Endoplasmic reticulum stress drives macrophages to produce IL-33 to favor Th2 polarization in the airways.

Interleukin (IL)-33 is a key driver of T helper 2 (Th2) cell polarization. Endoplasmic reticulum (ER) stress plays a role in the skewed T cell activation. The objective of this project is to elucidate the role of IL-33 derived from macrophages in inducing Th2 polarization in the airways. In this study, bronchoalveolar lavage fluids (BALF) were collected from patients with asthma and healthy control subjects. Macrophages were isolated from the BALF by flow cytometry cell sorting. An asthmatic mouse model was established using the ovalbumin/alum protocol. The results showed that increased IL33 gene activity and ER stress-related molecules in BALF-derived M2a macrophages was observed in asthmatic patients. Levels of IL33 gene activity in M2a cells were positively correlated with levels of asthma response in asthma patients. Sensitization exacerbated the ER stress in the airway macrophages, which increased the expression of IL-33 in macrophages of airway in sensitized mice. Conditional ablation of Il33 or Perk or Atf4 genes in macrophages prevented induction of airway allergy in mice. In conclusion, asthma airway macrophages express high levels of IL-33 and at high ER stress status. Inhibition of IL-33 or ER stress in macrophages can effectively alleviate experimental asthma.

Endoplasmic reticulum stress interferes with the development of type 1 regulating T cells.

BACKGROUND: A variety of stimuli can cause endoplasmic reticulum (ER) stress, which is a common cellular reaction. It is not yet clear how ER stress contributes to the pathogenesis of ulcerative colitis (UC). The deregulation of regulatory T cell (Treg) is associated with UC. The goal of this study is to shed light on how ER stress affects Treg's development. METHODS: CD4+ CD25- T cells were isolated from blood samples collected from UC patients and healthy control (HC) subjects. ER stress-associated molecule expression in CD4+ CD25- T cell was assessed by RNA sequencing and RT-qPCR. RESULTS: The presence of ER stress in peripheral CD4+ CD25- T cells was observed in patients with UC compared to HC subjects. The induction of ER stress in HC CD4+ CD25- T cells by polyclonal activation was made worse by the presence of 3-methyl-4-nitrophenol (MNP; a common environmental pollutant). Exposure to MNP in culture resulted in an increase in the expression of ring finger protein 20 (Rnf20) in CD4+ CD25- T cells. The synergistic effects of MNP and ER stress on the reduction of IL-10 levels in CD4+ CD25- T cells are mediated by Rnf20, which prevents the development of Tr1 cells. Inhibition of Rnf20 resulted in the development of Tr1 cells from CD4+ CD25- T cells in UC patients. CONCLUSIONS: The synergistic effects of ER stress and MNP interfere with the development of Tr1 cells. The development of Tr1 from CD4+ CD25- T cells in patients with UC is re-established by Rnf20 inhibition.

Structure/epitope analysis and IgE binding activities of three cyclophilin family proteins from Dermatophagoides pteronyssinus.

Cyclophilins (CyPs) are involved in basic cellular functions and a wide variety of pathophysiological processes. Many CyPs have been identified as the aetiological agent and influence on the immune system. In the present study, the physicochemical and immunologic characteristics of three proteins of CyPs family (CyPA, CyPB and CyPE) were analyzed. The results indicated that CyPE showed a closer evolutionary relationship with allergenic CyPA. The structure and antigenicity of CyPE was significantly similar with CyPA. B-cell epitopes of CyPE and CyPA were predicted via multiple immunoinformatics tools. Three consensus B-cell epitopes of CyPE and CyPAs were finally determined. To verify results of in silico analysis, three proteins of CyPs family (CyPA, CyPE and CyPB) were cloned and expressed from Dermatophagoides pteronyssinus. ELISA results indicated that the positive reaction rates of the three proteins to patient serum are CyPA (21.4%), CyPE (7.1%), and CyPB (0%), illustrating that the IgE activity was exhibited in CypA and CypE excluding CyPB. Structure and immunoinformatics analysis demonstrated that the RNA-binding motif of CyPE could reduce the immunogenicity of PPIase domain of CyPE. The reason that CyPB has no IgE activity might be the structure mutation of CyPB on B-cell epitopes.

