive cross-reactivity and attenuated virulence. We prepared inactivated Z9 vaccines with different adjuvants. Immunization of inactivated Z9 antigen induced adjuvant-, dosage- and inoculation time-dependent antibody titers in cows and mice. Furthermore, immunization with SP01-adjuvanted inactivated Z9 vaccine protected cows against severe clinical mastitis caused by LZ06 and protected mice against death due to LZ06. An SP01-adjuvanted inactivated Z9 vaccine was successfully developed and found to protect cows against severe mastitis caused by Escherichia coli .

Non-alcoholic fatty liver disease (NAFLD) has emerged as a leading public health challenge and is closely associated with metabolic syndromes, such as obesity. Intestinal microbiota dysbiosis could play a vital role in the pathogenesis and progression of NAFLD. Tea is the second most popular health drink in the world behind water, and exhibits many health-promoting effects. In this study, the protective effects of different black and dark teas on NAFLD induced by long-term high-fat diet (HFD) exposure and their regulation of gut microbiota were evaluated and explored. The results indicated that supplementation with different black and dark tea extracts could significantly suppress the energy intake, alleviate abnormal accumulation of visceral fat, and prevent obesity, hepatic abnormal lipid deposition and liver steatosis in HFD-fed mice at varying degrees. In addition, Dianhong tea and Liupao tea interventions could significantly decrease the ratio of Firmicutes to Bacteroidetes, and selenium-enriched black tea and selenium-enriched dark rea supplementation could remarkably reduce the relative abundance of Actinobacteria compared to the model group. Moreover, these teas could partly shift the relative abundances of Allobaculum, Roseburia and Dubosiella. Taken together, black teas and dark teas could prevent HFD-induced features of obesity and NAFLD, which might partly be due to the modulation of gut microbiota.

Douchi is a traditional salt-fermented soybean food with various bioactivities, such as anti-oxidation, anti-diabetes, and anti-hypertension, which are greatly affected by the activities of protease and β-glucosidase during koji production. Edible mushroom by-products are ideal ingredients for enhancing food flavor and nutritional quality due to their unique nutritional characteristics of high protein, rich amino acids, and low calories. However, there is no research on the preparation of Douchi by the mixed fermentation of edible mushroom by-products and soybeans. In this study, response surface methodology (RSM) was used to optimize the fermentation conditions of edible mushroom by-product Douchi koji (EMDK) with protease and β-glucosidase activities as indicators, and the changes in the main bioactive compounds and antioxidant activities of unfermented raw samples (URS), Douchi koji without edible mushroom by-product (DKWE), and EMDK were compared. The results of single-factor tests and RSM showed that the optimal fermentation conditions of EMDK were the Aspergillus oryzae to Mucor racemosus ratio of 1:1, inoculation amount of 6%, edible mushroom amount of 21%, and fermentation time of 63 h, and the activities of protease and β-glucosidase under these conditions were 796.03 ± 15.01 U/g and 1175.40 ± 36.98 U/g, respectively. Additionally, compared with URS and DKWE, the contents of total isoflavones and β-glucoside isoflavones in EMDK were notably decreased, while the contents of amino nitrogen, total phenolics, total flavonoids, and aglycone isoflavone, as well as the antioxidant capacity were significantly increased. Furthermore, significant correlations were found between the above components and antioxidant capacity. These results showed that edible mushroom by-product could be incorporated into soybeans for co-fermentation, conferring higher nutritional value to and antioxidant capacity of Douchi koji.

Targeting the immune-stimulatory receptor 4-1BB has only yielded modest benefit in cancer treatment. In this study, the authors show that CD73 expression on effector T cells sustained by TGF-β drives tumor resistance to anti-4-1BB therapy and therefore TGF- β blockade can be used to overcome such resistance.

Brucellosis is a serious zoonotic infection worldwide. To date, vaccination is the most effective measure against brucellosis. This study was aimed at obtaining a vaccine strain that has high protective efficacy and low toxicity, and allows vaccination to be differentiated from infection. Using homologous recombination, we constructed a double gene-deletion Brucella strain MB6 Δbp26ΔwboA (RM6) and evaluated its characteristics, safety and efficacy. The RM6 strain had good proliferative ability and stable biological characteristics in vivo and in vitro. Moreover, it had a favorable safety profile and elicited specific immune responses in mice and sheep. The RM6 strain may have substantial practical application value.

