Active polysaccharides: a new roadmap for the prevention and treatment of food allergy.

Active polysaccharides are extensively utilized in the fields of food and medicine because of their rich functional properties and structural plasticity. However, there are still few systematic studies and reviews on active polysaccharides for allergy. Allergy, especially food allergy, occurs frequently around the world and is related to a variety of factors such as age, genetics and dietary habits. Currently in medicine, avoiding allergens and desensitizing can effectively relieve allergy symptoms, but these are difficult to maintain over the long term and come with risks. Based on the supplementation of dietary nutrition to these two treatments, it has been discovered in recent years that the use of active ingredients from natural substances can effectively intervene in allergies. Considering the potential of active polysaccharides in this regard, we systematically characterize the latent patterns of polysaccharides in allergic symptoms and pathogenesis, including the aspects of gut, immunomodulatory, oxidative stress and signaling pathways, as well as the application prospect of them in allergy. It can be found that active polysaccharides have excellent anti-allergic potential, especially from the ocean. We believe that the active polysaccharides are associated with the treatment of allergic diseases, which may provide the benefits to allergy sufferers in the future.

Epigenetic modification of Kiss1 gene expression in the AVPV is essential for female reproductive aging.

Female reproductive senescence is heralded by hypothalamus region-specific changes in the transcription of genes such as Kiss1 under estradiol (E2) positive feedback, associated with luteinizing hormone (LH) surge dysfunction and reproductive decline. The current study explored whether the anteroventral periventricular nucleus (AVPV) displayed epigenetic changes mediated by age-related dysregulation of gene expression and whether an epigenetic-based intervention could alleviate an aging-related neuroendocrine disorder. Chromatin immunoprecipitation sequencing (ChIP-seq) and ChIP-qPCR were used to assess the differential acetylation of histone H3 in the AVPV and the expression of genes in hormone-primed middle-aged rats. The association between acetylated histone H3 and Kiss1 expression and the underlying mechanisms of dysregulation were determined using pharmacological inhibitors and molecular experiments in vitro and in vivo. An AVPV gene expression program failed to initiate in middle-aged females displaying typical genome-wide hypoacetylation of histone H3, and this coincided with decreased LH. Hypoacetylation of histone H3 at the 3' intergenic region of Kiss1 in particular was associated with enhanced chromatin looping between the promoter and enhancer. Restoration of physiological histone H3 acetylation by intracerebroventricular injection of trichostatin A (TSA) restored the expression of Kiss1 by modifying chromatin looping and led to the restoration of Kiss1 neuronal activation and Kiss1 synthesis as well as circulating LH. These findings have revealed novel epigenetic-associated changes in gene expression in female reproductive aging. These results also suggest that HDAC enzyme-based treatment is a potential therapeutic approach for insufficient preovulatory LH release in aging females.

Decidualization-derived cAMP promotes decidual NK cells to be angiogenic phenotype.

BACKGROUND: During early pregnancy, a large number of CD56bright natural killer cells (NKs) are accumulated in the decidua; unlike peripheral and cord blood NK cells (pNK and cNK), these decidual NK cells (dNK) display a great capacity to secrete a series of angiogenic/vascular factors, which are essential for placental development. However, the mechanism underlying the formation of dNK cells with an angiogenic phenotype remains unclear. METHODS: First, we compared the difference between dNK and cNK/pNK cells in terms of the expression of CD56 and VEGF, and the regulation of the tube formation. The effect of cAMP on the differentiation of NK cells was evaluated by its analog and inhibitor stimulation. We further analyzed the differences in the phenotype of dNK cells and the expression of VEGF in dNK cells from normal pregnancies and miscarriages. RESULTS: Different from cNK and pNK, dNK cells displayed high expression of CD56 and VEGF. And dNK cells showed a higher capacity of inducing tube formation of HUVEC by trophoblast. Meanwhile, we observed that cAMP-analogue increased the percentage of CD56bright NK population in cNK cells with up-regulated VEGF secretion and tube formation of HUVEC by trophoblast, which could be inhibited by pretreatment with VEGFR neutralizing antibody. Similar changes occurred when co-culturing cNK cells with DSCs but not ESCs. Interestingly, the inhibitor of cAMP signaling (Metadoxine, META) could significantly inhibit the upregulation of VEGF in cNK cells by DSCs. Furthermore, DSCs could secret much more cAMP than ESCs. Notably, decreased CD56bright NK population and VEGF secretion by dNK were related to pregnancy loss. CONCLUSIONS: These findings suggest that dNK cells display an angiogenic phenotype that can be induced by decidualized cAMP signaling. Our study indicates the significance of decidualization-derived cAMP in regulating angiogenesis of decidual NKs and reveals complex crosstalk between different cell types in a critical period during early pregnancy.

