Exploring the Autoimmune Pathogenesis in Severe Asthma.

INTRODUCTION: Severe asthma has a poor response to hormone therapy and a poor level of control, so the discovery of new pathogenetic mechanisms is important for diagnosing and treating severe asthma. IL-35 may play a protective role in autoimmune diseases by directly or indirectly inhibiting the secretion of IL-17, which is an important proinflammatory factor involved in the occurrence and development of autoimmune diseases. The autologous serum skin test (ASST) is a good sensitivity and specificity screening test for autoimmune functional autoantibodies. We compared the levels of IL-35 and IL-17 in serum samples, the positive rate of ASST, the level of exhaled nitric oxide (FeNO), and the atopic constitution in patients with severe asthma to those with mild-to-moderate asthma so as to explore the possible autoimmune pathogenesis of severe asthma. METHODS: Patients with mild-to-moderate and severe asthma were enrolled. Their age, gender, smoking history, family history of asthma, history of allergic rhinitis, positive allergen results, serum total IgE (TlgE), allergen-specific IgE (slgE), routine blood, ASST results, and FeNO test results were compared and analyzed. The IL-35 and IL-17 levels in serum samples from both groups were measured by enzyme-linked immunosorbent assay for comparison and analysis. The SPSS 22.0 software package was used for statistical analysis. RESULTS: A total of 50 patients with mild-to-moderate asthma and 31 patients with severe asthma were included in this study. The proportion of patients with a history of smoking and a family history of asthma was significantly higher in the severe asthma group compared to the mild-to-moderate asthma group (all p < 0.05); the number of positive allergen tests was significantly lower in patients with severe asthma compared to those with mild-to-moderate asthma (p < 0.001). The rate of positive ASST was significantly higher in patients with severe asthma than in patients with mild-to-moderate asthma (p < 0.05). Serum IL-17 levels were significantly higher in patients with severe asthma than in patients with mild-to-moderate asthma (p < 0.05), but serum IL-35 level between the two group was not significantly different (p = 0.113). ASST-positive patients had a statistically significant increase in the risk of developing severe asthma, while patients with allergen positive were less likely to develop severe asthma (positive ASST: OR = 5.277, p = 0.024; allergen positivity: OR = 0.123, p = 0.001). CONCLUSIONS: IL-35 has a weaker inhibitory effect on high IL-17 expression in patients with severe asthma, and the rate of positive ASST was significantly higher in patients with severe asthma, which all suggested the possibility of autoimmune pathogenesis in patients with severe asthma.

Allergen Differences and Correlation Analysis in Siblings Diagnosed with Respiratory Allergic Diseases.

INTRODUCTION: Many parents of children with allergies are worried whether their subsequent children will have allergic reactions to the same allergens. Much of the current research on sibling allergens has been focused on twins; however, in real life, very few children are twins. Our study provides an opportunity to initially explore the sensitivity to allergens in siblings diagnosed with respiratory allergic diseases. METHODS: Siblings diagnosed with bronchial asthma and/or allergic rhinitis in the Outpatient Department of Allergy Department of Yantai Yuhuangding Hospital from January 2018 to December 2021 were selected. The siblings were divided into elder group and younger group. Data of gender, age, feeding history, serum total IgE (TIgE), absolute eosinophil counts, and allergen-specific IgE (sIgE) were collected and analyzed. The sIgEs of allergens were divided into six categories and analyzed. RESULTS: A total of 98 sibling pairs of patients were included in this study. There were no differences in the positive rates of the different types of allergens, TIgE values, and the absolute eosinophil values between the elder and younger groups and between different genders. Logistic regression analysis indicated that the elder siblings allergic to dust mites, fungi, weed pollens, or food had a statistically significant increased risk of having their younger sibling sensitive to these types of allergens (all p <0.05), and the risk of allergy to dust mites, weed pollens, and tree pollens of younger group increased with age (all p <0.05). Except for the sIgE values of dust mites, the sIgE values of the other allergens were significantly correlated between the two groups (all p <0.05). CONCLUSION: The positive rates of different allergens were similar between siblings. Elder siblings with dust mites, fungi, weed pollen, or food allergen positivity will have younger siblings sensitive to the same types of allergens.