The prevalence of allergic rhinitis (AR) and obesity in children increased concurrently during recent decades. However, the molecular pathway involved in the interaction between obesity and AR is still unclear. We aimed to investigate the interaction between leptin and osteopontin (OPN) and their effect on T helper (TH) response in the development of AR in children. Thirty AR and 30 healthy children with or without obesity were enrolled. Serum leptin and OPN levels were measured and their relationship with TH1/2 cytokines was analyzed. TH cell differentiation and cytokine production in peripheral blood mononuclear cells (PBMCs) stimulated by leptin and/or OPN were analyzed by enzyme linked immunosorbent assay (ELISA). Obese AR mice models were established to verify the effect of obesity on leptin and OPN as well TH regulation. Immunoprecipitation was performed to confirm the interaction between OPN and leptin in CD4+ T cells. Our results showed elevated serum leptin and OPN in AR children correlated with TH2 cytokines expression. Leptin and OPN enhanced TH2 inflammation in house dust mite stimulated PBMCs from AR children synergistically. Obese AR mice showed as more severe inflammatory reaction, symptoms and expression of nasal leptin and OPN compared with other groups. Immunoprecipitation suggested that OPN and leptin may interact with each other and this process may be mediated by α4 integrin and PI3K/AKT pathway in CD4+ T cells. Our data provide evidence that leptin-mediated OPN upregulation promote TH2 inflammation in AR and this process is achieved through the α4 integrin and PI3K/AKT signaling pathways. Keywords: Allergic rhinitis, Leptin, Osteopontin, Obesity, T helper cell

Nonalcoholic fatty liver diseases (NAFLD) represent a set of liver disorders progressing from steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma, which induce huge burden to human health. Many pathophysiological factors are considered to influence NAFLD in a parallel pattern, involving insulin resistance, oxidative stress, lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory cascades, fibrogenic reaction, etc. However, the underlying mechanisms, including those that induce NAFLD development, have not been fully understood. Specifically, oxidative stress, mainly mediated by excessive accumulation of reactive oxygen species, has participated in the multiple NAFLD-related signaling by serving as an accelerator. Ameliorating oxidative stress and maintaining redox homeostasis may be a promising approach for the management of NAFLD. Green tea is one of the most important dietary resources of natural antioxidants, above which epigallocatechin gallate (EGCG) notably contributes to its antioxidative action. Accumulative evidence from randomized clinical trials, systematic reviews, and meta-analysis has revealed the beneficial functions of green tea and EGCG in preventing and managing NAFLD, with acceptable safety in the patients. Abundant animal and cellular studies have demonstrated that green tea and EGCG may protect against NAFLD initiation and development by alleviating oxidative stress and the related metabolism dysfunction, inflammation, fibrosis, and tumorigenesis. The targeted signaling pathways may include, but are not limited to, NRF2, AMPK, SIRT1, NF-κB, TLR4/MYD88, TGF-β/SMAD, and PI3K/Akt/FoxO1, etc. In this review, we thoroughly discuss the oxidative stress-related mechanisms involved in NAFLD development, as well as summarize the protective effects and underlying mechanisms of green tea and EGCG against NAFLD.

Summary: The Foxp3 transcription factor is a crucial determinant of both regulatory T (TREG) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires the tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in TREG cells can be regulated by a TGF-β activated kinase 1 (TAK1)-Nemo-like kinase (NLK) signaling pathway. NLK interacts and phosphorylates Foxp3 in TREG cells, resulting in the stabilization of protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase. Conditional TREG cell NLK-knockout (NLKΔTREG) results in decreased TREG cell-mediated immunosuppression in vivo, and NLK-deficient TREG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through the stabilization of protein levels, thereby maintaining TREG cell suppressive function. : The maintenance of Foxp3 expression is critical for correct TREG cell function. Fleskens et al. demonstrate a molecular mechanism in which TCR engagement can stabilize Foxp3 protein expression through TAK1-NLK-regulated phosphorylation, thereby maintaining TREG cell suppressive function. Keywords: Foxp3, phosphorylation, regulatory T cell, NLK, TCR, ubiquitination, immune tolerance

Fas–Fas ligand (FasL) signaling plays an important role in the development of allergic inflammation, but the cellular and molecular mechanisms are still not well known. By using the bone marrow-derived dendritic cell (BMDC) transfer-induced pulmonary inflammation model, we found that house dust mite (HDM)-stimulated FAS-deficient BMDCs induced higher Th2-mediated allergic inflammation, associated with increased mucus production and eosinophilic inflammation. Moreover, FAS-deficient BMDCs promoted Th2 cell differentiation upon HDM stimulation in vitro. Compared to wild-type BMDCs, the Fas-deficient BMDCs had increased ERK activity and decreased IL-12 production upon HDM stimulation. Inhibition of ERK activity could largely increase IL-12 production, consequently restored the increased Th2 cytokine expression of OT-II CD4+ T cells activated by Fas-deficient BMDCs. Thus, our results uncover an important role of DC-specific Fas signaling in Th2 differentiation and allergic inflammation, and modulation of Fas signaling in DCs may offer a useful strategy for the treatment of allergic inflammatory diseases.

