Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screening.

Primary cilia dyskinesia (PCD) is a rare genetic disease caused by ciliary structural or functional defects. It causes severe outcomes in patients, including recurrent upper and lower airway infections, progressive lung failure, and randomization of heterotaxy. To date, although 50 genes have been shown to be responsible for PCD, the etiology remains elusive. Meanwhile, owing to the lack of a model mimicking the pathogenesis that can be used as a drug screening platform, thereby slowing the development of related therapies. In the current study, we identified compound mutation of DNAH9 in a patient with PCD with the following clinical features: recurrent respiratory tract infections, low lung function, and ultrastructural defects of the outer dynein arms (ODAs). Bioinformatic analysis, structure simulation assay, and western blot analysis showed that the mutations affected the structure and expression of DNAH9 protein. Dnah9 knock-down (KD) mice recapitulated the patient phenotypes, including low lung function, mucin accumulation, and increased immune cell infiltration. Immunostaining, western blot, and co-immunoprecipitation analyses were performed to clarify that DNAH9 interacted with CCDC114/GAS8 and diminished their protein levels. Furthermore, we constructed an airway organoid of Dnah9 KD mice and discovered that it could mimic the key features of the PCD phenotypes. We then used organoid as a drug screening model to identify mitochondrial-targeting drugs that can partially elevate cilia beating in Dnah9 KD organoid. Collectively, our results demonstrated that Dnah9 KD mice and an organoid model can recapture the clinical features of patients with PCD and provide an excellent drug screening platform for human ciliopathies.

Effectiveness and safety of Danmu extract syrup for acute upper respiratory tract infection in children: A real-world, prospective cohort study.

AIM: To evaluate the effectiveness and safety of Danmu Extract Syrup for the treatment of acute upper respiratory tract infection (AURI) in children. METHODS: In this prospective cohort study, we enrolled children with AURI in the pediatric outpatient department and emergency department of West China Second Hospital. According to the treatment, they were divided into two groups: Danmu Extract Syrup Group (Danmu Group) and Xiaoer Chiqiao Granule Group (Chiqiao Group). The primary outcome was time to symptom remission, and the secondary outcomes were defervescence time, relief time, admission rate, and adherence. We used restricted mean survival time (RMST) to quantify the treatment effects and test noninferiority for primary outcome. Propensity score matching (PSM) was used to adjust confounding. Subgroup analysis and sensitivity analysis were used to verify the robustness of results. RESULTS: We enrolled 1036 children with AURI, including 516 in Danmu Group and 520 in Chiqiao Group. After PSM, no significant difference was observed in the baseline characteristics of the two groups. The primary results showed that the RMST difference was -3 h (95% CI: -15.1 to 9.1) and the upper limit of the 95% CI was less than the noninferiority margin of 11 h. There was no statistical difference in the secondary outcomes except for defervescence between the two groups. The results of safety analysis showed that the incidence of adverse events occurred is 4.1% in Danmu Group, which was lower than the incidence of Chiqiao Group (6.9%). CONCLUSION: This study indicated that Danmu extract syrup is noninferiority to Chiqiao Granule for AURI in children.

Efficacy of Huaiqihuang granules as adjuvant therapy for bronchial asthma in children: a real-world study. / æ§æžé»„é¢—ç²’è¾ åŠ©æ²»ç–—å„¿ç«¥æ”¯æ°”ç®¡å“®å–˜ç–—æ•ˆçš„çœŸå®žä¸–ç•Œç ”ç©¶.

OBJECTIVES: To study the efficacy of Huaiqihuang granules as adjuvant therapy for bronchial asthma in children. METHODS: A multicenter, prospective, and registered real-world study was performed for the children, aged 2-5 years, who had a confirmed diagnosis of bronchial asthma in the outpatient service of 21 hospitals in China. Among these children, the children treated with medications for long-term asthma control (inhaled corticosteroid and/or leukotriene receptor antagonist) without Huaiqihuang granules were enrolled as the control treatment group, and those treated with medications for long-term asthma control combined with Huaiqihuang granules were enrolled as the combined treatment group. The medical data of all children were collected. Outpatient or telephone follow-up was performed at weeks 4, 8, 12, 20, 28, and 36 after treatment, including asthma attacks and rhinitis symptoms. A statistical analysis was performed for the changes in these indices. RESULTS: There was no significant difference in the frequency of asthma attacks or rhinitis attacks between the two groups before treatment (P>0.05). After treatment, the combined treatment group had significantly lower frequencies of asthma attacks, severe asthma attacks, and rhinitis attacks compared with the control treatment group (P<0.05). There was no signification difference in the incidence rate of adverse reactions between the two groups (P=0.667). CONCLUSIONS: Huaiqihuang granules in addition to medications for long-term asthma control can alleviate the symptoms of bronchial asthma and rhinitis and improve the level of asthma control in children with bronchial asthma, with good safety and little adverse effect. Citation.