Risk Factors for Acute Rhinosinusitis in Childhood Asthma.

INTRODUCTION: Specific pathogen infections associated with acute rhinosinusitis (ARS) in infants are risk factors for allergic asthma in adolescents. However, the risk factors for ARS onset remain largely unknown in asthmatic children. In this study, we aim to investigate the risk factors for ARS in childhood asthma. METHODS: This study retrospectively compared and analyzed the clinical characteristics of asthmatic children with (n = 194) or without ARS (n = 799). Univariate regression analyses were performed to identify ARS-associated risk factors in asthmatic children, and subsequent multivariate backward stepwise logistic regression analyses were performed to identify independent risk factors. RESULTS: The onset age, values of blood eosinophils (EOS) (%), and total IgE were significantly lower in patients with ARS than in those without ARS. Moreover, the proportions of patients allergic to Dermatophagoides pteronyssinus (d1) and Dermatophagoides farinae (d2) were significantly smaller in children with ARS (all p values <0.05). Univariate analyses showed that an older onset age, a higher body mass index, a higher value of blood EOS (%) were protective factors, while a higher value of blood lymphocytes (%) and a higher degree of sensitization to d1 and d2 were risk factors for ARS. Further backward stepwise multivariate logistic regression analyses confirmed that a younger onset age and allergic sensitization to d1 were independent risk factors for ARS in childhood asthma. CONCLUSION: Younger onset age and allergic sensitization to d1 are risk factors for the onset of ARS in childhood asthma, so allergen intervention should be performed as early as possible in asthmatic children.

Effects of plateau hypoxia on population pharmacokinetics and pharmacodynamics of metformin in patients with Type 2 diabetes. / 高原低氧对2åž‹ç³–å°¿ç— æ‚£è€ äºŒç”²åŒèƒç¾¤ä½“è¯åŠ¨å­¦å’Œè¯æ•ˆå­¦çš„å½±å“ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM). METHODS: A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups. RESULTS: The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T1/2), area under the curve (AUC), time to reach maximum concentration (Tmax). Compared with the control group, AUC was increased by 23.5%, Tmax and T1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population. CONCLUSIONS: Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.

Effects of salidroside on exercise tolerance of mice under high altitude hypoxia environment.

OBJECTIVE: To investigate the effect of salidroside on the exercise tolerance of mice under high altitude hypoxia environment. METHODS: C57BL/6J healthy male mice were randomly divided into normoxia control group, model control group, Rhodiola rosea capsule group and salidroside low-dose (5 mg/kg), medium-dose (10 mg/kg) and high-dose (20 mg/kg) groups, with 15 mice in each group. After 3 days, all groups (except the normoxia control group) entered a plateau with an altitude of 4010 m. After 1 day of hypoxia exposure, the exhausted swimming test was performed to determine the exhaustive time of mice; the pathological changes of liver and muscle tissue were observed with hematoxylin and eosin staining. The levels of malondialdehyde (MDA), hydrogen peroxide (H 2O 2), glutathione (GSH), total superoxide dismutase (T-SOD), glycogen, lactate and ATPase were measured and compared among groups. RESULTS: Compared with the normoxia control group, the exhaustive swimming time of the model control group was shortened ( P<0.05), the liver tissue and muscle tissue were pathologically damaged, the level of oxidative stress was significantly increased, the levels of sodium potassium ATPase and calcium magnesium ATPase were significantly increased. Compared with the model control group, the exhaustive swimming time of the mice in the Rhodiola rosea capsule group and salidroside groups was significantly prolonged ( P<0.05). The oxidative stress injury was alleviated, the contents of MDA, H 2O 2 and lactic acid in liver and muscle tissues decreased, the contents of GSH, liver glycogen and muscle glycogen increased, and the activities of T-SOD and ATPase increased (all P<0.05). CONCLUSION: Salidroside has significant anti-fatigue activity, and its anti-fatigue effect is related to the reduction of oxidative stress damage, the reduction of the accumulation of undesirable metabolites and the increase in the reserve of energy substances.