Gut microbiota dysbiosis has been a crucial contributor to the pathogenesis of alcoholic fatty liver disease (AFLD). Tea is a popular beverage worldwide and exerts antioxidant and anti-inflammatory activities, as well as hepatoprotective effects. However, the potential role of gut microbiota regulated by tea in the prevention and management of AFLD remains unclear. Here, the protective effects of oolong tea, black tea, and dark tea on AFLD and its regulation of gut microbiota in chronic alcohol-exposed mice were explored and investigated. The results revealed that tea supplementation significantly prevented liver steatosis, decreased oxidative stress and inflammation, and modulated gut microbiota in chronic alcohol-exposed mice, especially oolong tea and dark tea. However, black tea showed less effectiveness against liver injury caused by alcohol. Moreover, the diversity, structure and composition of chronic alcohol-disrupted gut microbiota were restored by the supplementation of oolong tea and dark tea based on the analysis of gut microbiota. Furthermore, the relationship between liver injury biochemical indicators and gut microbiota indicated that some specific bacteria, such as Bacteroides, Alloprevotella, and Parabacteroides were closely associated with AFLD. In addition, the phytochemical components in tea extracts were measured by high-performance liquid chromatography, which could contribute to preventive effects on AFLD. In summary, oolong tea and dark tea could prevent chronic alcohol exposure-induced AFLD by modulating gut microbiota.

Hrd1 is an E3 ubiquitin ligase involved in ER-associated degradation and MHC I turnover. Here the authors use T-cell-specific ko mice and a mouse model of multiple sclerosis to show that Hrd1 also drives pro-inflammatory T helper cell responses and contributes to pathogenesis of autoimmune disease.

Recent studies indicated that CXCR5+CD8+ T cells in lymph nodes could eradicate virus-infected target cells. However, in the current study we found that a subset of CXCR5+CD8+ T cells in the germinal centers from human tonsils or lymph nodes are predominately memory cells that express CD45RO and CD27. The involvement of CXCR5+CD8+ T cells in humoral immune responses is suggested by their localization in B cell follicles and by the concomitant expression of costimulatory molecules, including CD40L and ICOS after activation. In addition, CXCR5+CD8+ memory T cells produced significantly higher levels of IL-21, IFN-γ, and IL-4 at mRNA and protein levels compared to CXCR5−CD8+ memory T cells, but IL-21-expressing CXCR5+CD8+ T cells did not express Granzyme B and perforin. When cocultured with sorted B cells, sorted CXCR5+CD8+ T cells promoted the production of antibodies compared to sorted CXCR5−CD8+ T cells. However, fixed CD8+ T cells failed to help B cells and the neutralyzing antibodies against IL-21 or CD40L inhibited the promoting effects of sorted CXCR5+CD8+ T cells on B cells for the production of antibodies. Finally, we found that in the germinal centers of lymph nodes from HIV-infected patients contained more CXCR5+CD8+ T cells compared to normal lymph nodes. Due to their versatile functional capacities, CXCR5+CD8+ T cells are promising candidate cells for immune therapies, particularly when CD4+ T cell help are limited.

ObjectiveTo investigate the role of IL-2 in the balance of Th17 and Tregs and elucidate the underlying mechanisms of enhanced Th17 differentiation in primary Sjögren’s syndrome (pSS) patients.MethodsThis study involved 31 pSS patients, 7 Sicca patients, and 31 healthy subjects. Th17 and Treg cells were determined by flow cytometry, and IL-17A was detected by immunohistochemistry. IL-2 and IL-6 levels were assessed by ELISA and qPCR. p-STAT5 and p-STAT3 in salivary glands (SGs) were evaluated by immunohistochemistry and flow cytometry. The binding of STAT5 and STAT3 to the Il17a gene locus was measured by chromatin immunoprecipitation.ResultsWe found that the percentage of Th17 cells was increased in the periphery and SG of pSS patients when compared with healthy subjects, but the Treg cells was unchanged. Meanwhile, the IL-2 level was reduced, and the IL-6 and IL-17A level was increased in the plasma of pSS patients. The ratio of IL-2 and IL-6 level was also decreased and IL-2 level was negatively correlated with the level of IL-17A. The expression of Il6 and Il17a mRNA was significantly increased, whereas Foxp3, Tgfb1, Tnfa, and Ifng mRNA were comparable. Furthermore, the level of STAT5 phosphorylation (p-STAT5) was reduced and p-STAT3 was enhanced in the SGs and in peripheral CD4+ T cells of pSS patients. In vitro IL-2 treatment-induced STAT5 competed with STAT3 binding in human Il17a locus, leading to decreased Th17 differentiation, which was associated with the reduced transcription activation marker H3K4me3.ConclusionOur findings demonstrated a Treg-independent upregulation of Th17 generation in pSS, which is likely due to a lack of IL-2-mediated suppression of Th17 differentiation. This study identified a novel mechanism of IL-2-mediated immune suppression in pSS.