WNT16 from decidual stromal cells regulates HTR8/SVneo trophoblastic cell function via AKT/beta-catenin pathway.

Decidual stromal cells (DSCs) modulate the function of trophoblasts through various factors. Wnt signaling pathway is active at the maternal-fetal interface. Here, we isolated endometrial stromal cells (ESCs) from women of reproductive ages and DSCs from normal pregnancy during the first trimester (6-10 weeks). Real-time quantitative PCR and western blotting were used to screen out the most variable WNT ligands between ESCs and DSCs, which turned out to be WNT16. Both culture mediums from DSCs and recombinant protein of human WNT16 enhanced the survival and invasion of HTR8/SVneo trophoblastic cells. Furthermore, the regulation of DSCs on trophoblast was partly blockaded after we knocked down WNT16 in DSCs. Treating HTR8/SVneo trophoblastic cells with small molecular inhibitors and small interfering RNA (siRNA), we found that the activity of AKT/beta-catenin (CTNNB1) correlated with the effect of WNT16. The crosstalk of WNT16/AKT/beta-catenin between DSCs and trophoblasts was determined to be downregulated in unexplained recurrent spontaneous abortion. This study suggests that WNT16 from DSCs promotes HTR8/SVneo trophoblastic cells invasion and survival via AKT/beta-catenin pathway at the maternal-fetal interface in human early pregnancy. The disturbance of this crosstalk between DSCs and trophoblasts might cause pregnancy failure.

Circadian rhythm-associated Rev-erbα modulates polarization of decidual macrophage via the PI3K/Akt signaling pathway.

PROBLEM: Circadian rhythms are involved not only in the repair and regeneration of the immune system, but may also be associated with regulation of inflammation and immune responses. Rev-erbα could constitute a link between immunity and circadian rhythms since it is a transcription factor that regulates circadian rhythms and has functions in multiple physiological and pathological processes. Decidual macrophages (dMφs) play crucial roles in immune balance at the maternal-fetal interface, and abnormal macrophage polarization is related to adverse pregnancy outcomes, such as infertility, recurrent spontaneous abortion, and preterm labor. However, whether Rev-erbα could modulate the polarization of macrophages is unknown. METHODS OF STUDY: In this study, we analyzed the phenotype of dMφs and the expression of Rev-erbα in dMφs from normal pregnancies and miscarriages. The effect of Rev-erbα on macrophage polarization was evaluated by its knockdown or pharmacological activation. The mechanism by which the Rev-erbα agonist SR9009 regulates macrophage polarization was also estimated. RESULTS: A type-1 macrophage (M1)-like dominance was observed in dMφs from human miscarriages, with a decreased expression of Rev-erbα compared to that from normal pregnancies. Rev-erbα knockdown promoted M1 polarization in macrophages differentiated from the THP1 cell line, whereas pharmacological activation of Rev-erbα by SR9009 induced type-2 macrophage (M2)-like polarization in dMφs. Furthermore, we found that SR9009 induced M2 polarization in macrophages differentiated from the U937 cell line via the PI3K/Akt signaling pathway. CONCLUSION: Rev-erbα may play an essential role in macrophage polarization. These findings might help elucidate the role of Rev-erbα in regulating the differentiation and functions of macrophages and suggest a therapeutic target for pregnancy loss and pregnancy complications.

Pigment epithelium-derived factor, a novel decidual natural killer cells-derived factor, protects decidual stromal cells via anti-inflammation and anti-apoptosis in early pregnancy.