Protective effects of areca nut polyphenols on hypoxic damage of rat pulmonary microvascular endothelial cells.

OBJECTIVE: To investigate the protective effects of areca nut polyphenols on hypoxic damage of rat pulmonary microvascular endothelial cells (PMVECs). METHODS: Malondialdehyde and superoxide dismutase (SOD) were used to determine the optimal modeling of lung hypoxic injury cells. CCK-8 method was used to detect cell viability for determining the effective dose of areca nut polyphenols. Rat PMVECs were divided into control group, hypoxia model group and areca nut polyphenols group. BCA method was used to detect the protein concentration of each group, and the oxidative stress level in PMVECs was measured. Western blotting was used to detect the expression of inflammatory and apoptosis-related proteins. Immunofluorescence staining was used to detect the expression of occludin and zonula occludens (ZO) 1. Transwell chamber was used to detect transendothelial electrical resistance, and rhodamine fluorescent dye was used to detect PMVECs barrier permeability. RESULTS: The hypobaric hypoxia-induced cell injury model was established by culturing PMVECs for 48 h at 1% oxygen concentration. The 20 µg/mL areca nut polyphenols significantly reversed the survival rate and the oxidative stress of PMVECs in hypoxia model group (all P<0.05). Areca nut polyphenols had significant inhibitory effect on the up-regulation of inflammation-related proteins, including nuclear factor-κB (NF-κB) and nuclear factor-E2-related factor (Nrf) 2 in hypoxia model group (all P<0.05). And areca nut polyphenols could reduce hypoxia-induced PMVECs apoptosis by down-regulating the expressions of apoptosis-related proteins, including cysteine aspartic acid specific protease (caspase) 3, Bcl-2 associated X protein (Bax) in PMVECs (all P<0.05). In addition, areca nut polyphenols effectively improves the transendothelial electrical resistance and barrier permeability of PMVECs through elevating the expression of occludin and ZO-1 (all P<0.05). CONCLUSION: Areca nut polyphenols can inhibit the hypoxic damage of PMVECs by reducing oxidative stress and apoptosis down-regulating the expression of inflammatory proteins and reducing membrane permeability.

The IgE Blocking Activity Induced by Dermatophagoides pteronyssinus Subcutaneous Immunotherapy Does Not Correlate with Specific IgA but with IgG4 in both Serum and Saliva.

BACKGROUND: The role of salivary-specific IgG4 and IgA in subcutaneous immunotherapy (SCIT) is not well defined. We aimed to investigate the change of IgG4 and IgA in both serum and saliva and their correlations with IgE-blocking-factor (IgE-BF) during SCIT. METHOD: 307 Dermatophagoides pteronyssinus (DP) allergic rhinitis and/or asthma patients were recruited for this study. 286 patients received DP-SCIT for 1 year. Twenty-one patients received only symptomatic treatment. DP-, Der p 1-, and Der p 2-specific IgE in serum, specific-IgG4 and Der p 2-specific IgA1 and IgA2 in both serum and saliva were measured at timepoints 0, 4, and 12 months during DP-SCIT. Correlation between salivary and serological IgG4, IgA, and their correlation with DP-specific IgE-BF measured in serum was evaluated. RESULTS: During DP-SCIT, the allergen-specific IgG4 in both saliva and serum increased and correlated significantly, the correlation becomes stronger over the treatment time. DP-specific IgE-BF significantly correlated with DP-specific IgG4 in serum (p < 0.0001) at different timepoints and in saliva at 12 months of SCIT (p < 0.01). No change in Der p 2-specific IgA during DP-SCIT was observed, and the IgA in serum did not correlate with IgA in saliva. There was no correlation between DP IgE-BF and Der p 2-specific IgA in serum or saliva. The control group did not exhibit significant changes in any antibody level measured. CONCLUSION: The IgE blocking activity induced by DP-SCIT treatment correlated with specific IgG4 and not IgA. The IgG4 in saliva correlates with serum IgG4 and can be an alternative immunological marker beyond 1 year of SCIT treatment.

Function of hesperidin alleviating inflammation and oxidative stress responses in COPD mice might be related to SIRT1/PGC-1α/NF-κB signaling axis.