The dual role of ethanol in regulating both pro-inflammatory and anti-inflammatory response has recently been reported. Myeloid-derived suppressor cells (MDSCs) are one of the major components in the immune suppressive network in both innate and adaptive immune responses. In this study, we aim to define the role of a population expressing CD11b+Ly6GhighLy6Cint with immunosuppressive function in response to ethanol-induced acute liver damage. We find this increased granulocytic-MDSCs (G-MDSCs) population in the blood, spleen, and liver of mice treated with ethanol. Depletion of these cells increases serum alanine aminotransferase and aspartate aminotransferase levels, while G-MDSCs population adoptive transfer can ameliorate liver damage induced by ethanol, indicating the protective role in the early stage of alcoholic liver disease. The significant changes of T-cell profiles after G-MDSCs populations adoptive transfer and anti-Gr1 injection signify that both cytotoxic T and T helper cells might be the targeted cells of G-MDSCs. In the in vitro study, we find that myeloid precursors preferentially generate G-MDSCs and improve their suppressive capacity via chemokine interaction and YAP signaling when exposed to ethanol. Furthermore, IL-6 serves as an important indirect factor in mediating the expansion of G-MDSCs populations after acute ethanol exposure. Collectively, we show that expansion of G-MDSCs in response to ethanol consumption plays a protective role in acute alcoholic liver damage. Our study provides novel evidence of the immune response to acute ethanol consumption.

Background. Interleukin-37 (IL-37), a newly described member of IL-1family, functioned as a fundamental inhibitor of innate inflammatory and immune responses, especially its isoform IL-37b. Objective. This study was undertaken to evaluate the expression and regulation of IL-37b in children with allergic rhinitis (AR). Methods. Forty children with AR and twenty-five normal controls were included. The relationship between IL-37b and Th1/2 cytokines production in serum and nasal lavage was examined by enzyme-linked immunosorbent assay (ELISA). Peripheral blood mononuclear cells (PBMCs) were purified for in vitro regulation experiment of IL-37b. Intranasal mometasone furoate was given in AR children and IL-37b change after one-month treatment was detected using ELISA. Results. We observed significantly decreased IL-37b expression levels in both serum and nasal lavage compared to controls. IL-37b was negatively correlated with Th2 cytokines. Our results also showed that IL-37b downregulated Th2 cytokine expressed by PBMCs and this modulation was through mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathway. We also found that intranasal mometasone furoate therapy can promote nasal IL-37b expression. Conclusion. IL-37b may be involved in Th2 cytokine regulation in AR and its expression was related to the efficacy of intranasal steroid therapy.

BACKGROUND: Recent studies demonstrated that nasal polyps (NP) patients in China and other Asian regions possessed distinct Th17-dominant inflammation and enhanced tissue remodeling. However, the mechanism underlying these observations is not fully understood. This study sought to evaluate the association of interleukin (IL)-17A with MUC5AC expression and goblet cell hyperplasia in Chinese NP patients and to characterize the signaling pathway underlying IL-17A-induced MUC5AC expression in vitro. METHOD: We enrolled 25 NP patients and 22 normal controls and examined the expression of IL-17A, MUC5AC and act1 in polyp tissues by immunohistochemical (IHC) staining, quantitative polymerase chain reaction (qPCR) and western blot. Moreover, by using an in vitro culture system of polyp epithelial cells (PECs), IL-17A-induced gene expression was screened in cultured PECs by DNA microarray. The expression of IL-17RA, IL-17RC, act1 and MUC5AC and the activation of the MAPK pathway (ERK, p38 and JNK), were further examined in cultured PECs and NCI-H292 cells by qPCR and western blotting, respectively. RESULTS: We found that increased IL-17A production was significantly correlated with MUC5AC and act1 expression and goblet cell hyperplasia in polyp tissues (p

