Icariin Improves Glucocorticoid Resistance in a Murine Model of Asthma with Depression Associated with Enhancement of GR Expression and Function.

Icariin, a flavonoid glycoside isolated from Epimedium brevicornum, exerts a variety of biological activities. However, its effects on depression-induced glucocorticoid resistance in asthma and the underlying mechanisms have not been elucidated. In this study, a murine model of asthma with depression was established by exposure to ovalbumin combined with chronic unpredictable mild stress, and icariin was given orally during ovalbumin challenge and chronic unpredictable mild stress exposure. Depression-like behaviors were assessed by the open field test, forced swim test, and tail suspension test. The characteristic features of allergic asthma, including airway hyperreactivity, histopathology, inflammatory cytokine levels in bronchoalveolar lavage fluid, and immunoglobulin E and corticosterone levels in serum, were examined. Following splenocyte isolation in vitro, the inhibitory effects of corticosterone on the proliferation and cytokine secretion of splenocytes, glucocorticoid receptor DNA-binding activity, and expression of p-glucocorticoid receptor s226, glucocorticoid receptor α, and p-p38 mitogen-activated protein kinase in splenocytes were determined. We found that icariin had limited effects on depression-like behaviors, however, it markedly suppressed airway hyperresponsiveness, inflammatory infiltration in lung tissues, levels of interleukin-4, interleukin-5, and interleukin-6 in bronchoalveolar lavage fluid, and immunoglobulin E in serum. Furthermore, icariin improved the inhibitory effects of corticosterone on lipopolysaccharide-stimulated splenocytes, increased the glucocorticoid receptor expression and glucocorticoid receptor DNA-binding activity, and inhibited the phosphorylation of glucocorticoid receptors S226 and p38 mitogen-activated protein kinase. Taken together, icariin improved glucocorticoid resistance in a murine model of asthma with depression associated with enhancement of glucocorticoid receptor function and glucocorticoid receptor expression, and its effects on the glucocorticoid receptor function were related to decreased phosphorylation of glucocorticoid receptors S226 and p38 mitogen-activated protein kinase.

Modified Si-Jun-Zi-Tang Attenuates Airway Inflammation in a Murine Model of Chronic Asthma by Inhibiting Teff Cells via the mTORC1 Pathway.

Background: Modified Si-Jun-Zi-Tang (MSJZT), a multi-herb formulation, is frequently used in traditional Chinese medicine for patients during the remission stage of asthma. However, the pharmacological basis underlying the effects of MSJZT on asthma has yet to be elucidated. This study aims at evaluating the anti-asthmatic effects of MSJZT and investigating its possible mechanism. Methods: A chronic murine model of asthma was established by sensitization and repeated challenge with ovalbumin (OVA) in female BALB/c mice, followed with oral administration of MSJZT during remission, and then mouse were re-challenged by OVA. The chemical profile of MSJZT was analyzed by high-performance liquid chromatography. The characteristic features of allergic asthma, including airway hyperreactivity, histopathology, cytokine levels (IL-4, -5, -13, -17, and INF-γ), T regulatory (Treg) lymphocytes (Foxp3+CD4+CD25+), and T effector (Teff) lymphocytes (Foxp3-CD25+CD4+) in bronchoalveolar lavage fluid (BALF), and downstream proteins of mTORC1/2 signaling pathway were examined. Results: MSJZT markedly suppressed airway hyper-responsiveness to aerosolized methacholine, and reduced levels of IL-4, IL-5, and IL-13 in the BALF. Histological studies showed that MSJZT significantly reduced inflammatory infiltration in lung tissues. The percentage and absolute number of Teff cells were suppressed to a remarkable level by MSJZT without affecting Treg cells. Furthermore, MSJZT effectively inhibited the mTORC1 activity, but exerted limited effects on mTORC2, as assessed by the phosphorylation of the mTORC1 and mTORC2 substrates, S6 ribosomal protein, p70 S6 kinase, mTOR S2481, and Akt, respectively. Conclusion: MSJZT attenuated chronic airway inflammation in a mouse model of asthma by inhibiting Teff cells, which occurred, at least in part, via modulation of the mTORC1 signaling pathway.

Astragaloside IV Ameliorates Airway Inflammation in an Established Murine Model of Asthma by Inhibiting the mTORC1 Signaling Pathway.