Purpose: Hesperidin has anti-inflammatory and anti-oxidant stress effects, but its functions in chronic obstructive pulmonary disease (COPD) remains unknown. This study analyzed the role of hesperidin in COPD mice, aiming to provide a basis for the hesperidin application.Materials and methods: Mice were injected with cigarette smoke extract (CSE) to construct COPD models and then treated with budesonide or hesperidin. Hematoxylin-eosin (HE) and TUNEL assays were used to observe the pathological changes and cell death of lung tissue. The levels of interleukin (IL)-6, IL-8, malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) in bronchoalveolar lavage fluid (BLAF), as well as myeloperoxidase (MPO) content in lung tissues were confirmed. The expression levels of SIRT1, PGC-1α, and p65 proteins were measured by western blotting (WB) analysis.Results: CSE induced inflammatory cell infiltration and cell death in the lung tissues of mice, whereas budesonide and hesperidin effectively alleviated these pathological changes. The levels of IL-6, IL-8, and MDA in BLAF and pulmonary MPO content in the COPD mice were effectively increased, while the levels of SOD and CAT in BLAF were decreased, which could be reversed by budesonide and hesperidin. Moreover, the addition of budesonide or hesperidin reliably accelerated the expression levels of PGC-1α and SIRT1 but suppressed the phosphorylation of p65 in COPD mice. In general, high-dose hesperidin had a stronger regulatory effect on COPD mice.Conclusions: Hesperidin alleviated inflammation and oxidative stress responses in CES-induced COPD mice, associated with SIRT1/PGC-1α/NF-κB signaling axis, which might become a new direction for COPD treatment.

MiR-222-3p ameliorates glucocorticoid-induced inhibition of airway epithelial cell repair through down-regulating GILZ expression.

GILZ expression is induced by glucocorticoids (GCs) and is involved in the mechanism of airway epithelial cell repair in patients with asthma. The present study aimed to investigate the role of miR-222-3p/GILZ pathway in treatment of airway epithelial cell repair by GCs. 9HTE cells were treated by 10 µmol/L dexamethasone (Dex) for 6, 12, and 24 hours (h). MiR-222-3p mimic and GILZ were used for cell transfection. Cell vitality, migration, and invasion were detected by methyl-thiazolyl tetrazolium (MTT), wound healing, and Transwell. The targeting relationship between miR-222-3p and GILZ was predicted by TargetScan and further confirmed by dual-luciferase reporter assay. The expressions of relative mRNAs or proteins were detected by Western blot and quantitative polymerase chain reaction (qPCR). The results showed that Dex treatment up-regulated the GILZ expression level but inhibited the levels of p-Raf1, p-MEK1/2, p-ERK1/2, and miR-222-3p of the cells, moreover, it also inhibited cell activity, migration, and invasion in a time-dependent manner. MiR-222-3p specifically targeted GILZ. MiR-222-3p mimic ameliorated the cell viability, migration, and invasion reduced by Dex treatment, increased the expression levels of p-Raf1 and p-MEK1/2, p-ERK1/2, and partially reversed the effects of GILZ overexpression on the above indexes. Moreover, GILZ showed the opposite effects to miR-222-3p. MiR-222-3p activated MAPK signaling pathway through inhibiting the GILZ expression, thus promoting the cell viability, migration, and invasion previously reduced by Dex.

Management of medically inoperable and tyrosine kinase inhibitor-naïve early-stage lung adenocarcinoma with epidermal growth factor receptor mutations: a retrospective multi-institutional analysis.

