Oligodeoxynucleotides containing CpG motifs (CpG-ODN) restores immune regulatory functions of airway macrophages of patients with asthma.

Allergic asthma is characterized by the polarization of Th2 cells and impaired immune regulation. Macrophages occupy the largest proportion of airway immune cells. This study aims to discover the mechanism that hinders the immune regulatory functions of airway macrophages. In this study, macrophages were isolated from cells in bronchoalveolar lavage fluids (BALF) collected from asthma patients and normal control (NC) subjects. The results indicated that macrophages occupied the largest portion of the cellular components in BALF. The frequency of IL-10+ macrophage was significantly lower in asthma patients than in NC subjects. The expression of IL-10 in macrophages of BALF was associated with the levels of asthma-related parameters. The immune-suppressive functions of BALF M0 cells were defective in asthma patients. The inducibility of IL-10 expression was impaired in BALF macrophages of asthma patients, which could be restored by exposing to CpG. In conclusion, the induction of IL-10 in macrophages of BALF in asthma patients was impaired, and it could be restored by exposure to CpG.

Pseudoamaolide P, a 1,2:3,4:9,10:9,19-tetraseco-cycloartane triterpene spiroketal lactone from seeds of Pseudolarix amabilis.

A 1,2:3,4:9,10:9,19-tetraseco-cycloartane triterpene spiroketal lactone, pseudoamaolide P (1), two new labdane-type diterpenoids, pseudoamains A and B (2-3), and four known cembrane-type diterpenoids (4-7) were isolated from the seeds of Pseudolarix amabilis. The structures of these compounds were elucidated by spectroscopic analyses, including HRESIMS, 1D-, and 2D-NMR. The anti-inflammatory activities of the compounds were evaluated by suppressing the transcription of the NF-κB-dependent reporter gene in LPS-induced 293 T/NF-κB-luc cells. All compounds do not show potent activity.

Recent developments in the immunopathology of COVID-19.

There has been an important change in the clinical characteristics and immune profile of Coronavirus disease 2019 (COVID-19) patients during the pandemic thanks to the extensive vaccination programs. Here, we highlight recent studies on COVID-19, from the clinical and immunological characteristics to the protective and risk factors for severity and mortality of COVID-19. The efficacy of the COVID-19 vaccines and potential allergic reactions after administration are also discussed. The occurrence of new variants of concerns such as Omicron BA.2, BA.4, and BA.5 and the global administration of COVID-19 vaccines have changed the clinical scenario of COVID-19. Multisystem inflammatory syndrome in children (MIS-C) may cause severe and heterogeneous disease but with a lower mortality rate. Perturbations in immunity of T cells, B cells, and mast cells, as well as autoantibodies and metabolic reprogramming may contribute to the long-term symptoms of COVID-19. There is conflicting evidence about whether atopic diseases, such as allergic asthma and rhinitis, are associated with a lower susceptibility and better outcomes of COVID-19. At the beginning of pandemic, the European Academy of Allergy and Clinical Immunology (EAACI) developed guidelines that provided timely information for the management of allergic diseases and preventive measures to reduce transmission in the allergic clinics. The global distribution of COVID-19 vaccines and emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with reduced pathogenic potential dramatically decreased the morbidity, severity, and mortality of COVID-19. Nevertheless, breakthrough infection remains a challenge for disease control. Hypersensitivity reactions (HSR) to COVID-19 vaccines are low compared to other vaccines, and these were addressed in EAACI statements that provided indications for the management of allergic reactions, including anaphylaxis to COVID-19 vaccines. We have gained a depth knowledge and experience in the over 2 years since the start of the pandemic, and yet a full eradication of SARS-CoV-2 is not on the horizon. Novel strategies are warranted to prevent severe disease in high-risk groups, the development of MIS-C and long COVID-19.

Impacts of defects on the mechanical and thermal properties of SiC and GeC monolayers.