STUDY QUESTION: What is the role of pigment epithelium-derived factor (PEDF) from decidual natural killer (dNK) cells during early pregnancy? SUMMARY ANSWER: PEDF from dNK cells limits the lipopolysaccharide (LPS)-induced apoptosis and inflammation of decidual stromal cells (DSCs) to maintain DSCs homoeostasis and immune balance at the maternal-foetal interface during early pregnancy. WHAT IS KNOWN ALREADY: dNK cells, which secrete PEDF, play critical roles during pregnancy via a series of key regulators. PEDF, a multifunctional endogenous glycoprotein, exhibits a wide range of biological actions upon angiogenesis, inflammation, metabolic homoeostasis, immunomodulation etc., providing potential clinical applications. STUDY DESIGN, SIZE, DURATION: Natural killer (NK) cells from decidua and peripheral blood as well as DSCs isolated from normal pregnancy (NP) during the first trimester (6-10 weeks) and the matched patients suffering recurrent miscarriage (RM) were studied. RNA-sequencing analysis of dNK cells was performed to screen for potential key genes involved in RM. The expression of PEDF in dNK cells in NP and RM was examined. A coculture system with LPS-stimulated DSCs and NK cell supernatants derived from NP or RM was established to explore the regulatory mechanisms of PEDF at the maternal-foetal interface. PARTICIPANTS/MATERIALS, SETTING, METHODS: Peripheral blood and decidual tissues were obtained from women with NP (n = 61) and RM (n = 21). The expression levels of PEDF in NK cells and its receptor (PEDFR) on DSCs were analysed using flow cytometry, western blot and immunohistochemistry. Purified peripheral natural killer (pNK) cells were cocultured with DSCs or trophoblast cells or a combination of both cell types, and PEDF expression in pNK cells was then examined by flow cytometry. DSCs were treated with LPS, an outer-membrane component of Gram-negative bacteria, thereby mimicking an enhanced inflammatory status within decidua, and were cocultured with dNK cell supernatants from NP or RM. In the coculture system, plasmids expressing short hairpin RNA were used to silence PEDFR on DSCs and block the PEDF/PEDFR interaction. Inflammatory cytokines and apoptosis of DSCs treated as described above were assessed by flow cytometry. Western blotting was performed, and the specific signal pathway inhibitors were used to determine downstream PEDF/PEDFR signalling in early decidua. MAIN RESULTS AND THE ROLE OF CHANCE: Markedly higher RNA (P < 0.001) and protein expression of PEDF (P < 0.01) was detected in normal dNK cells when compared with pNK cells. Compared with pNK cells cultured alone, PEDF expression in pNK cells was elevated after coculture with DSCs (P < 0.01) or trophoblast cells (P < 0.001). The increased pro-inflammatory cytokine, tumour necrosis factor-α and apoptosis of DSCs following LPS stimulation were suppressed by recombinant human PEDF (P < 0.001) or the supernatant of dNK cells derived from NP (P < 0.001). However, these effects were somewhat abrogated when the PEDF/PEDFR interaction was blocked with PEDFR short hairpin sRNA (P < 0.01). Furthermore, dNK cell-derived PEDF protected DSCs from LPS-induced inflammation via inhibition of nuclear factor kappa-B activation, while also protecting DSCs from LPS-induced apoptosis via promotion of extracellular signal-regulated kinase expression. Compared with NP, both significantly decreased PEDF RNA (P < 0.001) and protein expression (P < 0.001) in dNK cells, but not in pNK cells (P > 0.05), were detected in women with RM. PEDFR on DSCs was also decreased within RM compared with that within NP (P < 0.001). As a result, dNK cell-mediated anti-inflammation (P < 0.01) and anti-apoptosis (P < 0.05) for protection of LPS-treated DSCs was attenuated in patients suffering from RM. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: We cannot exclude the possibility that the differences in amounts of PEDF and its receptor in tissue from NP versus RM women could be caused by the miscarriage event in women with RM. Our experiments only involved human samples investigated in vitro. Experiments in animal models and human study cohorts are still needed to confirm these findings and further clarify the role of PEDF-PEDFR in NP and/or RM. WIDER IMPLICATIONS OF THE FINDINGS: To the best of our knowledge, this is the first study to demonstrate PEDF expression and function at the maternal-foetal interface in the first trimester, providing further evidence that PEDF exhibits functional diversity and has great potential for clinical application(s). The findings of selectively high expression of PEDF in normal dNK cells and the PEDF-mediated role of dNK cells during NP and RM help to further elucidate the immune mechanisms behind RM. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Basic Research Programme of China (2017YFC1001403 and 2015CB943300), Nature Science Foundation from National Nature Science Foundation of China (NSFC; 31970859, 81630036, 81501334, 91542116, 31570920, 81490744 and 31171437), the Innovation-oriented Science and Technology Grant from NHC Key Laboratory of Reproduction Regulation (CX2017-2), the Programme of Shanghai Academic/Technology Research Leader (17XD1400900) and the Key Project of Shanghai Basic Research from Shanghai Municipal Science and Technology Commission (STCSM; 12JC1401600). None of the authors has any conflict of interest to declare.