BACKGROUND: The clinical value of combined local radiation and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for medically inoperable and TKI-naïve early-stage lung adenocarcinoma patients with EGFR mutations has not yet been determined. In this study, we aimed to pool multi-institutional data to compare the therapeutic effect of EGFR-TKI treatment alone and combined radiation and TKI treatment on the survival outcomes in this patient subgroup. METHODS: A total of 132 cases of medically inoperable stage I to III EGFR mutant lung adenocarcinoma were retrospectively reviewed based on data from 5 centers. Among these patients, 65 received combined radiation and EGFR-TKI therapy (R + TKI) (49.2%), while 67 received EGFR-TKI (50.8%) treatment alone. All patients were followed until death. RESULTS: For the R + TKI group, the median overall survival (OS) after primary therapy was 42.6 months, while that of the TKI alone group was 29.4 months (log-rank p < 0.001). In terms of progression-free survival (PFS), the median PFS in these two treatment groups was 24 months and 14.7 months respectively (log-rank p < 0.001). Multivariate analysis showed that R + TKI was independently associated with improved OS (adjusted HR 0.420; 95% CI 0.287 to 0.614; p < 0.001) and PFS (adjusted HR 0.420; 95% CI 0.291 to 0.605; p < 0.001) compared to TKI alone. Subgroup analysis confirmed the significant OS benefits in stage III patients and RFS benefits in stage II/III patients. CONCLUSIONS: Upfront radiation to primary sites with subsequent TKI treatment is a feasible option for patients with medically inoperable EGFR-mutant non-small-cell lung carcinoma (NSCLC) during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with those yielded by TKI treatment alone.

Bulleyaconitine A inhibits the lung inflammation and airway remodeling through restoring Th1/Th2 balance in asthmatic model mice.

The current study aimed to study the effects of Bulleyaconitine A (BLA) on asthma. Asthmatic mice model was established by ovalbumin (OVA) stimulation, and the model mice were treated by BLA. After BLA treatment, the changes in lung and airway resistances, total and differential leukocytes in the bronchoalveolar lavage fluid (BALF) were detected, and the changes in lung inflammation and airway remodeling were observed. Moreover, the secretion of IgE, Th1/Th2-type and IL-17A cytokines in BALF and serum of the asthmatic mice were determined. The resuts showed that BLA attenuated OVA-induced lung and airway resistances, inhibited the inflammatory cell recruitment in BALF and the inflammation and airway remodeling of the asthmatic mice. In addition, BLA suppressed the secretion of IgE, Th2-type cytokines, and IL-17A, but enhanced secretions of Th1-type cytokines in BALF and serum. The current study discovered that BLA inhibited the lung inflammation and airway remodeling via restoring the Th1/Th2 balance in asthmatic mice.

Artemisia pollen allergy in China: Component-resolved diagnosis reveals allergic asthma patients have significant multiple allergen sensitization.

BACKGROUND: Artemisia pollen allergy is a major cause of asthma in Northern China. Possible associations between IgE responses to Artemisia allergen components and clinical phenotypes have not yet been evaluated. This study was to establish sensitization patterns of four Artemisia allergens and possible associations with demographic characteristics and clinical phenotypes in three areas of China. METHODS: Two hundred and forty patients allergic to Artemisia pollen were examined, 178 from Shanxi and 30 from Shandong Provinces in Northern China, and 32 from Yunnan Province in Southwestern China. Allergic asthma, rhinitis, conjunctivitis, and eczema symptoms were diagnosed. All patients' sera were tested by ImmunoCAP with mugwort pollen extract and the natural components nArt v 1, nArt ar 2, nArt v 3, and nArt an 7. RESULTS: The frequency of sensitization and the IgE levels of the four components in Artemisia allergic patients from Southwestern China were significantly lower than in those from the North. Art v 1 and Art an 7 were the most frequently recognized allergens (84% and 87%, respectively), followed by Art v 3 (66%) and Art ar 2 (48%). Patients from Northern China were more likely to have allergic asthma (50%) than patients from Southwestern China (3%), and being sensitized to more than two allergens increased the risk of allergic asthma, in which co-sensitization to three major allergens Art v 1, Art v 3, and Art an 7 is prominent. CONCLUSIONS: Component-resolved diagnosis of Chinese Artemisia pollen-allergic patients helps assess the potential risk of mugwort-associated allergic asthma.

Allergen Sensitization of Parents and Children With Respiratory Allergic Diseases.