Defect engineering has been considered as an effective way for controlling the heat transport properties of two-dimensional materials. In this work, the effects of point vacancies and grain boundaries on the mechanical and thermal performances of SiC and GeC monolayers are investigated systematically by molecular dynamics calculations. The failure strength in SiC and GeC is decreased by introducing vacancies at room temperature, and the stress-strain relationship can be tuned significantly by different kinds of vacancies. When the grain boundary of 21.78° is applied, the maximal fracture strengths can be as large as 27.56% for SiC and 23.56% for GeC. Also, the thermal properties of the two monolayers show a remarkable dependence on the vacancies and grain boundaries. The high vacancy density in SiC and GeC can induce disordered heat flow and the C/Ge point defect is crucial for thermal conductivity regulation for the Si/GeC monolayer. More importantly, the SiC and GeC monolayers with a grain boundary of 5.09° show excellent interfacial thermal conductance. Our findings are of great importance in understanding SiC and GeC monolayers and seeking their potential applications.

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.

Pseudoamaolides A-O, anti-inflammatory triterpene spiroketal lactones from seeds of Pseudolarix amabilis.

Fifteen new triterpenoids (1-15), along with twenty known ones (16-35), were isolated from Pseudolarix amabilis. The triterpenoid structures include multiple skeleton types, such as 2,3-seco-cycloartane, 3,4-seco-cycloartane, 3,4:9,10-diseco-cycloartane, and 3,4:8,9:9,10-triseco-cycloartane, as elucidated by extensive spectroscopy (1D NMR, 2D NMR, HRESIMS, and IR) and single-crystal X-ray diffraction. The anti-inflammatory activities of compounds 1-35 were evaluated. Compounds 3, 11, 16, 24, 25, and 26 suppressed the transcription of the NF-κB-dependent reporter gene in LPS-induced 293T/NF-κB-Luc cells with IC50 values of 0.12, 0.10, 0.30, 0.09, 0.49, and 0.35 µM, respectively. In addition, compound 16 showed anti-inflammatory activity against xylene-induced ear swelling in vivo with an inhibition rate of 44.7 % (30 mg/kg). Compound 16 significantly improved the disease activity index (DAI) of ulcerative colitis at a dose of 400 mg/kg in a dextran sodium sulfate (DSS)-induced mouse model of experimental ulcerative colitis (P < 0.01).

CARsomes inhibit airway allergic inflammation in mice by inducing antigen-specific Th2 cell apoptosis.

BACKGROUND: Skewed T helper (Th)2 response plays a crucial role in the pathogenesis of allergic diseases. The therapeutic efficacy for allergic diseases is unsatisfactory currently. This study aims to regulate the skewed Th2 response with CARsomes. METHODS: The CARsome consisted of an epitope of Dermatophagoides farina-1 (Derf1), a segment of the anti-DEC205 antibody, the scFv, and an open reading frame of perforin. This fusion protein binds to DEC205 molecule on the surface of exosomes derived from dendritic cells (DC). The effects of CARsome on inducing antigen (Ag)-specific Th2 cell apoptosis were assessed both in vivo and in vitro. RESULTS: Exposure to CARsomes in the culture induced Ag-specific Th2 cell apoptosis. Injection of CARsomes through the vein puncture also induced Ag-specific Th2 cell apoptosis in the lungs of sensitized mice. CARsomes could induce Ag-specific regulatory T cells. Administration of CARsomes efficiently inhibited experimental allergic airway inflammation. CONCLUSIONS: The CARsomes can inhibit allergic airway inflammation by inducing Ag-specific Th2 cell apoptosis and induce Ag-specific regulatory T cells. The data suggest that CARsomes have the translational potential to be used to treat allergic airway inflammation.

A new ascorbic acid derivative and two new terpenoids from the leaves and twigs of Rhododendron decorum.

The phytochemical study of the ethanol extract of the leaves and twigs of Rhododendron decorum afforded a new ascorbic acid derivative (1), a new ionone analogue (2), a new ursane-type triterpenoid glucoside (3), and four known compounds (4-7). The structures were elucidated by spectroscopic analyses, including HRESIMS, 1D, and 2D NMR. The anti-neuroinflammatory activities of the compounds were evaluated by measuring inhibitory effects of LPS-induced NO production in BV2 cells.

Antinociceptive Diterpenoids from the Leaves and Twigs of Rhododendron decorum.