Oral administration of bacterial extracts (eg, Broncho-Vaxom (BV)) has been proposed to attenuate asthma through modulating Treg cells. However, the underlying mechanism has not been fully characterized. This study sought to assess the effects of oral administration of BV on GSK-3β expression and Treg cells in ovalbumin (OVA)-induced asthmatic mice models.Asthmatic mice models were established with OVA challenge and treated with oral administration of BV. Next, infiltration of inflammatory cells including eosinophil and neutrophils, mucous metaplasia, levels of Th1/Th2/Treg-typed cytokines and expression of GSK3β and Foxp3 were examined in asthmatic mice models by histological analysis, Bio-Plex and western blot, respectively. Moreover, the frequencies of Treg cells were evaluated in cultured splenocytes by flow cytometry in the presence of BV or GSK3β siRNA interference.We found significant decrease of infiltrated inflammatory cells in bronchoalveolar lavage fluid (BALF) in asthmatic mice models after oral administration of BV. Oral administration of BV was shown to significantly suppress mucus metaplasia, Th2-typed cytokine levels and GSK3β expression while increasing Foxp3 production in asthmatic mice models. Moreover, BV significantly enhanced GSK3β-related expansion of Treg cells in cultured spleen cells in vitro.Our findings provide evidence that oral administration of BV is capable of attenuating airway inflammation in asthmatic mice models, which may be associated with GSK3β-related expansion of Treg cells.

BACKGROUND: Although allergen specific immunotherapy (SIT) represents the only immune- modifying and curative option available for patients with allergic rhinitis (AR), the optimal schedule for specific subcutaneous immunotherapy (SCIT) is still unknown. The objective of this study is to systematically assess the efficacy and safety of cluster SCIT for patients with AR. METHODS: By searching PubMed, EMBASE and the Cochrane clinical trials database from 1980 through May 10th, 2013, we collected and analyzed the randomized controlled trials (RCTs) of cluster SCIT to assess its efficacy and safety. RESULTS: Eight trials involving 567 participants were included in this systematic review. Our meta-analysis showed that cluster SCIT have similar effect in reduction of both rhinitis symptoms and the requirement for anti-allergic medication compared with conventional SCIT, but when comparing cluster SCIT with placebo, no statistic significance were found in reduction of symptom scores or medication scores. Some caution is required in this interpretation as there was significant heterogeneity between studies. Data relating to Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) in 3 included studies were analyzed, which consistently point to the efficacy of cluster SCIT in improving quality of life compared to placebo. To assess the safety of cluster SCIT, meta-analysis showed that no differences existed in the incidence of either local adverse reaction or systemic adverse reaction between the cluster group and control group. CONCLUSION: Based on the current limited evidence, we still could not conclude affirmatively that cluster SCIT was a safe and efficacious option for the treatment of AR patients. Further large-scale, well-designed RCTs on this topic are still needed.

BACKGROUND:Enhancer of zeste homolog 2 (EZH2) has been shown to contribute to tumour development and/or progression. However, the signalling pathway underlying the regulation of EZH2 in nasopharyngeal carcinoma (NPC) remains unclear. Since EZH2 contains the putative Glycogen synthase kinase 3 beta (GSK3β) phosphorylation motif ADHWDSKNVSCKNC (591) and may act as a possible substrate of GSK-3β, it is possible that inactivation of GSK3β may lead to excessive EZH2 expression in NPC. METHOD:We first examined the expression of EZH2 and phosphorylated GSK3β (p-GSK3β) by immunohistochemical staining in NPC samples. Then, we evaluated the interaction of GSK3β and EZH2 using immunoprecipitation and immune blot. Moreover, we determined the effect of inhibition of GSK3β activity on EZH2 expression and tumor invasiveness in NPC cell lines in vitro. Finally, we evaluated the invasive properties of NPC cells after knocking down EZH2 expression with EZH2 siRNA. RESULTS:We found that expression of EZH2 correlated with phosphorylated GSK3β (p-GSK3β) at Ser 9 (an inactivated form of GSK3β) in human nasopharyngeal carcinoma (NPC) samples. We also provided evidence that GSK3β is able to interact with EZH2 using immunoprecipitation and immune blot. Furthermore, we found that inhibition of GSK3β activity can lead to upregulation of EZH2 in NPC cell lines in vitro, with enhanced local invasiveness. By knocking down EZH2 expression with EZH2 siRNA, we found that these invasive properties were EZH2 dependent. CONCLUSION:Our findings indicate that GSK3β inactivation may account for EZH2 overexpression and subsequent tumour progression, and this mechanism might be a potential target for NPC therapy.