Maternal periconceptional folic acid supplementation reduced risks of non-syndromic oral clefts in offspring.

Maternal periconceptional folic acid supplementation (FAS) has been documented to be associated with decreased risk of nonsyndromic oral clefts (NsOC). However, the results remain inconclusive. In this population-based case-control study of 807 singletons affected by NsOC and 8070 healthy neonates who were born between October 2010 and September 2015 in Chengdu, China, we examined the association of maternal FAS with the risk of nonsyndromic cleft lip with or without cleft palate (NsCL/P), and cleft palate (NsCP). Unconditional logistic regression analysis was used to estimate the crude and adjusted odds ratios (ORs) and 95% confidential intervals (CI). Significant associations were found between maternal periconceptional FAS and decreased risk of NsCL/P (aOR = 0.41, 95% CI 0.33-0.51). This protective effect was also detected for NsCL (aOR = 0.42, 95% CI 0.30-0.58) and NsCLP (aOR = 0.41, 95% CI 0.31-0.54). Both maternal FAS started before and after the last menstrual period (LMP) were inversely associated with NsCL/P (before LMP, aOR = 0.43, 95% CI 0.33-0.56; after LMP, aOR = 0.41, 95% CI 0.33-0.51). The association between NsCP and maternal FAS initiating before LMP was also found (aOR = 0.52, 95% CI 0.30-0.90). The findings suggest that maternal periconceptional FAS can reduce the risk of each subtype of NsCL/P in offspring, while the potential effect on NsCP needs further investigations.

Leaf extract from Vitis vinifera L. reduces high fat diet-induced obesity in mice.

Despite the health benefits of Vitis vinifera L. leaves, its anti-obesity potential has not been fully explored. In this work, we showed that Vitis vinifera L. leaf extract (VLE) inhibits the pancreatic lipase activity. Intragastric administration of VLE to mice led to a significant decrease in the body weight, tissue fat accumulation, levels of cholesterol, low-density lipoprotein and triglyceride compared to mice fed with high fat diet. We also found a lower level of neuropeptide-Y (NPY) in the serum and hypothalamus and a higher level of fibroblast growth factor 15 in mice supplemented with VLE. These results suggested that VLE regulates both the NPY-mediated pathway and the bile acid-FGF15 pathway to control energy metabolism and body weight gain. The composition of VLE was further investigated by a targeted metabolomics approach, which identified 21 compounds including phenolic acids, flavones, flavanols, flavanones, coumarins, and stilbenes. Taken together, we demonstrated the capacity of grape leaves in reducing obesity, which could be mediated by NPY and bile acids. Identification of putative active compounds in VLE also open the path for further studies to determine their effectiveness individually to treat obesity.

The clinical efficiency of lycium-rehmannia pills in treating dry eye symptom: A meta-analysis.

BACKGROUND: Dry eye symptom threatens human health and causes a larger burden of disease, the study aims to systematically compare the therapeutic effect of Lycium-rehmannia pills combined with topical eye drops and pure western medicine (western medicine eye drops) on dry eye symptom, to provide a reflection and enlightenment for clinical treatment. METHOD: PubMed, The Cochrane Library, EMbase, MEDLINE, CBM, WanFang, VIP, and CNKI databases were searched manually and automatically by the computer until March 2019 and relevant randomized controlled trials (RCTs) were selected. Article selection and data extraction were conducted by 2 researchers independently, then RevMan 5.3 was applied for meta-analysis. RESULT: Fifteen randomized controlled trials were included, including 1222 patients (eyes = 2382). The meta-analysis results showed that Lycium-rehmannia pills combined with western medicine were superior to the control group in terms of therapeutic efficiency [OR = 4.38, 95% confidence interval (CI) (3.26, 5.89), P < .00001]. There were controversial results that the study group was better than the control group in Basic Schirmer test [MD, 2.46, 95% CI (1.49, 3.44), P < .00001], tear break up time [MD, 3.79, 95% CI (3.57, 4.01), P < .00001], and Fluorescein test [MD, -1.29, 95% CI (-1.42, -1.15), P < .00001], but Lycium-rehmannia pills combined with western medicine could not reduce the incidence of adverse reactions, including eyelid inflammation [OR = 1.00, 95% CI (0.37, 2.72), P = 1.00] and congestion symptom [OR = 0.55, 95% CI (0.18, 1.65), P = .28]. CONCLUSION: Lycium-rehmannia pills combined with western medicine is better than the control group of therapeutic efficiency in the treatment of dry eye symptom. Due to the quantity and quality limitations of the literature, there were controversial results that the study group was better than the control group in Basic Schirmer test, Tear break up time, Fluorescein test, and reduced adverse reactions, including inflammation of the eyelids and congestion. The above conclusion needs more clinical trials to test and verify.