Three new leucothane-type (1-3), two new micrathane-type (4, 5), eight new grayanane-type diterpenoids (6-13), and four known compounds were obtained from the ethanol extract of the leaves and twigs of Rhododendron decorum. The structures were determined based on NMR spectra, quantum chemical calculations, and X-ray crystallography. The antinociceptive activities of compounds 1, 3, 4, 6, 8, 10-13, and 15-17 were evaluated via the acetic acid-induced writhing test. Compounds 1, 8, 11-13, and 15 exhibited significant antinociceptive activities. In particular, 12 and 15 were found to be effective at doses of 0.8 and 0.08 mg/kg, respectively.

Thrombospondin-1 (TSP1)-producing B cells restore antigen (Ag)-specific immune tolerance in an allergic environment.

Restoration of the antigen (Ag)-specific immune tolerance in an allergic environment is refractory. B cells are involved in immune regulation. Whether B cells facilitate the generation of Ag-specific immune tolerance in an allergic environment requires further investigation. This paper aims to elucidate the mechanism by which B cells restore the Ag-specific immune tolerance in an allergic environment. In this study, a B cell-deficient mouse model was created by injecting an anti-CD20 antibody. The frequency of tolerogenic dendritic cell (TolDC) was assessed by flow cytometry. The levels of cytokines were determined by enzyme-linked immunosorbent assay. The expression of thrombospondin-1 (TSP1) was assessed by quantitative real-time RT-PCR, Western blotting, and methylation-specific PCR. The results showed that B cells were required in the generation of the TGF-ß-producing TolDCs in mice. B cell-derived TSP1 converted the latent TGF-ß to the active TGF-ß in DCs, which generated TGF-ß-producing TolDCs. Exposure to IL-13 inhibited the expression of TSP1 in B cells by enhancing the TSP1 gene DNA methylation. Treating food allergy mice with Ag-specific immunotherapy and IL-13 antagonists restored the generation of TolDCs and enhanced the effect of specific immunotherapy. In conclusion, B cells play a critical role in the restoration of specific immune tolerance in an allergic environment. Blocking IL-13 in an allergic environment facilitated the generation of TolDCs and enhanced the therapeutic effect of immunotherapy.

[Preparation of TBSI with NS-Acetic Anhydride Method and Its Spectral Analysis].

In the study, N-t-butyl-2-benzothiazole sulfenimide (TBSI) was prepared by NS-acetic anhydride method with acetic anhydride as solvent. It was detected with FTIR, XRD, UV-Vis, TG-DTA. Micro-structure and essence disciplinarian of them were disclosed. Chemical bond types into TBSI molecule were revealed with FTIR. TBSI phase composition and structure were revealed with crystallographic data from XRD detecting such as cell parameters and crystal face index. The phase composition and qualitative identification of TBSI structure were completed. The absorption peaks were detected by UV-vis at 228.3, 281.3 and 298.3 nm, respectively caused by n→σ*, π→π*, n→π* electron transition. It could provide basic data with the enterprise of ZBPD product quality inspection. Two kinds of information were detected with TG-DTA as quality change and thermal effect. There were three absorption peaks of 46.5, 188.9, 368. 5 ℃ due to a few residual solvent volatilization in the sample, phase transition peak and decomposition peak. The decomposition temperature of TBSI was very high. It could provided reference with research on rubber vulcanizing properties with TBSI on rubber vulcanizing machine. This study could provide basis experimental data on the enterprises to designate the working standard tracing detection of TBSI industrialized production. Performance index of TBSI was judged. The project of TBSI industry standard could be declared by the enterprises, written a draft standard.

[Advances in lineage-specific genes].

Lineage-specific genes (LSGs) are defined as genes found in one particular taxonomic group but have no significant sequence similarity with genes from other lineages, which compose about 10%?20% of the total genes in the genome of a focal organism. LSGs were first uncovered in the yeast genome in 1996. The development of the whole genome sequencing leads to the emergence of studies on LSGs as a hot topic in comparative genomics. LSGs have been extensively studied on microbial species, lower marine organisms, plant (such as Arabidopsis thaliana, Oryza sativa, Populus), insects, primate, etc; the biological functions of LSGs are important to clarify the evolution and adaptability of a species. In this review, we summarize the progress of LSGs studies, including LSGs identification, gene characterization, origin and evolution of LSGs, biological function, and expression analysis of LSGs. In addition, we discuss the existing problems and future directions for studies in this area. Our purpose is to provide some unique insights into the researches of LSGs.