Astragaloside IV (AS-IV), a main active constituent of Astragalus membranaceus, has been confirmed to have antiasthmatic effects. However, it remained unclear whether the beneficial effects of AS-IV on asthma were attributed to the mTOR inhibition; this issue was the focus of the present work. BALB/c mice were sensitized and challenged with ovalbumin followed with 3 weeks of rest/recovery and then reexposure to ovalbumin. AS-IV was administrated during the time of rest and reexposure. The characteristic features of allergic asthma, including airway hyperreactivity, histopathology, cytokines (IL-4, IL-5, IL-13, IL-17, and INF-γ), and CD4+CD25+Foxp3+Treg cells in bronchoalveolar lavage fluid (BALF), and downstream proteins of mTORC1/2 signaling were examined. AS-IV markedly suppressed airway hyperresponsiveness and reduced IL-4, IL-5, and IL-17 levels and increased INF-γ levels in the BALF. Histological studies showed that AS-IV markedly decreased inflammatory infiltration in the lung tissues. Notably, AS-IV inhibited mTORC1 activity, whereas it had limited effects on mTORC2, as assessed by phosphorylation of mTORC1 and mTORC2 substrates S6 ribosomal protein, p70 S6 Kinase, and Akt, respectively. CD4+CD25+Foxp3+Treg cells in BALF were not significantly changed by AS-IV. Together, these results suggest that the antiasthmatic effects of AS-IV were at least partially from inhibiting the mTORC1 signaling pathway.

Effects of two Chinese herbal formulae for the treatment of moderate to severe stable chronic obstructive pulmonary disease: a multicenter, double-blind, randomized controlled trial.

OBJECTIVE: The study aims to evaluate the efficacy and safety of two Chinese herbal formulae for the treatment of stable COPD. METHODS: A multicenter, double-blind, double-dummy, and randomized controlled trial (RCT) was conducted. All groups were treated with additional conventional medicines. There were a 6-month treatment and a 12-month follow-up for 5 times. Primary outcomes included lung function test, exacerbation frequency, score of SGRQ. Second outcomes consisted of 6MWD, BODE index, psychological field score, inflammatory factors and cortisol. RESULTS: A total of 331 patients were randomly divided into two active treatment groups (Bushen Yiqi (BY) granule group, n = 109; Bushen Fangchuan (BF) tablet group, n = 109) and a placebo group (n = 113). Finally 262 patients completed the study. BY granule & BF tablet increased the values of VC, FEV1 (%) and FEV1/FVC (%), compared with placebo. BY granule improved PEF. Both treatments reduced acute exacerbation frequency (P = 0.067), BODE index and psychological field score, while improved 6MWD. In terms of descent rang of SGRQ score, both treatments increased (P = 0.01). Both treatments decreased inflammatory cytokines, such as IL-8, and IL-17(P = 0.0219). BY granule obviously descended IL-17(P<0.05), IL-1ß (P = 0.05), IL-6, compared with placebo. They improved the level of IL-10 and cortisol. BY granule raised cortisol (P = 0.07) and decreased TNF-α. Both treatments slightly descended TGF-ß1. In terms of safety, subject compliance and drug combination, there were no differences (P>0.05) among three groups. CONCLUSIONS: BY granule and BF tablet were positively effective for the treatment of COPD, and the former performed better in general. TRIAL REGISTRATION: Chinese Clinical Trial Register center ChiCTR-TRC-09000530.

Effects of Psoraleae fructus and its major component psoralen on Th2 response in allergic asthma.