SET1A-Mediated Mono-Methylation at K342 Regulates YAP Activation by Blocking Its Nuclear Export and Promotes Tumorigenesis.

YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well-studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis. Clinically, YAP K342 methylation is reversely correlated with cancer survival. Collectively, our study identifies SET1A-mediated mono-methylation at K342 as an essential regulatory mechanism for regulating YAP activity and tumorigenesis.

Enhanced hydrogen adsorption on Li-coated B12C6N6.

The hydrogen storage property of Li-coated B12C6N6 is investigated by density functional theory calculations. B12C6N6 is an electron deficient fullerene. Li atoms can be strongly bound to this cage by donating their valance electrons to the virtual 2p orbitals of carbon in the cluster. The binding energy (-2.90 eV) is much larger than the cohesive energy (1.63 eV) of bulk Li, and it prevents the Li atoms from aggregation. The coated Li atoms have large positive charges and the adsorbed hydrogen molecules can be moderately polarized by the Li+ ions. The computation shows that each Li atom coated on B12C6N6 can hold 2-3 H2 molecules with adsorption energies in the range of 0.21-0.24 eV/H2. The B12C6N6Li8 can adsorb 16 H2 and achieve a gravimetric hydrogen density of 8.63 wt. %. The present results indicate that alkali-metal atoms coated on electron deficient fullerenes can serve as hydrogen storage materials that can operate at ambient temperatures with high recycling storage capacity.

Human neutrophil elastase induces MUC5AC overexpression in chronic rhinosinusitis through tumour necrosis factor-α converting enzyme.

Conclusion The HNE-TACE signalling pathway has an important role in the process of MUC5AC overexpression in chronic rhinosinusitis (CRS). Objectives To provide evidence of HNE-induced MUC5AC overexpression in CRS via TACE. Method HE and PAS staining were used to assess the pathological changes in sinus mucosa samples from CRS or normal control. HNE, TACE, and MUC5AC expression in the sinonasal mucosa was determined using immunohistochemistry (IHC) and real-time polymerase chain reaction (qRT-PCR). In addition, the MUC5AC and TACE expression was determined in a primary culture of human nasal mucosa epithelial cells in vitro. Results On HE staining, the main pathological feature in the sinus mucosa of CRS patients was hyperplasia of goblet cells, inflammatory cells, and submucosal glands. Mucosa from the two experimental groups also showed strong expression on PAS staining. IHC and qRT-PCR demonstrated that HNE, TACE, and MUC5AC expression was significantly higher in the CRS patients compared with control samples (p < 0.05). MUC5AC mRNA expression was higher in cells stimulated by HNE than in untreated cells (p < 0.05). MUC5AC mRNA expression was significantly reduced in cells pre-treated with the TACE inhibitor TAPI-1 prior to HNE stimulation, compared with untreated and HNE-stimulated cells (p < 0.01).

H3K4 Methyltransferase Set1a Is A Key Oct4 Coactivator Essential for Generation of Oct4 Positive Inner Cell Mass.

Limited core transcription factors and transcriptional cofactors have been shown to govern embryonic stem cell (ESC) transcriptional circuitry and pluripotency, but the molecular interactions between the core transcription factors and cofactors remains ill defined. Here, we analyzed the protein-protein interactions between Oct4, Sox2, Klf4, and Myc (abbreviated as OSKM) and a large panel of cofactors. The data reveal both specific and common interactions between OSKM and cofactors. We found that among the SET1/MLL family H3K4 methyltransferases, Set1a specifically interacts with Oct4 and this interaction is independent of Wdr5. Set1a is recruited to and required for H3K4 methylation at the Oct4 target gene promoters and transcriptional activation of Oct4 target genes in ESCs, and consistently Set1a is required for ESC maintenance and induced pluripotent stem cell generation. Gene expression profiling and chromatin immunoprecipitation-seq analyses demonstrate the broad involvement of Set1a in Oct4 transcription circuitry and strong enrichment at TSS sites. Gene knockout study demonstrates that Set1a is not only required for mouse early embryonic development but also for the generation of Oct4-positive inner cell mass. Together our study provides valuable information on the molecular interactions between OSKM and cofactors and molecular mechanisms for the functional importance of Set1a in ESCs and early development.

[Expression and relationship of pendrin and MUC5AC in patients with chronic rhinosinusitis].