5-HT modulates the properties of dendritic cells to interfere with the development of type 1 regulating T cells.

BACKGROUND: 5-hydroxytryptamine (5-HT, serotonin) is a major mediator in allergic reactions. The number of tolerogenic dendritic cell (tolDC) and regulatory T cell is reduced in allergic disorders. The mechanism is unclear. The objective of this study is to elucidate the role of 5-HT in interfering with tolDC generation and regulatory Type 1 T cell (Tr1 cell). METHODS: BALB/c mice were treated with 5-HT-containing nasal instillations. The frequency of tolDC and Tr1 cell was evaluated by flow cytometry. RESULTS: Following treatment with 5-HT nasal instillations for one week, the frequency of tolDC and Tr1 cell was significantly reduced in the respiratory tissues. Higher levels of SOS1 were detected in DCs isolated from the airway tissues of mice treated with 5-HT. A complex of SOS1 and c-Maf was detected in DCs in response to 5-HT stimulation. The expression of IL-10 was suppressed by the presence of 5-HT. The induction of Tr1 cell by DC was substantially compromised by 5-HT. CONCLUSIONS: 5-HT inhibits the expression of IL-10 in DCs. DCs primed with 5-HT lose the ability to induce Tr1 cells.

The transcription factor XBP1 in dendritic cells promotes the TH2 cell response in airway allergy.

Dendritic cells (DCs) that express T cell immunoglobulin domain molecule-4 (TIM4), a cell surface receptor for phosphatidylserine, induce T helper 2 (TH2) cell responses and allergic reactions. We elucidated the role of the transcription factor X-box-binding protein-1 (XBP1) in the induction of the TH2 cell response through its role in generating TIM4+ DCs. We found that XBP1 was required for TIM4 mRNA and protein expression in airway DCs in response to the cytokine interleukin-2 (IL-2) and that this pathway was required for TIM4 expression on DCs in response to the allergens PM2.5 and Derf1. The IL-2-XBP1-TIM4 axis in DCs contributed to Derf1/PM2.5-induced, aberrant TH2 cell responses in vivo. An interaction between the guanine nucleotide exchange factor Son of sevenless-1 (SOS1) and the GTPase RAS promoted XBP1 and TIM4 production in DCs. Targeting the XBP1-TIM4 pathway in DCs prevented or alleviated experimental airway allergy. Together, these data suggest that XBP1 is required for TH2 cell responses by inducing the development of TIM4+ DCs, which depends on the IL-2-XBP1-SOS1 axis. This signaling pathway provides potential therapeutic targets for the treatment of TH2 cell-dependent inflammation or allergic diseases.

Substance P promotes immunotherapy efficacy for airway allergy.

Background: Allergen-specific immunotherapy (AIT) has been employed in the treatment of allergic diseases for many years. However, the effectiveness of AIT requires improvement. Substance P (SP) can interact with immune cells, modulate immune cell activity, and regulate immune reaction. The purpose of this study is to use SP as an immune regulator to enhance the therapeutic efficacy of AIT. Methods: An established mouse model of the airway allergy disorder (AAD) was employed with ovalbumin as a specific antigen. The AAD response was evaluated through established procedures. AAD mice were treated with AIT employing SP as an immune regulator. Dendritic cells were isolated from the airway tissues by magnetic cell sorting, and were analyzed by RNA sequencing (RNAseq). Results: We observed that after sensitization with ovalbumin, mice exhibited AAD-like symptoms, serum specific IgE, and Th2 polarization. The presence of SP in the course of sensitization prevented the development of AAD. Treating mice with SP by nasal instillations induced IL-10, but not TGF-ß, in dendritic cells of the airway tissues. The most differentially expressed genes (DEG) in the dendritic cells were those related to the IL-10 expression, including Il10, Tac1r, and Mtor. The gene ontology analysis showed that these DEGs mainly mapped to the tachykinin-PI3K-AKT-mTOR pathway. The addition of SP substantially enhanced the therapeutic efficacy of AIT for AAD by inducing antigen specific type 1 regulatory T cells (Tr1 cells). Conclusion: Acting as an immune regulator, SP promotes the therapeutic efficacy for AAD by inducing antigen specific Tr1 cells in the airway tissues.

