Efficacy and safety of modified Bushen Yiqi formulas (MBYF) as an add-on to formoterol and budesonide in the management of COPD: study protocol for a multicentre, double-blind, placebo-controlled, parallel-group, randomized clinical trial: FB-MBYF Trial.

BACKGROUND: Inhaled glucocorticoid corticosteroid (ICS), long-acting ß2-adrenoceptor agonist (LABA), and other drugs have limited therapeutic effects on COPD with significant individual differences. Traditional Chinese medicine (TCM)-modified Bushen Yiqi formula (MBYF) demonstrates advantages in COPD management in China. This study aims to evaluate the efficacy and safety of MBYF as an add-on to budesonide/formoterol in COPD patients and confirm the related genes affecting the therapeutic effect in the treatment of COPD. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, parallel-group study, eligible patients with COPD will randomly receive a 360-day placebo or MBYF as an adjuvant to budesonide/formoterol in a 1:1 ratio and be followed up with every 2 months. The primary outcomes will be the frequency, times, and severity of acute exacerbation of COPD (AECOPD), COPD assessment test (CAT) score, and pulmonary function tests (PFTs). The secondary outcomes will include the modified Medical Research Council (mMRC) dyspnoea scale, 6-min walking test (6MWT), BODE index, quantitative scores of syndromes classified in TCM, inflammation indices, and hypothalamic-pituitary-adrenaline (HPA) axis function. We will also test the genotype to determine the relationship between drugs and efficacy. All the data will be recorded in case report forms (CRFs) and analysed by SPSS V.20.0. DISCUSSION: A randomized clinical trial design to evaluate the efficacy and safety of MBYF in COPD is described. The results will provide evidence for the combination therapy of modern medicine and TCM medicine, and individual therapy for COPD. TRIAL REGISTRATION: ID:  ChiCTR1900026124 , Prospective registration.

Comprehensive Analysis of Myoferlin in Human Pancreatic Cancer via Bioinformatics.

Pancreatic cancer is the fourth leading cause of cancer-related death and urgently needs biomarkers for clinical diagnosis and prognosis. It has been reported that myoferlin (MYOF) is implicated in the regulation of proliferation, invasion, and migration of tumor cells in many cancers including pancreatic cancer. To confirm the prognostic value of MYOF in pancreatic cancer, a comprehensive cancer versus healthy people analysis was conducted using public data. MYOF mRNA expression levels were compared in many kinds of cancers including pancreatic cancer via the Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA) databases. The results have shown that MYOF mRNA expression levels were upregulated in most types of cancers, especially in pancreatic cancer, compared with healthy people's tissues. Data from the Cancer Cell Line Encyclopedia (CCLE) and European Bioinformatics Institute (EMBL-EML) database also revealed that MYOF mRNA is highly expressed in most cancer cells, particularly in pancreatic cancer cell lines. Furthermore, the prognostic value of MYOF was evaluated using GEPIA and Long-term Outcome and Gene Expression Profiling Database of pan-cancers (LOGpc) database. Higher expression of MYOF was associated with poorer overall survival, especially in the lower stage and lower grade. Coexpressed genes, possible regulators, and the correlation between MYOF expressions were analyzed via the GEPIA and LinkedOmics database. Nineteen coexpressed genes were identified, and most of these genes were related to cancer. The Tumor Immune Estimation Resource (TIMER) database was used to analyze the correlation between MYOF and immune response. Notably, we found that MYOF might have a potential novel immune regulatory role in tumor immunity. These results support that MYOF is a candidate prognostic biomarker for pancreatic cancer, which calls for further genomics research of pancreatic cancer and deeply functional studies on MYOF.

Efficacy and safety of Jia Wei Bushen Yiqi formulas as an adjunct therapy to systemic glucocorticoids on acute exacerbation of COPD: study protocol for a randomized, double-blinded, multi-center, placebo-controlled clinical trial.

BACKGROUND: Systemic glucocorticoids are effective for the management of chronic obstructive pulmonary disease (COPD) exacerbation but have serious adverse effects. Traditional Chinese medicine (TCM) can bring additional benefits to these patients but has few adverse effects. The present study aims to evaluate the efficacy and safety of Jia Wei Bushen Yiqi (JWBY) formulas in patients who suffer from COPD exacerbations and to investigate whether the short-term (5-days) systemic glucocorticoid therapy is non-inferior to the long-term (9-day) regime. METHODS: In this multi-center, randomized, double-blinded trial, eligible inpatients with COPD exacerbation are randomly assigned to four groups (A, B, C, and D). Group A will receive placebo plus 5-day prednisone, group B will receive placebo plus 9-day prednisone, group C will receive JWBY formulas plus 5-day prednisone, and group D will receive JWBY formulas plus 9-day prednisone. The primary outcomes are the time interval to the patient's next exacerbation during a 180-day following up and the COPD assessment test (CAT) during treatment. Secondary outcomes include lung function, TCM syndrome assessment, laboratory tests, and safety. The changes of the hypothalamic pituitary adrenaline axis (HPA axis) and inflammatory cytokine will be measured as well. DISCUSSION: By demonstrating the advantages of utilizing TCM and an appropriate duration of systemic glucocorticoids, this effectiveness comparison trial will provide new references to physicians on how to improve the management of COPD exacerbation. The results of HPA axis and inflammation cytokine measurements will shed light on the molecular mechanisms and entail further mechanism studies. TRIAL REGISTRATION: www.chictr.org.cn ChiCTR1900023364. Registered on 24 May 2019.