OBJECTIVE: To study the differences in allergen sensitization of parents and their offspring with respiratory allergic diseases. METHODS: We included parents and their children who were both diagnosed with allergic asthma and/or allergic rhinitis, between January 2018 and December 2022. Parent-child dyads were evaluated for sensitization to six categories of allergens viz, dust mite, fungus, animal dander, weed pollen, tree pollen and food allergen, by measuring the allergen-specific immunoglobulin E levels (sIgE). Data of gender, age, feeding history, serum total IgE (tIgE), and absolute eosinophil counts (AEC) were collected and analyzed for differences in allergen sensitization of parents and children. RESULTS: Overall, the AEC in children were significantly higher than that of parents. The sensitivity to fungal allergens in children was significantly higher than that in fathers (33.3% vs 6.7%, P = 0.01) as well as mothers (29.3% vs 8.3%, P = 0.03). Sensitization to food allergens was also higher in children compared to fathers (25.4% vs 7.9%, P = 0.01). Fathers with tree pollen allergen sensitivity, and mothers with weed pollen allergen sensitivity had a significantly increased risk (aOR, 95% CI) of having increased sensitivity to these allergens in their offspring; 24.01 (1.08, 53.99; P = 0.04) and 3.27 (1.08, 9.92; P = 0.04), respectively. CONCLUSION: Children had greater sensitivity for fungal allergens compared to both parents, as well as food allergy compared to fathers. Fathers with tree pollen allergen sensitivity, and mothers with weed pollen allergen sensitivity had an increased risk of having their children sensitive to these types of allergens.

Glycyrrhizin Protects Submandibular Gland Against Radiation Damage by Enhancing Antioxidant Defense and Preserving Mitochondrial Homeostasis.

Aims: Radiotherapy inevitably causes radiation damage to the salivary glands (SGs) in patients with head and neck cancers (HNCs). Excessive reactive oxygen species (ROS) levels and imbalanced mitochondrial homeostasis are serious consequences of ionizing radiation in SGs; however, there are few mitochondria-targeting therapeutic approaches. Glycyrrhizin is the main extract of licorice root and exhibits antioxidant activity to relieve mitochondrial damage in certain oxidative stress conditions. Herein, the effects of glycyrrhizin on irradiated submandibular glands (SMGs) and the related mechanisms were investigated. Results: Glycyrrhizin reduced radiation damage in rat SMGs at both the cell and tissue levels, and promoted saliva secretion in irradiated SMGs. Glycyrrhizin significantly downregulated high-mobility group box-1 protein (HMGB1) and toll-like receptor 5 (TLR5). Moreover, glycyrrhizin significantly suppressed the increases in malondialdehyde and glutathione disulfide (GSSG) levels; elevated the activity of some critical antioxidants, including superoxide dismutase, catalase, glutathione peroxidase, and glutathione (GSH); and increased the GSH/GSSG ratio in irradiated cells. Importantly, glycyrrhizin effectively enhanced thioredoxin-2 levels and scavenged mitochondrial ROS, inhibited the decline in mitochondrial membrane potential, improved adenosine triphosphate synthesis, preserved the mitochondrial ultrastructure, activated the proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α)/nuclear respiratory factor 1/2 (NRF1/2)/mitochondrial transcription factor A (TFAM) signaling pathway, and inhibited mitochondria-related apoptosis in irradiated SMG cells and tissues. Innovation: Radiotherapy causes radiation sialadenitis in HNC patients. Our data suggest that glycyrrhizin could be a mitochondria-targeted antioxidant for the prevention of radiation damage in SGs. Conclusion: These findings demonstrate that glycyrrhizin protects SMGs from radiation damage by downregulating HMGB1/TLR5 signaling, maintaining intracellular redox balance, eliminating mitochondrial ROS, preserving mitochondrial homeostasis, and inhibiting apoptosis.

Comprehensive Investigation of the Influence of High-Altitude Hypoxia on Clopidogrel Metabolism and Gut Microbiota.