This study is aimed to evaluate the effects of Psoraleae fructus (PF) on Th2 responses in a rat model of asthma in vivo and psoralen, a major constituent in PF, on Th2 responses in vitro. A rat model of asthma was established by sensitization and challenged with ovalbumin (OVA). Airway hyperresponsiveness was detected by direct airway resistance analysis. Lung tissues were examined for cell infiltration and mucus hypersecretion. Bronchoalveolar lavage fluid (BALF) was assessed for cytokine levels. In vitro study, Th2 cytokine production was evaluated in the culture supernatant of D10.G4.1 (D10 cells) followed by the determination of cell viability, meanwhile Th2 transcription factor GATA-3 expression in D10 cells was also determined. The oral administration of PF significantly reduced airway hyperresponsiveness (AHR) to aerosolized methacholine and decreased IL-4 and IL-13 levels in the BALF. Histological studies showed that PF markedly inhibited inflammatory infiltration and mucus secretion in the lung tissues. In vitro study, psoralen significantly suppressed Th2 cytokines of IL-4, IL-5 and IL-13 by ConA-stimulated D10 cells without inhibitory effect on cell viability. Furthermore, GATA-3 protein expression was also markedly reduced by psoralen. This study demonstrated that PF exhibited inhibitory effects on hyperresponsiveness and airway inflammation in a rat model of asthma, which was associated with the suppression of Th2 response. Psoralen, a major constituent of PF, has immunomodulatory properties on Th2 response in vitro, which indicated that psoralen might be a critical component of PF for its therapeutic effects.

[Effects of resolving method of Chinese medicine on the lipid metabolism in polycystic ovary syndrome accompanied with non-alcoholic fatty liver disease].

OBJECTIVE: To observe the therapeutic effect of resolving method of Chinese medicine (CM) on the lipid metabolism in polycystic ovary syndrome (PCOS) patients accompanied with non-alcoholic fatty liver disease (NAFLD), to analyze the correlation between PCOS and NAFLD, and to study its mechanisms. METHODS: Totally 70 female PCOS patients in the reproductive age (20 -40 years old) were recruited. Among them, 35 PCOS patients accompanied with NAFLD were recruited as Group A, and 35 PCOS patients without complicated NAFLD were recruited as Group B. At the same time, 20 healthy female volunteers were recruited as the control group. All subjects had their personal medical records after relevant questionnaire. Their clinical data including body height (BH), body weight (BW), body mass index (BMI), waist circumference (WC), hip circumference (HC), testosterone (T), prolactin (PRL), follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), leptin, fasting blood glucose (FBG), fasting insulin (FINS), 2 h postprandial blood glucose (2 h PBG), homeostatic model assessment for insulin resistance (HOMA-IR), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), etc. were detected. Patients in Group A were treated by the resolving method for 3 months. The follow-up was continued for 6 months after ending treatment. RESULTS: The levels of BW, BMI, WHR, T, LH, LH/FSH, leptin, FINS, 2 h PBG, HOMA-IR, and LDL-C were significantly higher in Group B than in the control group (P < 0.05). The level of FSH was significantly lower in Group B than in the control group (P < 0.05). The levels of BW, BMI, WC, HC, waist-hip-ratio (WHR), leptin, FINS, 2 h PBG, HOMA-IR, TG, LDL-C, ALT, and AST were significantly higher in Group A than in Group B (P < 0.05). The HDL-C level was significantly lower in Group A than in Group B (P < 0.05). In Group A after treatment by resolving method of CM, the menstrual cycle was recovered in 83.87% patients (26/31 cases), reduced fatty liver degree or disappearance of fatty liver degree occurred in 32.26% patients (10/31 cases), with the total effective rate being 85.71% (24/28 cases).48.28% (14/29) patients were pregnant. The levels of BW, BMI, FBG, leptin, TG, ALT, and AST significantly decreased when compared with those before treatment (P < 0.05). The level of SHBG significantly increased (P < 0.05). There was no significant difference in the levels of HOMA-IR, FINS, T, FSH, LH, or LH/FSH between before and after treatment (P > 0. 05). CONCLUSIONS: The metabolic disorder of glycolipid exists in PCOS patients, and more serious in PCOS patients accompanied with NAFLD. Resolving method can effectively restore the metabolic disturbance in PCOS patients accompanied with NAFLD, recover their fatty liver degrees, recover normal menstrual cycles, and elevate their pregnancy rates. Further studies are necessary on whether its mechanisms lie on lowering leptin levels and correcting lipid metabolisms to relieve patient's clinical symptoms.

Establishment and comparison of combining disease and syndrome model of asthma with "kidney yang deficiency" and "abnormal savda".