TAFA4-IL-10 axis potentiate immunotherapy for airway allergy by induction of specific regulatory T cells.

Allergen-specific immunotherapy (AIT) is the main treatment for allergic diseases. The therapeutic efficacy of AIT has to be improved. Neuropeptides, such as TAFA4, have immune-regulating features. The objective of this study is to promote the efficacy of AIT in experimental allergic rhinitis (AR) by the concurrent use of TAFA chemokine as a family member 4 (TAFA4). In this study, an AR mouse model was developed using ovalbumin (OVA) as the specific antigen. The AR response was assessed in mice after treatment with AIT or/and TAFA4. We found that exposure to TAFA4 activated dendritic cells (DCs) in the airway tissues. Activation of DC by TAFA4 resulted in the expression of IL-10. TAFA4 also promoted the activities of c-Maf inducing protein. The FPR1-MyD88-AKT signal pathway was associated with the TAFA4-induced Il10 expression in the DCs. Co-administration of AIT/TAFA4 attenuated the AR response in mice by inducing antigen-specific Tr1 cells. In conclusion, TAFA4 induces the expression of IL-10 in DCs. Acting as an adjuvant, TAFA4 significantly improves AIT's therapeutic efficacy against AR by inducing antigen-specific Tr1 cells.

5-HT is associated with the dysfunction of regulating T cells in patients with allergic rhinitis.

The dysfunction of regulating T lymphocytes (Treg) is associated with the pathogenesis of many diseases. 5-hydroxytryptamine (5-HT) is capable of interacting with immune cells. The objective of the present study is to shed light on the role of 5-HT in regulating Treg activities. Blood samples were collected from patients with perennial allergic rhinitis (AR). Tregs were isolated from blood samples by magnetic cell sorting. The levels of 5-HT and other cytokines were determined by enzyme-linked immunosorbent assay. The results showed that serum 5-HT levels in patients with AR were higher than in healthy control (HC) subjects. A positive correlation was identified in the data between 5-HT concentrations and AR-related cytokine concentrations in the serum. A negative correlation was found between serum levels of 5-HT and the peripheral frequency of Treg. Exposure to 5-HT enhanced the expression of IL-6 and IL-21 in dendritic cells (DC). Co-culture of 5-HT-primed DCs with Tregs led to the conversion of Th17 cells. STAT3 blockade efficiently abolished the 5-HT-associated conversion of Th17 cells from Tregs. In summary, patients with AR exhibited higher serum concentrations of 5-HT. 5-HT-primed DCs could convert Tregs to Th17 cells.

Semaphorin-3 Promotes Specific Immunotherapy Effects on Experimental Food Allergy.

Sustaining higher frequency of mast cells in the allergic lesion site has been recognized. Factors causing high numbers of mast cells in the local tissues are not fully understood yet. RAS signaling plays a role in sustaining certain cell activities. This study is aimed at elucidating the role of RAS activation in the apoptosis resistance induction in mast cells and at employing semaphorin 3A to regulate RAS activities in sensitized mast cells and alleviating the allergic response in the intestine. A food allergy (FA) mouse model was developed. Mast cells were isolated from FA mouse intestinal tissues by flow cytometry. Mast cell apoptosis was assessed by staining with annexin V and propidium iodide. We found that aberrantly higher p21-activated kinase-1 (Pak1) expression in FA mast cells was associated with mast cell aggregation in the intestine. Sensitization increased Pak1 expression and apoptosis resistance in intestinal mast cells. RAS and Pak1 mutually potentiated each other in sensitized mast cells. Semaphorin 3A (sema3A) suppressed the Pak1 expression and RAS activation in mast cells. sema3A restored the apoptosis sensitivity in sensitized mast cells. Administration of sema3A potentiated allergen-specific immunotherapy in experimental FA. In conclusion, mast cells of FA mice showed higher Pak1 expression and high RAS activation status that contributed to apoptosis resistance in mast cells. Administration of sema3A restored the sensitivity to apoptosis inducers and promoted the therapeutic effects of specific immunotherapy on experimental FA.

