PTPRH Alleviates Airway Obstruction and Th2 Inflammation in Asthma as a Protective Factor.

PURPOSE: PTPRH inhibits EGFR activity directly in cancer patients and activated EGFR induces goblet cell hyperplasia and mucus hypersecretion in asthma. However, the function of PTPRH in asthma remains unknown. The purpose of this study was to access the association of PTPRH with asthma and its underlying mechanism. PATIENTS AND METHODS: We examined the PTPRH level in asthma patients (n = 108) and healthy controls (n = 35), and analyzed the correlations between PTPRH and asthma-related indicators. Human bronchial epithelial cell (HBECs) transfected with PTPRH and asthma mouse model were set up to investigate the function of PTPRH. RESULTS: The expression of PTPRH was significantly increased and correlated with pulmonary function parameters, including airway obstruction, and T-helper2 (Th2) associated markers in asthma patients. PTPRH increased in the house dust mite (HDM)-induced asthmatic mice, while Th2 airway inflammation and Muc5ac suppressed when treated with PTPRH. Accordingly, PTPRH expression was markedly increased in IL-13-stimulated HBECs but PTPRH over-expression suppressed MUC5AC. Moreover, HBECs transfected with over-expressed PTPRH inhibited the phosphorylation of EGFR, ERK1/2 and AKT, while induced against PTPRH in HBECs dephosphorylated of EGFR, ERK1/2 and AKT. CONCLUSION: PTPRH reduces MUC5AC secretion to alleviate airway obstruction in asthma via potential phosphorylating of EGFR/ERK1/2/AKT signaling pathway, which may provide possible therapeutic implications for asthma.

Neuronal nitric oxide synthase alteration accounts for the role of 5-HT1A receptor in modulating anxiety-related behaviors.

Increasing evidence suggests that 5-HT(1A) receptor (5-HT(1A)R) is implicated in anxiety disorders. However, the mechanism underlying the role of 5-HT(1A)R in these diseases remains unknown. Here, we show that 5-HT(1A)R-selective agonist 8-OH-DPAT and selective serotonin reuptake inhibitor (SSRI) fluoxetine downregulated hippocampal neuronal nitric oxide synthase (nNOS) expression, whereas 5-HT(1A)R-selective antagonist NAN-190 upregulated hippocampal nNOS expression. By assessing anxiety-related behaviors using the novelty suppressed feeding, open-field, and elevated plus maze tests, we show that mice lacking nNOS gene [knock-out (KO)] or treated with nNOS-selective inhibitor 7-nitroindazole (7-NI; i.p., 30 mg/kg/d for 28 d; or intrahippocampal microinjection, 16.31 microg/1.0 microl) displayed an anxiolytic-like phenotype, implicating nNOS in anxiety. We also show that, in wild-type (WT) mice, administrations of 8-OH-DPAT (i.p., 0.1 mg/kg/d) or fluoxetine (i.p., 10 mg/kg/d) for 28 d caused anxiolytic-like effects, whereas NAN-190 (i.p., 0.3 mg/kg/d for 28 d) caused anxiogenic-like effects. In KO mice, however, these drugs were ineffective. Moreover, intrahippocampal infusion of 8-OH-DPAT (45.963 microg/100 microl) using 14 d osmotic minipump produced anxiolytic effects. Intrahippocampal microinjection of 7-NI (16.31 microg/1.0 microl) abolished the anxiogenic-like effects of intrahippocampal NAN-190 (4.74 microg/1.0 microl). Additionally, NAN-190 decreased and 8-OH-DPAT increased phosphorylated cAMP response element-binding protein (CREB) levels in WT mice but not in KO mice. Blockade of hippocampal CREB phosphorylation by microinjection of H89 (5.19 microg/1.0 microl), a PKA (protein kinase A) inhibitor, abolished the anxiolytic-like effects of 7-NI (i.p., 30 mg/kg/d for 21 d). These findings indicate that both hippocampal nNOS and CREB activity mediate the anxiolytic effects of 5-HT(1A)R agonists and SSRIs.

Prognostic Values of Radiosensitivity Genes and CD19 Status in Gastric Cancer: A Retrospective Study Using TCGA Database.