Prolactin mediates psychological stress-induced dysfunction of regulatory T cells to facilitate intestinal inflammation.

OBJECTIVE: The dysfunction of immune regulation plays a critical role in the pathogenesis of a number of chronic inflammatory disorders, such as IBD. A close relationship between psychological stress and intestinal inflammation has been noted; the underlying mechanism remains elusive. This study aims to elucidate a pathological pathway between psychological stress and the dysfunction of regulatory T cells (Treg), and its effect on facilitating intestinal inflammation. DESIGN: A restraint stress model was employed to induce psychological stress in mice. The functions of Tregs were determined by assessing the immune suppressor effects in the intestine. A mouse model of intestinal inflammation was established using a low dose of trinitrobenzene sulfonic acid (TNBS) or dextran sulfate sodium (DSS) together with the challenge of chronic stress. RESULTS: After treating mice with restraint stress, the suppressor function of intestinal Treg was compromised, although the frequency of Treg was not changed in the intestine. Further observation revealed that stress induced Tregs in the intestine to differentiate into foxhead box P3(+) interleukin (IL)-17(+) tumour necrosis factor (TNF)-α(+) T cells. We also observed that exposure to stress-derived prolactin induced dendritic cells (DC) to produce IL-6 and IL-23 in vitro and in vivo, which played a critical role in altering Treg's phenotypes. Treating mice with chronic stress facilitated the initiation of intestinal inflammation by a low dose of TNBS or DSS, which was abolished by pretreatment with an inhibitor of prolactin, the cabergoline. CONCLUSIONS: Psychological stress-derived prolactin alters DC and Treg's properties to contribute to intestinal inflammation.

Nemo mRNA vaccination improves airway barrier function in mice with airway allergy.

Epithelial barrier dysfunction plays an important role in the pathogenesis of Th2 bias. The mechanism requires further clarification. NEMO is associated with regulating apoptotic activities in the cell. The purpose of this study is to investigate the role of insufficient Nemo signals in developing Th2 bias in the respiratory tract. Nemof/fEpcam-Cre mice (A mouse strain carrying NEMO-deficient epithelial cells. NemoKO mice, in short) was generated. An airway Th2 bias mouse model was established with the ovalbumin/alum protocol. The NemoKO mice exhibited spontaneous airway Th2 bias. Respiratory tract epithelial barrier integrity was compromised in NemoKO mice. Apoptosis was found in approximately 10% of the epithelial cells of the respiratory tract in NemoKO mice. The reconstruction of the Nemo expression restored homeostasis within the epithelial barrier of the airways. Restoration of Nemo gene expression in epithelial cells by Nemo mRNA vaccination alleviated Th2 bias in mice with airway allergy. To sum up, NEMO plays an important role in maintaining the integrity of the epithelial barrier in the respiratory tract. Administration of NEMO mRNA vaccines can restore epithelial barrier functions and alleviate Th2 bias in the airways.

PI3K/AKT/mTOR signaling pathway: an important driver and therapeutic target in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It has higher aggressiveness and metastasis than other subtypes, with limited effective therapeutic strategies, leading to a poor prognosis. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway is prevalently over-activated in human cancers and contributes to breast cancer (BC) growth, survival, proliferation, and angiogenesis, which could be an interesting therapeutic target. This review summarizes the PI3K/AKT/mTOR signaling pathway activation mechanism in TNBC and discusses the relationship between its activation and various TNBC subtypes. We also report the latest clinical studies on kinase inhibitors related to this pathway for treating TNBC. Our review discusses the issues that need to be addressed in the clinical application of these inhibitors.

Direct exposure to CpG and specific antigens mitigate airway allergy through modulating dendritic cell properties.