T cell activator-carrying extracellular vesicles induce antigen-specific regulatory T cells.

The mechanism of antigen-specific regulatory T cell (Treg ) induction is not yet fully understood. Curcumin has an immune regulatory function. This study aims to induce antigen-specific Tregs by employing extracellular vesicles (EVs) that carry two types of T cell activators. Two types of T cell activators, ovalbumin (OVA)/major histocompatibility complex-II (MHC-II) and tetramethylcurcumin (FLLL31) (a curcumin analog) were carried by dendritic cell-derived extracellular vesicles, designated OFexo. A murine model of allergic rhinitis (AR) was developed with OVA as the specific antigen. AR mice were treated with a nasal instillation containing OFexo. We observed that OFexo recognized antigen-specific T cell receptors (TCR) on CD4+ T cells and enhanced Il10 gene transcription in CD4+ T cells. Administration of the OFexo-containing nasal instillation induced antigen-specific type 1 Tregs (Tr1 cells) in the mouse airway tissues. OFexo-induced Tr1 cells showed immune suppressive functions on CD4+ T cell proliferation. Administration of OFexo efficiently alleviated experimental AR in mice. In conclusion, OFexo can induce antigen-specific Tr1 cells that can efficiently alleviate experimental AR. The results suggest that OFexo has the translational potential to be employed for the treatment of AR or other allergic disorders.

Benzo(a)pyrene Enhanced Dermatophagoides Group 1 (Der f 1)-Induced TGFß1 Signaling Activation Through the Aryl Hydrocarbon Receptor-RhoA Axis in Asthma.

We have previously demonstrated that benzo(a)pyrene (BaP) co-exposure with dermatophagoides group 1 allergen (Der f 1) can potentiate Der f 1-induced airway inflammation. The underlying mechanism, however, remains undetermined. Here we investigated the molecular mechanisms underlying the potentiation of BaP exposure on Der f 1-induced airway inflammation in asthma. We found that BaP co-exposure potentiated Der f 1-induced TGFß1 secretion and signaling activation in human bronchial epithelial cells (HBECs) and the airways of asthma mouse model. Moreover, BaP exposure alone or co-exposure with Der f 1-induced aryl hydrocarbon receptor (AhR) activity was determined by using an AhR-dioxin-responsive element reporter plasmid. The BaP and Der f 1 co-exposure-induced TGFß1 expression and signaling activation were attenuated by either AhR antagonist CH223191 or AhR knockdown in HBECs. Furthermore, AhR knockdown led to the reduction of BaP and Der f 1 co-exposure-induced active RhoA. Inhibition of RhoA signaling with fasudil, a RhoA/ROCK inhibitor, suppressed BaP and Der f 1 co-exposure-induced TGFß1 expression and signaling activation. This was further confirmed in HBECs expressing constitutively active RhoA (RhoA-L63) or dominant-negative RhoA (RhoA-N19). Luciferase reporter assays showed prominently increased promoter activities for the AhR binding sites in the promoter region of RhoA. Inhibition of RhoA suppressed BaP and Der f 1 co-exposure-induced airway hyper-responsiveness, Th2-associated airway inflammation, and TGFß1 signaling activation in asthma. Our studies reveal a previously unidentified functional axis of AhR-RhoA in regulating TGFß1 expression and signaling activation, representing a potential therapeutic target for allergic asthma.

Modulating oxidative stress counteracts specific antigen-induced regulatory T-cell apoptosis in mice.