THE STUDY WAS THE FIRST TIME TO ESTABLISH AND COMPARE TWO RAT MODELS OF TWO COMMON SYNDROMES: Kidney Yang Deficiency syndrome (KYDS) in traditional Chinese medicine (TCM) and abnormal savda syndrome (ASS) in traditional Uighur medicine (TUM). Then, we also established and evaluated rat models of combining disease and syndrome models of asthma with KYDS or ASS. Results showed that usage of the high dose of corticosterone (CORT) injection or external factors could successfully establish the KYDS or ASS rat models, and the two models had similar changes in biological characterization, abnormal behaviors, dysfunction of hypothalamic-pituitary-target organ axes (HPTOA), and sympathetic/parasympathetic (S/P) nerve system but varied in different degrees. The rat models of combining disease and syndrome of asthma with KYDS or ASS had either pathological characteristics of asthma such as airway hyperresponsiveness (AHR), airway inflammation, airway remodeling, which were more serious than allergy exposure alone, or the syndrome performance of Kidney Yang Deficiency in TCM and abnormal savda in TUM. These findings provide a biological rationale for further investigation of combining disease and syndrome model of asthma as an effective animal model for exploring asthma based on the theory of traditional medicine.

CD4+CD25+Foxp3+ T cells contribute to the antiasthmatic effects of Astragalus membranaceus extract in a rat model of asthma.

Astragalus membranaceus (AM), a traditional Chinese medicinal herb, has been widely used for centuries to treat asthma in China. Previous studies demonstrated that AM had inhibitory effects on airway hyperresponsiveness, inflammation and airway remodeling in murine models of asthma. However, it remained unclear whether the beneficial effects of AM on asthma were associated with CD4(+)CD25(+)Foxp3(+) Treg cells; this issue is the focus of the present work. An asthma model was established in Sprague-Dawley (SD) rats that were sensitized and challenged with ovalbumin. Bronchoalveolar lavage fluid (BALF) was assessed for inflammatory cell counts and cytokine levels. Airway hyperresponsiveness was detected by direct airway resistance analysis. Lung tissues were examined for cell infiltration, mucus hypersecretion and airway remodeling. CD4(+)CD25(+)Foxp3(+) Treg cells in the BALF and Foxp3 mRNA expression in lung tissues were examined. The oral administration of AM significantly reduced airway hyperresponsiveness to aerosolized methacholine and inhibited eosinophil counts and reduced IL-4, IL-5 and IL-13 levels and increased INF-γ levels in the BALF. Histological studies showed that AM markedly decreased inflammatory infiltration, mucus secretion and collagen deposition in the lung tissues. Notably, AM significantly increased population of CD4(+)CD25(+)Foxp3(+) Treg cells and promoted Foxp3(+) mRNA expression in a rat model of asthma. Together, these results suggest that the antiasthmatic effects of AM are at least partially associated with CD4(+)CD25(+)Foxp3(+) Tregs.

[Study on the relation between Pi-deficiency pattern and metabolic syndrome in patients with polycystic ovarian syndrome].

OBJECTIVE: To evaluate the relation between Pi-deficiency syndrome (PDS) pattern and metabolic syndrome (MS) in patients with polycystic ovarian syndrome (PCOS), for exploring their internal pathologic mechanism. METHODS: Among the 102 PCOS patients, 22 complicated with MS (PCOS-MS) and 80 not complicated with MS (PCOS-NMS), the Chinese medicine syndrome pattern was differentiated as PDS in 50 patients and non-PDS in 52. The clinical data, in terms of fasting blood glucose (FBG), fasting insulin (FINS), waistline, body weight (BW), stature, blood pressure (BP), etc. was collected and compared and the relation between data was analyzed. RESULTS: Levels of FINS and homeostasis model of assessment for insulin resistence index (HOMA-IR), in PCOS-MS patients were significantly higher than those in PCOS-NMS patients, also higher in patients of PDS pattern than those of non-PDS pattern (P < 0.01); the occurrences of MS and PDS were highly positively correlated with levels of FINS and HOMA-IR (P < 0.01); incidence of MS in patients of PDS pattern was significantly higher than those in patients of non-PDS pattern (P < 0.05); presenting of PDS was positively related with the existence of MS (P < 0.05), but in case of the FINS or HOMA-IR factor being controlled, statistical meaning of the relativity between them turned to insignificant (P > 0.05). CONCLUSIONS: PCOS patients of PDS pattern are the high-risk population of MS, which might be related with the insulin resistance. So, early treatment of PCOS, especially on patients of PDS pattern, is of important significance for preventing the complication, as MS, of the disease.