BACKGROUND: The correlation between the radiosensitivity genes combined with CD19 status and clinical outcome was investigated to identify gastric cancer (GC) patients who would benefit from radiotherapy combined with CAR-T cell therapy. METHODS: The gene expression and clinical features were downloaded from The Cancer Genome Atlas (TCGA) Stomach Cancer (STAD). To identify the hub radiosensitivity genes and CD19 status, 407 patients were categorized into two groups: radiosensitivity (RS) and radioresistance (RR) based on the prognosis. The chi-square test, Mann-Whitney test, and Kaplan-Meier survival analysis were applied to compare the differential expression in these groups and analyze the correlation between the gene expression and clinical outcome and features. Finally, the influencing factors for the prognosis of GC were investigated by multiple Cox regression, especially in RS patients. RESULTS: A total of 15 differential expression genes, containing two communities with 8 hub radiosensitivity genes, were identified. We also identified a 2-gene signature model with a negative coefficient and calculated the risk score for the prognosis of GC. Also, Helicobacter pylori infection was validated, and the high-risk score of radiosensitivity genes was the risk factor, and high CD19 expression was the protective factor for the prognosis. CONCLUSION: The radiosensitivity gene signature and CD19 expression predicted the clinical outcome of GC patients.

Evaluation of the Characteristics of Asthma in Severe and Extremely Severe COPD.

Background: Biotherapy for asthma may be useful in patients suffering from chronic obstructive pulmonary disease (COPD) with asthma characteristics. Therefore, the evaluation and close monitoring of asthma characteristics in severe and extremely severe COPD can guide treatment decisions to improve prognosis. Methods: Stable patients suffering from COPD and having a forced expiratory volume in 1 s (FEV1%) of ≤50% (GOLD 3-4) in the First Affiliated Hospital of Sun Yat-Sen University from December 2014 to June 2018 were retrospectively enrolled in this study and evaluated in terms of their asthma characteristics (blood eosinophil counts, fractional exhaled NO [FeNO] values, and reversibility). Results: A total of 178 patients with an average age of 65.62±9.28 years were enrolled in this study. A total of 85 patients had an improvement of ≥12% in FEV1%, and 61 of these patients had an absolute increase of >200 mL. Of 122 patients, 68 had blood eosinophil counts of ≥150 cells/µl, whereas 27 showed blood eosinophil counts ≥300 cells/µl. The blood eosinophil of ≥2% was found in 66/122 (54.10%) patients, whereas ≥3% was found in 51/122 (41.80%) patients. A total of 46 of 58 patients had an increased serum IgE level of ≥30 IU/mL, and 32 patients had an IgE of ≥100 IU/mL. The FeNO value of ≥25 ACO (ppb) was found in 51/155 (32.90%) patients. Furthermore, 43 patients had asthma-COPD overlap (ACO), and the FeNO values in the ACO group was 26.13±14.91 ppb, which was significantly higher than that in the COPD alone group (20.99±9.16 ppb; P=0.016). A total of 12 patients with ACO had a negative response after bronchodilation. In the COPD alone group, 34 patients had an absolute increase of >200 mL, whereas 55 of the 95 patients had blood eosinophil counts of ≥150 cells/µl. The blood eosinophilia of ≥2% was found in 54/95 (56.84%) patients. A total of 36 of 45 patients had an increased serum IgE level of ≥30 IU/mL. The FeNO value of 34/123 (27.64%) patients was ≥25 ppb. Conclusion: The characteristics of asthma are common findings in patients with severe and extremely severe COPD. Biomarkers should be actively used to evaluate the characteristics of asthma in these patients. If the characteristics of asthma exist, then anti-IgE or anti-IL-5 therapy should be considered to reduce exacerbation.

DETA/NONOate, a nitric oxide donor, produces antidepressant effects by promoting hippocampal neurogenesis.

RATIONALE: Increasing evidence suggests that depression may be associated with a lack of hippocampal neurogenesis. Our recent study shows that endogenous nitric oxide (NO) contributes to chronic mild stress (CMS)-induced depression by suppressing hippocampal neurogenesis. OBJECTIVES: The aim of this study was to investigate the effects of exogenous NO in CMS-induced depression in young adult mice. RESULTS: In normal mice, administration of a pure NO donor (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio] diazen-1-ium-1,2-diolate (DETA/NONOate; 0.4 mg/kg, i.p., for 7 days) produced an antidepressant-like effect and significantly increased hippocampal neurogenesis. The mice exposed to CMS exhibited behavioral changes typical of depression and impaired neurogenesis in the hippocampus. Treatment with DETA/NONOate (0.4 mg/kg, i.p., for 7 days) reversed CMS-induced behavioral despair and hippocampal neurogenesis impairment. We treated mice with a telomerase inhibitor 3'-azido-deoxythymidine (AZT; 100 mg/kg, i.p., for 14 days) to disrupt neurogenesis. From day 4 to day 11 of AZT treatment, mice were injected with DETA/NONOate (0.4 mg/kg, i.p., for 7 days). Disrupting hippocampal neurogenesis blocked the antidepressant effect of DETA/NONOate. CONCLUSIONS: Our findings suggest that exogenous NO benefits chronic stress-induced depression by stimulating hippocampal neurogenesis and may represent a novel approach for the treatment of depressive disorders.