Icariin reduces LPS-induced acute lung injury in mice undergoing bilateral adrenalectomy by regulating GRα.

In the present study, we established the acute lung injury (ALI) model of mice with adrenal insufficiency, and to investigate the possible mechanism by which Icariin (ICA) reduces lipopolysaccharide (LPS) -induced ALI in mice undergoing bilateral adrenalectomy by regulating glucocorticoid receptor α (GRα). ALI of BALB/c mice with adrenal insufficiency was induced by LPS and bilateral adrenalectomy (ADX). The pathological and morphological changes in lung tissues were observed, the levels of corticosterone, IL-6, and TNF-α in serum and lung tissues by ELISA. The levels of GRα, IL-6, TNF-α, NF-κB p65, Stat3, and c-Jun in lung tissues were detected by RT-qPCR and Western Blotting, GRα activity was blocked by GRα antagonist RU486. It was found that the dual intervention of LPS and ADX had further aggravation the downregulation of GRα and upregulation of NF-κB p65, c-Jun, Stat3, and IL-6 and TNF-α, ICA enhanced the expression of GRα in lung tissues and inhibited the expression of NF-κB p65, c-Jun, Stat3, IL-6, and TNF-ɑ, thereby reducing ALI. However, RU486 could partially counteract the protective effect of ICA on lung injury and its downregulating effect on various inflammatory transcription factors and inflammatory cytokines. In conclusion, ICA reduces ALI in mice undergoing bilateral ADX by regulating GRα, and no inhibitory effect on hypothalamic pituitary adrenal (HPA) axis.

A review of traditional pharmacological uses, phytochemistry, and pharmacological activities of Tribulus terrestris.

Tribulus terrestris L. (TT) is an annual plant of the family Zygophyllaceae that has been used for generations to energize, vitalize, and improve sexual function and physical performance in men. The fruits and roots of TT have been used as a folk medicine for thousands of years in China, India, Sudan, and Pakistan. Numerous bioactive phytochemicals, such as saponins and flavonoids, have been isolated and identified from TT that are responsible alone or in combination for various pharmacological activities. This review provides a comprehensive overview of the traditional applications, phytochemistry, pharmacology and overuse of TT and provides evidence for better medicinal usage of TT.

The Anti-Inflammatory Effects of Invigorating Kidney and Supplementing Qi Chinese Herbal Formulae in Asthma Patients.

BACKGROUND: The theories of Shen-reinforcement and Qi-supplementation are important in asthma treatment based on traditional Chinese medicine theories. Early studies suggested that Invigorating Kidney and Supplementing Qi herbal formulae, Bu Shen Fang Chuan (BSFC) and Bu Shen Yi Qi (BSYQ), conveyed promising results in asthma treatment. However, the efficacy and safety of the formulae need to be further investigated by a randomized double-blind clinical trial. METHODS: 328 eligible patients were randomly sent to BSFC, BSYQ, and placebo group. The two formulae were received as add-on therapy. The primary endpoints were rate of asthma exacerbation and Hamilton Rating Scale for Depression (HAM-D) score. The secondary endpoints included HPA axis function and inflammatory cytokine production profile. All indexes were measured before and after treatment. RESULTS: The primary endpoints were not improved in both groups; however, the depression levels of subgroup patients with HAM-D score > 5 were improved in BSFC group. HPA axis functions and inflammatory cytokines level were also improved by two formulae. The incidences of adverse events were similar among groups. CONCLUSIONS: The two formulae had multiple advantage effects on neuroendocrine-immune system. They are worth used as a replacement therapy in asthma. TRIAL REGISTRATION: This trial is registered with clinical trial number ChiCTR-PRC-09000529.

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.

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.

[Study on the correlation between the inflammatory factors in the serum and the induced sputum and the hypothalamic-pituitary-adrenal axis function in advanced lung adenocarcinoma of different syndromes].