Treg are known to have a central role in orchestrating immune responses, but less is known about the destiny of Treg after being activated by specific Ags. This study aimed to investigate the role of superoxide dismutase, an active molecule in the regulation of oxidative stress in the body, in the prevention of Treg apoptosis induced by specific Ags. Ag-specific Tregs were isolated from the DO11.10 mouse intestine. A food allergy mouse model was developed with ovalbumin as the specific Ag and here, we observed that exposure to specific Ag induced Treg apoptosis through converting the precursor of TGF-ß to its mature form inside the Tregs. Oxidative stress was induced in Tregs upon exposure to specific Ags, in which Smad3 bound the latency-associated peptide to induce its degradation, converting the TGF-ß precursor to its mature form, TGF-ß. Suppressing oxidative stress in Tregs alleviated the specific Ag-induced Treg apoptosis in in vitro experiments and suppressed experimental food allergy by preventing the specific Ag-induced Treg apoptosis in the intestine. In conclusion, exposure to specific Ags induces Treg apoptosis and it can be prevented by upregulating superoxide dismutase or suppressing reactive oxidative species in Tregs.

Dust-mite-derived protein disulfide isomerase suppresses airway allergy by inducing tolerogenic dendritic cells.

House dust mites (HDMs) are a potent allergen source that are commonly found in human living environments. While HDMs are known to induce allergic diseases in humans, such as asthma, its other biological activities related to human health are less understood. Our laboratory recently purified the HDM protein PDI (protein disulfide isomerase). In this study, we assess the role of PDI in contributing to immune regulation. Using mass spectrometry, we analyzed the complexes of DEC205 and HDM extracts, and the role of PDI in the induction of tolerogenic dendritic cells (DCs) was assessed in human cell culture experiments and verified in a murine model. We found that more than 20 HDM-derived proteins, including PDI, bound to DCs by forming complexes with DEC205. Additionally, DEC205-mediated the endocytosis of PDI. HDM-derived PDI (HDM-PDI) promoted Foxp3 expression in DCs. HDM-PDI-primed DCs also showed tolerogenic properties that induced regulatory T cell development, indicating that the primed DCs were tolerogenic DCs. Our results suggested that the PDI/DEC205/TIEG1/Foxp3 signal pathway activation was involved in the HDM-PDI-induced Foxp3 expression in DCs. Finally, we found that HDM-PDI competitively counteracted the Th2 cytokines to restore DC's tolerogenicity, and administration of HDM-PDI could suppress experimental asthma. In conclusion, our data suggest that HDM-PDI contributes to immune regulation by inducing tolerogenic DC development. Administration of HDM-PDI can alleviate experimental asthma. These findings demonstrate that HDM-PDI has translational potential to be used in the treatment of immune disorders such as asthma.

Chimeric antigen-guiding extracellular vesicles eliminate antigen-specific Th2 cells in subjects with food allergy.

BACKGROUND: Antigen (Ag)-specific T helper (Th)2 cells play a central role in food allergy (FA) pathogenesis. Methods can be used to eliminate Ag-specific Th2 cells that are currently lacking. This study aims to eliminate the Ag-specific Th2 cells with a novel nanoparticle, the mEV (modified extracellular vesicles, that carry a chimeric antigen peptide, MHC II and caspase 3) in a murine FA model. METHODS: mEVs were generated by exposing dendritic cells (DC) to ovalbumin (OVA, a specific Ag) and recombinant caspase 3 (Casp3) in the culture overnight. Exosomes were purified from culture supernatant by the magnetic antibody approach. A murine FA model was developed with OVA as the specific Ag. RESULTS: Purified mEVs had the molecular markers of extracellular vesicle, CD81, CD63, and CD9, cleaved Casp3 and MHC II/OVA complexes. mEVs specifically bound to the surface of Ag-specific CD4+ T cells, induced Ag-specific CD4+ T cell apoptosis both in vitro and in vivo as well as increased regulatory T cells in the intestinal tissues. Administration of mEV efficiently suppressed experimental FA. CONCLUSIONS: mEVs carry Ag/MHC II complexes and Casp3, that can induce Ag-specific Th2 cell apoptosis. Administration of mEV can efficiently suppress experimental FA. The results suggest that the mEVs have the translational potential to be used in the treatment of FA and other allergic diseases.