BACKGROUND: CpG oligodeoxynucleotide (CpG-ODN; CpG, in short) has been employed as an adjuvant in allergen specific immunotherapy (AIT) to treat allergic diseases. The underlying mechanism needs to be further explained. The aim of this study is to examine the mechanism by which CpG and dust mite extracts (DME, a specific antigen) alleviate experimental airway allergy. METHODS: DME was used as the specific allergen to establish an airway allergy mouse model. The mice were directly exposed to DME and CpG through nasal instillations (the CpG.DME therapy). The response of DCs and allergic responses in the airways were assessed using immunological approaches. RESULTS: The airway allergy reaction was effectively suppressed by CpG.DME therapy. The administration of CpG or DME alone did not have any significant suppressive effects on the airway allergic response. Direct exposure to CpG.DME induced type 1 DCs (DC1s) and plasmacytoid DCs (pDCs), while CpG alone induced DC1s and DME alone induced DC2s in the airway tissues. Both DC1s and pDCs were required for the induction of type 1 regulatory T cells in the airway tissues by CpG.DME therapy. Depletion of either pDCs or DC1s abolished the induction of Tr1 cells, and abolished the suppressive effects on airway allergic response by the CpG.DME therapy. CONCLUSIONS: Direct exposure to CpG.DME induces DC1s and pDCs in the airway tissues. DC1s in synergy with pDCs induce type 1 regulatory T cells. The CpG.DME therapy is effective in suppressing allergic responses in mice with airway allergy.

Clinical outcomes and biomarkers of phyllodes tumors of the breast: A single-center retrospective study.

PURPOSE: Phyllodes tumors (PTs) are rare neoplasms with a certain risk of recurrence and/or metastasis. In clinical practice, there is a lack of high-quality clinical studies and unified guidelines to guide the treatment. MATERIALS AND METHODS: All malignant and recurrence/metastasis PTs were retrospectively collected, which were diagnosed from 2008 to 2022. RESULTS: A total of 82 patients were enrolled, including 69 malignant and 13 borderline tumors. 96.3% (79/82) received surgical treatment. During a median follow-up of 55.5 months, 20 patients (20/82, 24.4%) had distant metastasis (DM), while 32 (32/82, 39.0%) had local recurrence (LR). Univariate analysis showed the survival of PTs was associated with surgical methods (p < 0.001), tumor size (p = 0.026), and biological behavior (p = 0.017), but not age at diagnosis. In relapsed borderline PTs, we did not find deaths due to disease progression. Patients with DM were all malignant PTs, with disease-progression occurring within 3 years in more than 80% of patients. Among salvage treatments, the combination of antiangiogenic drugs improved the prognosis to some extent, with a significant increase in mPFS (2.77 vs. 1.53 months), but no significant statistical results were obtained (p = 0.168). Lactate dehydrogenase (LDH) was an independent predictor of the prognosis for malignant PTs (p = 0.001, HR = 1.203, 95%CI, 1.082-1.336). CONCLUSION: Borderline PTs rarely metastasize, and even if LR occurs, surgical resection can lead to long-term survival. In metastatic phyllodes tumors (MPT), systemic therapy is not effective, but antiangiogenic drugs may prolong survival. LDH is an independent prognostic factor for malignant PTs to identify high-risk tumors.

Targeting epithelial cell-derived TWIST1 alleviates allergic asthma.

It is well known that the T Helper (Th)2 bias plays a critical role in allergic asthma. Whereas the Th2 bias is maintained in the local tissues is uncertain. IL-33 is vital for the development of the Th2 polarization. TWIST-1 has an effect on regulating cellular functions. The aberrant activation of RAS sustains certain cellular activities. The aim of this study is to study the role of the interaction between activation of TWIST1 and RAS in inducing and maintaining Th2 polarization in allergic asthma. The epithelial cells of the airways (AEC) were isolated from the broncho-alveolar lavage fluids in patients with asthma. The mediators involved in the over-expression of IL-33 were determined by RNA sequencing. A mouse model was established to test the role of TWIST1 and RAS in developing allergic asthma. We observed a strong expression of TWIST1 in patients with allergic asthma that showed a positive correlation with asthmatic responses. TWIST1 favored the expression of the IL-33 in the AEC. Twist1-deficient AEC-carrying mice did not induce Th2 polarization in the airways. The expression TWIST1 in AECs was positively associated with RAS activation in AECs in patients with allergic asthma. The interaction between RAS and TWIST1 in AECs sustained airway allergic inflammation. Inhibition of TWIST1 or RAS prevented asthma-like inflammation in the mouse airways. In summary, the interaction between TWIST1 and RAS induces and maintains IL-33 expression in AECs to facilitate allergic inflammation in the respiratory tract. Inhibition of TWIST1 or RAS can prevent experimental allergic asthma.