OBJECTIVE: To explore the expression of pendrin in sinonasal mucosal tissue of patients with chronic rhinosinusitis (CRS) and examine its relationship with mucin5AC (MUC5AC). METHODS: Thirty mucosal tissue (located on anterior wall of maxillary sinus ostium and close to uncinate process) of patients with CRS with or without nasal polyps and 10 normal sinonasal mucosal tissue located at the same sites as CRS were collected. Histological changes of sinonasal mucosa were examined by hematoxylin and eosin (HE) staining. The expression of total mucins was evaluated by periodic acid Schiff staining (PAS). And the expressions of pendrin and MUC5AC in sinonasal mucosa were determined by immunohistochemistry (IHC), quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. RESULTS: The tissue samples demonstrated mucosal thickening, goblet cell hyperplasia and metaplasia, epithelial cilia partial deletion, glandular hyperplasia and a dense infiltration of inflammatory cells in CRS with or without nasal polyps. IHC revealed that positive pendrin was expressed dominantly at apical membrane of epithelial cells and sparsely in submucosal glandular cells, there was a positive expression rate of CRS with nasal polyps and CRS without nasal polyps; MUC5AC was expressed abundantly in goblet cells and pseudostratified ciliated columnar epithelium cells and weakly in submucosal glandular cells in CRS. There were significant increases in positive expression rate of total mucins production, pendrin and MUC5AC in patients of CRS with nasal polyps or without nasal polyps than those in control (86.7% and 80.0% vs 20.0%, 73.3% and 70.0% vs 10.0%, 83.3% and 76.7% vs 20.0%, all P<0.05); the relative expression levels of mRNA and protein expression of pendrin were significantly greater in patients of CRS with or without nasal polyps than those in controls (1.685±0.111 and 1.537±0.262 vs 1.012±0.167, 2.066±0.188 and 1.996±0.153 vs 1.000±0.169, all P<0.05). The relative expression levels of mRNA expression of MUC5AC were significantly greater in patients of CRS with or without nasal polyps than in controls (1.861±0.718 and 1.562±0.428 vs 1.004±0.094, P<0.05). And the expression level of pendrin mRNA was positively correlated with that of MUC5AC mRNA in patients with CRS (r=0.670, P=0.006 and r=0.713, P=0.003). CONCLUSIONS: An up-regulation of pendrin is correlated with an over-expression of MUC5AC in patients with CRS. And pendrin is an important cause of mucus hypersecretion in CRS.

[A case of diagnosing and treating the remaining foreign body in nasal sinus and cranium via orbit].

This paper mainly reports a case with the foreign body staying in nasal sinus and cranium via orbit. CT manifests the foreign body staying in ethmoid sinus and entering the bottom of cranium. After completing the relevant inspection, the patient unerwent right eye exenteration, endoscopic sinus surgery with general anesthesia in emergency to take out the foreign body in nasal sinus, and Cerebrospinal fluid leak repair surgery . Then the patient recovers well, futhermore, the symptom of cerebrospinal fluid leakage doesn't appear after five months follow-up.

A methylation-phosphorylation switch determines Sox2 stability and function in ESC maintenance or differentiation.

Sox2 is a key factor for maintaining embryonic stem cell (ESS) pluripotency, but little is known about its posttranslational regulation. Here we present evidence that the precise level of Sox2 proteins in ESCs is regulated by a balanced methylation and phosphorylation switch. Set7 monomethylates Sox2 at K119, which inhibits Sox2 transcriptional activity and induces Sox2 ubiquitination and degradation. The E3 ligase WWP2 specifically interacts with K119-methylated Sox2 through its HECT domain to promote Sox2 ubiquitination. In contrast, AKT1 phosphorylates Sox2 at T118 and stabilizes Sox2 by antagonizing K119me by Set7 and vice versa. In mouse ESCs, AKT1 activity toward Sox2 is greater than that of Set7, leading to Sox2 stabilization and ESC maintenance. In early development, increased Set7 expression correlates with Sox2 downregulation and appropriate differentiation. Our study highlights the importance of a Sox2 methylation-phosphorylation switch in determining ESC fate.

[Tympanosclerosis etiology and treatment].

SUMMARY: Tympanosclerosis is the middle ear tissue hyalinization and calcification caused by chronic middle ear inflammation, which mainly results in conductive deafness with unobvious clinical symptom. Etiology is unclear. The treatment is given priority to surgical treatment at present, while long-term effect reported mostly poor. This article analyzed etiology and treatment of the tympanic cavity sclerosis.