Epithelial cell-derived CD83 restores immune tolerance in the airway mucosa by inducing regulatory T-cell differentiation.

The mechanism of generation of regulatory T cells (Treg) remains incompletely understood. Recent studies show that CD83 has immune regulatory functions. This study aims to investigate the role of epithelial cell-derived CD83 in the restoration of immune tolerance in the airway mucosa by inducing the Treg differentiation. In this study, CD83 and ovalbumin (OVA)-carrying exosomes were generated from airway epithelial cells. An airway allergy mouse model was developed to test the role of CD83/OVA-carrying exosomes in the suppression of airway allergy by inducing Treg generation. We observed that mouse airway epithelial cells expressed CD83 that could be up-regulated by CD40 ligand. The CD83 deficiency in epithelial cells retarded the Treg generation in the airway mucosa. CD83 up-regulated transforming growth factor-ß-inducible early gene 1 expression in CD4+ T cells to promote Foxp3 expression. Exposure of primed CD4+ T cells to CD83/OVA-carrying exosomes promoted antigen-specific Treg generation. Administration of CD83/OVA-carrying exosomes inhibited experimental airway allergic response. In summary, airway epithelial cells express CD83 that is required in the Treg differentiation in the airway mucosa. Administration of CD83/OVA-carrying exosomes can inhibit airway allergy that has the translation potential in the treatment of airway allergic disorders.

Integrin αvß6 cooperates with resiquimod to restore antigen-specific immune tolerance in airway allergy.

BACKGROUND: Integrin αvß6 can convert the transforming growth factor (TGF)-ß precursor to the mature form. Resiquimod (R848) can generate TGF-ß-producing regulatory T cells (Treg). Thus, to concurrent administration of specific antigen and R848 may generate antigen-specific Tregs, that is expected to restore immune tolerance in subjects with airway allergic diseases (AAD). METHODS: A bio-nanoparticle, designated Rexo, containing an antigen/MHC II complex and R848, was naturally assembled in dendritic cells, that was released as an exosome. An AAD mouse model was developed used to test the effects of Rexo on restoring the immune tolerance in the airways. RESULTS: Exposure to R848 failed to induce Tregs in the ß6-deficient mouse airway tissues, that were successfully induced in wild type mice. The results were validated inin vitro experiments. R848 activated the TLR7/MyD88/p38 signal pathway to increase the αvß6 levels in CD4+ T cells, the αvß6 then converted the TGF-ß precursor to its mature form, and thus, induced Treg generation. Administration of Rexo restored the antigen-specific immune tolerance in the airways manifesting efficiently suppressing experimental AAD by inducing antigen-specific Tregs in the airways and inhibiting antigen-specific Th2 response. CONCLUSIONS: Rexos can inhibit experimental AAD via inducing antigen-specific Tregs to restore immune tolerance in the airway tissues, suggesting that Rexos have the translational potential to be used in the treatment of AAD.

FcγRI plays a critical role in patients with ulcerative colitis relapse.

Ulcerative colitis (UC) is a disease that frequently relapses and affects more than 0.1% general population; the underlying mechanism is poorly understood. Published data show that polymorphonuclear neutrophils (PMN) contribute to the pathogenesis of UC. This study aims to identify antigen (Ag)-specific PMNs and investigate their role in UC relapse. In this study, the correlation between PMN activities and UC relapse was assessed in a group of UC patients. A UC mouse model was developed to expand the findings of UC patient study. The results showed that a positive correlation was detected between the high PMN activities and the food Ag-specific IgG amounts in colon biopsies of UC patients. UC patient-derived Ag-specific PMNs could be activated upon exposure to food specific Ag. The Ag/FcγRI complexes were detected on the surface of PMNs in UC patients. Re-exposure of sensitized PMNs to specific Ag triggered PMN activation and induced UC-like inflammation in the mouse colon. We conclude that FcγRI plays a critical role in UC relapse. Inhibition of FcγRI can efficiently inhibits experimental UC.