BACKGROUND: The amount of metabolites converted into active metabolites is correspondingly reduced since only more than 50% of clopidogrel is absorbed. OBJECTIVE: Exploring the effect of gut microbiota altered by altitude hypoxia on the pre-absorption metabolism of clopidogrel. METHODS: In vitro and in vivo experiments were conducted to analyze the metabolism of clopidogrel through LCMS/ MS, while 16S rRNA analysis was used to investigate the changes in the gut microbiota of high-altitude animals. RESULTS: We demonstrated that the intestinal flora is involved in the metabolism of clopidogrel through in vivo and in vitro experiments. In addition, the plateau environment caused changes in the number and composition of intestinal microbes. Intriguingly, alterations in the microbial population could lead to an increase in the pre-absorption metabolism of clopidogrel after rapid entry into the plateau, the amount of absorbed blood is thus reduced, which may affect the bioavailability and therapeutic effect of clopidogrel. CONCLUSION: Our results not only as a first clinical reference for dose adjustment of clopidogrel in high-altitude environments but also would be helpful to provide a statement on the broader significance within the field of pharmacokinetics or personalized medicine.

Research progress on the mechanism of intestinal barrier damage and drug therapy in a high altitude environment.

The plateau is a typical extreme environment with low temperature, low oxygen and high ultraviolet rays. The integrity of the intestinal barrier is the basis for the functioning of the intestine, which plays an important role in absorbing nutrients, maintaining the balance of intestinal flora, and blocking the invasion of toxins. Currently, there is increasing evidence that high altitude environments can enhance intestinal permeability and disrupt intestinal barrier integrity. This article mainly focuses on the regulation of the expression of HIF and tight junction proteins in the high altitude environment, which promotes the release of pro-inflammatory factors, especially the imbalance of intestinal flora caused by the high altitude environment. The mechanism of intestinal barrier damage and the drugs to protect the intestinal barrier are reviewed. Studying the mechanism of intestinal barrier damage in high altitude environment is not only conducive to understanding the mechanism of high altitude environment affecting intestinal barrier function, but also provides a more scientific medicine treatment method for intestinal damage caused by the special high altitude environment.

Randomized Trial of First-Line Tyrosine Kinase Inhibitor With or Without Radiotherapy for Synchronous Oligometastatic EGFR-Mutated Non-Small Cell Lung Cancer.

BACKGROUND: Adding radiotherapy (RT) to systemic therapy improves progression-free survival (PFS) and overall survival (OS) in oligometastatic non-small cell lung cancer (NSCLC). Whether these findings translate to epidermal growth factor receptor (EGFR)-mutated NSCLC remains unknown. The SINDAS trial (NCT02893332) evaluated first-line tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated synchronous oligometastatic NSCLC and randomized to upfront RT vs no RT; we now report the prespecified interim analysis at 68% accrual. METHODS: Inclusion criteria were biopsy-proven EGFR-mutated adenocarcinoma (per amplification refractory mutation system or next generation sequencing), with synchronous (newly diagnosed, treatment naïve) oligometastatic (≤5 metastases; ≤2 lesions in any one organ) NSCLC without brain metastases. All patients received a first-generation TKI (gefitinib, erlotinib, or icotinib), and randomization was between no RT vs RT (25-40 Gy in 5 fractions depending on tumor size and location) to all metastases and the primary tumor/involved regional lymphatics. The primary endpoint (intention to treat) was PFS. Secondary endpoints included OS and toxicities. All statistical tests were 2-sided. RESULTS: A total of 133 patients (n = 65 TKI only, n = 68 TKI with RT) were enrolled (2016-2019). The median follow-up was 23.6 months. The respective median PFS was 12.5 months vs 20.2 months (P < .001), and the median OS was 17.4 months vs 25.5 months (P < .001) for TKI only vs TKI with RT. Treatment yielded no grade 5 events and a 6% rate of symptomatic grade 3-4 pneumonitis in the TKI with RT arm. Based on the efficacy results of this prespecified interim analysis, the ethics committee recommended premature cessation of this trial. CONCLUSIONS: As compared with a first-line TKI alone, addition of upfront local therapy using RT statistically significantly improved PFS and OS for EGFR-mutated NSCLC.

Two single nucleotide polymorphisms in TSLP gene are associated with asthma susceptibility in Chinese Han population.