Activation of M1 macrophages plays a critical role in the initiation of acute lung injury.

The goal of the present study was to investigate the role of M1 macrophages in acute lung injury (ALI). To address this, we used lipopolysaccharide (LPS)-treated wild-type and CD11b-DTR mice, and examined their M1 macrophage levels, and the extent of their inflammation and pulmonary injuries. In addition, we evaluated pulmonary function by measuring the expressions of SP-A and SP-B in infiltrated M1 macrophages. Finally, we co-cultured the mouse type II-like alveolar epithelial cells (AT-II) and mouse pulmonary microvascular endothelial cells (PMECs) with M1 macrophages in the presence of TNF-α or H2O2 and assessed them for viability and apoptosis. After LPS treatment, we observed that the number of pulmonary M1/M2 macrophages and the serum levels of interleukin-1ß (IL-1ß), tumor necrosis factor α (TNF-α), and reactive oxygen species (ROS) significantly increased. Furthermore, the increase in cytokines was accompanied with the initiation of lung injury indicated by the decreased levels of SP-A and SP-B. In macrophage-depleted CD11b-DTR mice, ALI was attenuated, serum levels of IL-1ß, TNF-α and ROS were reduced, and lung levels of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) were decreased. After administering TNF-α and H2O2, the proapoptotic effect of M1 macrophages on AT-II or PMECs significantly increased, the cell viabilities significantly decreased, and apoptosis significantly increased. Our results suggest that M1 macrophages are recruited to the lungs where they significantly contribute to an increase in TNF-α and ROS production, thus initiating ALI.

Importance of fractional exhaled nitric oxide in diagnosis of bronchiectasis accompanied with bronchial asthma.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) measurement is a simple, rapid, highly reproducible, and noninvasive method of airway inflammation assessment. Therefore, FeNO is extensively used for the diagnosis and management of asthma. The feasibility of using FeNO as an alternative to conventional pulmonary function test to differentiate patients with bronchiectasis (BE) and bronchial asthma from those with BE only remains unclear. METHODS: From February 2013 to February 2015, 99 patients diagnosed with BE through high-resolution computed tomography (HRCT) were subjected to FeNO measurement, bronchial challenge test (BCT), or bronchodilator test. Bronchial hyperreactivity and/or reversible airway obstruction was used to define asthma. The receiver operating characteristic (ROC) curves were obtained to elucidate the clinical functions of FeNO in the diagnosis of asthmatic patients with BE, and the optimal operating point was also determined. RESULTS: Of 99 patients with BE, 20 patients presented asthma, and 12 of these patients received regular treatment, which were given with budesonide (200 µg, bid) for 12 weeks to evaluate changes in the concentration and assess the role of FeNO in the treatment. The area under the ROC curve was estimated as 0.832 for FeNO. Results also revealed a cut off value of >22.5 part per billion (ppb) FeNO for differentiating asthmatic from non-asthmatic (sensitivity, 90.0%; specificity, 62.5%) patients with BE. FeNO and forced expiratory volume for 1 second significantly improved after the treatment. CONCLUSIONS: Clinical FeNO measurement is a simple, noninvasive, and rapid method used to differentiate asthmatic from nonasthmatic patients with BE. This technique exhibits potential for asthma management.

Importance of fractional exhaled nitric oxide in the differentiation of asthma-COPD overlap syndrome, asthma, and COPD.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is an easy, sensitive, reproducible, and noninvasive marker of eosinophilic airway inflammation. Accordingly, FeNO is extensively used to diagnose and manage asthma. Patients with COPD who share some of the features of asthma have a condition called asthma-COPD overlap syndrome (ACOS). The feasibility of using FeNO to differentiate ACOS patients from asthma and COPD patients remains unclear. METHODS: From February 2013 to May 2016, patients suspected with asthma and COPD through physician's opinion were subjected to FeNO measurement, pulmonary function test (PFT), and bronchial hyperresponsiveness or bronchodilator test. Patients were divided into asthma alone group, COPD alone group, and ACOS group according to a clinical history, PFT values, and bronchial hyperresponsiveness or bronchodilator test. Receiver operating characteristic (ROC) curves were obtained to elucidate the clinical functions of FeNO in diagnosing ACOS. The optimal operating point was also determined. RESULTS: A total of 689 patients were enrolled in this study: 500 had asthma, 132 had COPD, and 57 had ACOS. The FeNO value in patients with ACOS was 27 (21.5) parts per billion (ppb; median [interquartile range]), which was significantly higher than that in the COPD group (18 [11] ppb). The area under the ROC curve was estimated to be 0.783 for FeNO. Results also revealed an optimal cutoff value of >22.5 ppb FeNO for differentiating ACOS from COPD patients (sensitivity 70%, specificity 75%). CONCLUSION: FeNO measurement is an easy, noninvasive, and sensitive method for differentiating ACOS from COPD. This technique is a new perspective for the management of COPD patients.