Novel method for evaluating the upper airway resistance using the ratio of neural respiratory drive to flow in OSA.

STUDY OBJECTIVES: Sleep is associated with a reduction in ventilation and an increase in upper airway resistance (UAR) in patients with obstructive sleep apnea (OSA). However, there is no consensus on the standard for assessment of UAR and therefore it is important to develop a method to reliably assess UAR in patients with OSA. The purpose of the present study is to determine whether the ratio of neural respiratory drive (NRD) to flow can be used to assess changes in UAR in OSA during sleep. METHODS: A total of 24 patients (21 men) with OSA and 10 normal subjects (6 males) were studied. The UAR was assessed by the ratio of NRD to flow, which measured by esophageal pressure (Poes), diaphragm electromyography (EMGdi) and superficial diaphragm electromyography (SEMGdi) in various stages including wakefulness, N2 sleep, N2 sleep with snoring, hypopneas, the in the "preapnea" states in OSA versus wakefulness, sleeponset, N2 sleep, N3 sleep in normal subjects. All subjects underwent overnight full polysomnography using standard techniques. RESULTS: Our study indicate that UAR was progressively higher from wakefulness to N2 sleep, N2 sleep with snoring, hypopneas, and the in the "preapnea" states in patients with OSA and had obvious difference in statistical significance (p < 0.05). We found NRD in hypopneas was lower than that in N2-snoring while the UAR in hypopneas was higher than that in N2-snoring.The UAR and NRD increased consecutively from wakefulness to N2 sleep and N3 sleep in normal subjects while the ventilation was reduced consecutively in NREM sleep. CONCLUSIONS: It is feasible to use the ratio of neural respiratory drive to flow to assess UAR in patients with OSA during sleep.

Specific antigen-guiding exosomes inhibit food allergies by inducing regulatory T cells.

The therapies for food allergy (FA) need to be improved. The generation of inducible regulatory T cells (Tregs) can support immune tolerance in the body. This study aims to suppress experimental FA by inducing Tregs through the employment of modified exosomes (mExosomes). In this study, mExosomes were prepared by incubating dendritic cells with interleukin (IL)-2 and ovalbumin (OVA, used as a specific antigen) in the culture. Exosomes were purified from culture supernatant and used as the mExosomes. A murine FA model was developed to test the effects of mExosomes on the generation of Tregs in the mouse intestinal tissues and inhibiting FA. The results showed that mExosomes, which carried IL-2 and a complex of OVA peptide-major histocompatibility complex class II on the surface of exosomes, bound to OVA-specific CD4+ T cells and induced CD4+ T cells to differentiate into Tregs. In the FA mouse intestinal tissues, we found low IL-2 levels that were positively correlated with the number of Tregs. Depletion of IL-2 in mice prevented the generation of Tregs. The levels of peroxisome proliferator-activated receptor-γ were increased in the FA intestinal tissues with inhibited IL-2 production. Administration of mExosomes induced Tregs in the intestinal tissues and efficiently suppressed FA in mice. We conclude that the mExosomes can suppress FA in mice through inducing Tregs. The data suggest that the mExosomes have translational potential in the treatment of FA and other allergic disorders.

LingZhi oligopeptides amino acid sequence analysis and anticancer potency evaluation.

LingZhi (Ganoderma lucidum) has been used as a therapeutic agent for decades, but the antitumor potency of LingZhi oligopeptides (LZOs) was not well explored. In current study, ten novel LZO amino acid sequences were identified, and anticancer potency was evaluated. We found that LZO-3 [EGHGF] significantly triggered A549 cell apoptosis via mitochondrial dysregulation, as evidenced by caspases activation, mitochondrial membrane potential collapse, Bcl-2/Bax ratio alteration, and cytochrome c release. Further, the down-regulation of Trx/TrxR reductase and the improvement of the MDM2/p53 state also contributed to the LZO-3-induced cell apoptosis. Notably, our findings provide evidence for the novel potency of LZOs, which could be developed as promising chemotherapeutic agents against lung cancer.