OBJECTIVE: To study the correlation between the inflammatory factors in the serum and the induced sputum and the hypothalamic-pituitary-adrenal (HPA) axis function in advanced lung adenocarcinoma patients of different syndromes. METHODS: Totally 71 patients with advanced lung adenocarcinoma were assigned to three groups according to syndrome differentiation, i.e., Shen-yang deficiency (SYD) group (28 cases), Fei-qi deficiency (FQD) group (23 cases), and yin deficiency fire excess (YDFE) group (20 cases). Another 41 healthy subjects were enrolled as the normal control group. Sputum was induced and blood samples were collected for measurement of cytokines including tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), interleukin-6 (IL-6), and interferon gamma (INF-gamma). The cytokine assay was performed using Bio-Plex Pro multi assay technology. 24-h collection of urine was performed and salivary samples of the diurnal rhythm profiles [including urinary free cortisol (UFC), urinary 17-hydroxycorticosteroids (17-OH), urinary 17-ketosteroid (17-KS), and cortisol in the serum and saliva] were obtained for assessment of the HPA axis activity. RESULTS: A higher level of serum IL-6 and a lower level of 24-h UFC and 17-OH were found in the SYD group (P < 0.05). The urinary 17-KS was obviously lower in the SYD group than in the normal control group and the YDEE group (P < 0.05). Compared with the FQD group and the normal control group, a higher serum level of TNF-alpha and a lower level of IFN-gamma were found in the SYD group and the YDFE group (P < 0.05). The TNF-alpha and TGF-beta levels in the induced sputum obviously increased in the SYD group (P < 0.05). The IFN-gamma level in the induced sputum obviously decreased in the YDFE group (P < 0.05). The serum and salivary cortisol obviously decreased from 8: 00 am to 8:00 am the next morning in the SYD group (P < 0.05). The serum cortisol level was negatively correlated with serum TNF-alpha (r = -0.26, P = 0.03) and serum IL-6 (r = -0.25, P = 0.03). The salivary cortisol level was negatively correlated with IL-6 in the induced sputum (r = -0.29, P = 0.02). The serum IFN-gamma was positively correlated with urinary 17-OH (r = 0.21, P = 0.03). CONCLUSIONS: The inflammatory factors of advanced lung adenocarcinoma patients of SYD syndrome were up-regulated, with the most obvious decreased or disarranged HPA axis functions. The levels of IL-6, TNF-alpha, and IFN-gamma were closely correlated with the HPA axis functions. The transformation from qi deficiency, yin deficiency to Shen-yang deficiency existed in lung adenocarcinoma patients. The levels of IL-6, TNF-alpha, and IFN-gamma in the serum and the induced sputum, as well as the HPA axis functions are important indices for microscopic syndrome typing of lung adenocarcinoma.

[Biomarkers and inflammatory characteristics for microcosmic syndrome differentiation of cold-phlegm syndrome and heat-phlegm syndrome in patients with bronchial asthma].

OBJECTIVE: To explore the biomarkers and inflammatory characteristics for microcosmic syndrome differentiation of cold-phlegm syndrome (CPS) and heat-phlegm syndrome (HPS) in patients with bronchial asthma. METHODS: Patients with bronchial asthma of chronic persistent condition were distributed into three groups according syndrome differentiation, the CPS group (27 patients), the HPS group (32 patients) and the non-cold/heat-phlegm syndrome group (NP group, 31 patients), besides, a control group was setup with 33 healthy persons. Percentages of neutrophils and eosinophils (NEU, EOS) in sputum sample (collected by induction) and peripheral blood were counted; and levels of interleukin-8, -5, and -4 (IL-8, IL-5 and IL-4), interferon-gamma (IFN-gamma), leukotriene B4 (LT-B4), eosinophil cationic protein (ECP), and C-reactive protein (CRP) in sputum supernatant and serum were determined by enzyme-linked immunosorbent assay. RESULTS: Percentage of NEU in sputum of HPS group was higher than that in the other three groups (P < 0.05); while percentages of EOS in serum and sputum of CPS group were higher than that in the other three groups (all P < 0.01). Level of ECP (a parameter closely associated with EOS) also was high in the CPS group, but IL-8 (a parameter closely associated with NEU) showed no significant difference in various groups (P > 0.05). Moreover, the CPS group showed a higher serum IL-4 (P < 0.05) but a lower IFN-gamma/IL-4 level as compared with those in the NP group (P < 0.01). CONCLUSION: Phlegm, which is considered by Chinese medicine as an inveterate root of asthma, might be closely related with the inflammation in modern medicine. The inflammatory characteristics of asthma in patients with CPS partially present as increase of EOS, possibly show Th2 dominant trend, similar to that presented in eosinophilic asthma. Asthma with HPS embodies increase of NEU in respiratory tract. EOS and ECP might be the important markers for microcosmic syndrome differentiation of CPS, and NEU might be that for HPS.