[Effect of rapid eye movement sleep deprivation on anxiety behavior and hippocampus NO level: different responses of adolescent and adult C57BL/6J mice].

OBJECTIVE: To explore the difference between adolescent and adult C57BL/6J mice in response to rapid eye movement sleep (REMS) deprivation in terms of anxiety behavior and hippocampal NO level. METHODS: Both adolescent and adult C57BL/6J mice were divided into normal control (NC) group, wide platform (WP) group, and 24-hour REMS deprivation group, each group consisting of 15 mice. REMS deprivation models were established using a small platform in water tank, and the elevated plus maze test was used to examine anxiety behavior of the mice. After behavioral tests, the mice were sacrificed to examine hippocampal NO levels using enzyme-linked immunosorbent assay, and hippocampal nNOS protein expression was detected with Western blotting. RESULTS: The adolescent C57BL/6J mice showed no obvious differences in anxiety behaviors between the 3 groups, but NO level and nNOS expression in the hippocampus was significantly higher in REMSD group than in NC and WP groups (P<0.01). The adult mice in REMSD group, compared with those in the other two groups, exhibited significantly increased total number of arm entry (P<0.01), lowered number of open arm entry and reduced open arm time (P<0.01), increased number of close arm entry and prolonged close arm time (P<0.01 or 0.05); no obvious differences in NO level or nNOS expression in the hippocampus were found in the 3 groups of adult mice. CONCLUSION: REMS deprivation produces different effects on anxiety-related behaviors between adolescent and adult mice possibly in relation to their different responses in terms of NO levels and nNOS expression in the hippocampus.

[Histological and ultrastructural changes of dog skin following hair removal by laser].

OBJECTIVE: To evaluate the cutaneous histological and ultrastructural changes of dogs following hair removal by Alexandrite laser. METHODS: Seven healthy dogs with dark hair were treated for hair removal with the Alexandrite laser and skin biopsies were taken after 0.5 h, 2, 3, 5, 10, and 30 days. Specimens were examined with light microscopy and transmission electron microscopy. RESULT: Laser-treated specimens showed widespread coagulation and charring subcutaneous hair shafts. These obviously damaged follicles were randomly dispersed among intact follicles within the same treatment sites. Microscopic changes were also seen in the basal epidermis where melanin was concentrated. A low level of inflammatory response was seen up to 10 days followed laser treatment. The efficiency in higher fluence test area was better than the lower one; the degree of damaged follicles with double pulse was similar to that with single pulse. CONCLUSION: Alexandrite laser irradiation results in selective damage to follicles and microscopic changes in the basal epidermis. Alexandrite laser hair removal does not lead to scar formation; the efficiency of laser hair removal is fluence-depent; the degree of damaged follicles with double pulse is not different with single one; the cooled hand piece can minimize epidermal injury.

Enhanced antitumor efficacy with combined administration of astragalus and pterostilbene for melanoma.

Astragalus, a commonly used traditional Chinese medicine, has exhibited antitumor actions in patients. In this study, in vitro and in vivo antitumor effects of astragalus and synergistic antitumor efficacy in combination with pterostilbene were investigated. Melanoma cells were treated with pterostilbene (Pt), graduated doses of astragalus injection (AI), or these in combination. Cell viability was measured using a MTT assay. Released nucleosomes and caspase activity were measured using enzyme-linked immunosorbent assay. Growth inhibition in vitro and in vivo was also assessed. Analysis of variance and t tests were used for statistical analysis. Significant reduction (p<0.05) in cellular proliferation were observed with AI and AI-Pt in a time- and concentration-dependent manner. Apoptosis and caspase-3/7 activity were significantly increased by AI and AI-Pt treatment (p<0.05). In vivo, AI inhibited melanoma tumor growth, with inhibition rates ranging from 36.5 to 62.3%, by inducing apoptosis via up-regulation Bax expression and the Bax/Bcl-2 ratio and down-regulating Bcl-2 expression. AI significantly inhibits the growth of melanoma in vitro and in vivo by inducing apoptosis. These data suggest that combined treatment of astragalus with pterostilbene enhances antitumor efficacy.