BACKGROUND: Asthma is a chronic inflammatory disease of the airway that is mediated by T-helper 2(TH2) cells. Thymic stromal lymphopoietin (TSLP) can aggravate asthmatic lung inflammation by activating dendritic cells (DCs) to promote TH2 differentiation. TSLP promoter polymorphisms are associated with susceptibility to bronchial asthma in Japanese population. We sought to determine whether single nucleotide polymorphisms (SNPs) in TSLP gene are associated with asthma in Chinese Han population. OBJECTIVE: To analyze the polymorphism of the two SNPs Rs2289276 and Rs2289278 in TSLP gene and to evaluate the association between the two SNPs and asthma susceptibility in Chinese Han population by using case-control study. METHODS: five hundred and thirty one asthmatic patients and 540 age-sex matched normal controls were collected and DNA were extracted from peripheral blood, then the genotypes of SNPs Rs2289276 and Rs2289278 in TSLP gene were detected with polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP), genotype and allele frequencies were calculated and analyzed with Chi-square test. RESULTS: Frequencies of CC/CT/TT genotypes at Rs2289276 site were 0.4706/0.4392/0.0902 in the asthmatic patients and 0.5604/0.3800/0.0595 in the healthy controls. Frequencies of CC/CG/GG genotypes at Rs2289278 site were 0.6502/0.2966/0.0532 in the asthmatic patients and 0.5795/0.3428/0.0777 in the healthy controls. The genotype and allele frequencies of the two SNPs in asthma patients were significantly different from those in the healthy controls. Rs2289278 C allele was correlated with decreased FEV(1): FVC (P ≤ .05). CONCLUSIONS: TSLP variants are significantly associated with bronchial asthma. TSLP might be a new therapeutic target molecule for asthma.

Recent Advances in the Allergic Cross-Reactivity between Fungi and Foods.

Airborne fungi are one of the most ubiquitous kinds of inhalant allergens which can result in allergic diseases. Fungi tend to grow in warm and humid environments with regional and seasonal variations. Their nomenclature and taxonomy are related to the sensitization of immunoglobulin E (IgE). Allergic cross-reactivity among different fungal species appears to be widely existing. Fungus-related foods, such as edible mushrooms, mycoprotein, and fermented foods by fungi, can often induce to fungus food allergy syndrome (FFAS) by allergic cross-reactivity with airborne fungi. FFAS may involve one or more target organs, including the oral mucosa, the skin, the gastrointestinal and respiratory tracts, and the cardiovascular system, with various allergic symptoms ranging from oral allergy syndrome (OAS) to severe anaphylaxis. This article reviews the current knowledge on the field of allergic cross-reactivity between fungal allergens and related foods, as well as the diagnosis and treatment on FFAS.

The mechanism of colon tissue damage mediated by HIF-1α/NF-κB/STAT1 in high-altitude environment.

The high-altitude environment damages the intestinal mucosal barrier, leading to a high incidence of intestinal diseases and seriously affects the working ability of people at high altitude. However, how high altitude induces intestinal mucosal barrier injury has not been well defined. The purpose of this study was to investigate the mechanism of colonic tissue injury induced by the influence of the high-altitude environment on the colonic microenvironment. Forty-eight SPF C57BL/6J mice were randomly divided into four groups: the control group and three other that were high-altitude exposure groups (Yushu, Qinghai; elevation: 4,010 m; 12 h, 24 h, 48 h). First, HE staining was used to observe the effect of the high-altitude environment on colon histomorphology of mice. The protein expression levels of claudin-1, occludin, and ZO-1 were analyzed by molecular biological methods. We found that altitude caused inflammatory damage to colon tissue. Intestinal hypoxia was measured with the hypoxic probe pimonidazole (PMDZ). Interestingly, we observed a decrease in the concentration of oxygen in the microenvironment in the colonic lumen. We sought to explore the mechanism of colonic mucosal barrier damage at different times when entering high altitude. The expression levels of hypoxia-inducible factors: HIF-1α, STAT1, and NF-κB and of inflammatory factors: IFN-γ, TNF-α, and IL-6 were significantly increased. This work highlights that the high-altitude environment leads to a reduction in the concentration of oxygen in the microenvironment of the colonic lumen, which disrupts the colonic mucosal barrier and ultimately induces and exacerbates intestinal injury.