Structural characterization and immunomodulatory activity of exopolysaccharides from submerged culture of Auricularia auricula-judae.

Submerged culture of Auricularia auricula-judae has been documented, but there have been few studies on the structural characterization and medicinal properties of its exopolysaccharides. In present study, two exopolysaccharides, named CEPSN-1 and CEPSN-2, were isolated from submerged culture of A. auricula-judae, and their structural features as well as immunomodulatory activity were analyzed. The two exopolysaccharides both had a backbone chain composed of (1 → 4)-α-d-glucose residues in glucopyranose type. At the tested concentration range of 50-200 µg/mL, CEPSN-1 and CEPSN-2 not only showed non-toxicity to RAW 264.7 cells, but also could promote the release of NO and cytokines (IL-6, IL-10 and TNF-α) in the cells. The release of NO was significantly enhanced by the two exopolysaccharides at 100 µg/mL (p < 0.05). The IL-10 secretion was significantly increased by 1.80 and 1.61-fold, compared to the control after treatment with 50 µg/mL of CEPSN-1 and CEPSN-2, respectively (p < 0.05). These results demonstrated that, though their structural feature were different from that of polysaccharides from fruit body, exopolysaccharides of A. auricula-judae from submerged culture with the backbone of (1 → 4)-α-D-glucan could be explored as potential immunomodulatory agents for the application in complementary medicine or functional foods.

Calcium channel blockers for pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is one of several forms of pulmonary hypertension: a chronic disease of the pulmonary vasculature. The mean age at diagnosis is around 50 years old, with increasing prevalence in people over 70 years old (10% to 17%). The median survival to be approximately seven years with one-, three-, five-, and seven-year survival rates from time of diagnostic right-sided heart catheterization were 85%, 68%, 57%, and 49%, respectively. Several studies showed that calcium channel blockers (CCBs) reduce right ventricular hypertrophy and improve long-term haemodynamics in PAH. OBJECTIVES: To evaluate the clinical efficacy and harms of CCBs for people with PAH. SEARCH METHODS: The search strategy was provided by the Cochrane Airways Group Trials Search Co-ordinator. The following databases were searched from their inception until September 2014: the Cochrane Airways Group Register of Trials (CAGR); the Cochrane Central Register of Controlled Clinical Trials (CENTRAL) (The Cochrane Library,Issue 8 2014); MEDLINE (1948 to September 2014); EMBASE (1974 to September 2014); ClinicalTrials.gov; WHO trial portal; the Chinese Biomedical Databases (1979 to September 2014); CNKI: the Chinese Journals Full Text Database (1979 to September 2014), the Chinese Journals Full Text Database Century Journals (1979 to September 2014), the Chinese Doctoral Degree Thesis Full Text Database (1979 to September 2014), the Chinese Outstanding Master Degree Thesis Full Text Database (1979 to September 2014); VIP Database (1989 to September 2014) and WANFANG Database (1993 to September 2014). No language restriction was applied. SELECTION CRITERIA: Fully published randomized controlled trials (RCTs) comparing CCBs with placebo or other treatment, or comparing CCBs as an adjunct to other treatments with other treatments alone, in patients with PAH. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. MAIN RESULTS: We found one RCT to include in this review but it was published only in abstract form with no data for evaluation. AUTHORS' CONCLUSIONS: Currently, as there is lack of valid evidence, the efficacy and safety of CCBs is unproven in the treatment of PAH. However, the search strategy used for this review did identify four controlled clinical trials without randomization, three of which suggested treatment with CCBs may be beneficial in PAH. No adverse side effects of CCBs were reported. Confirmation of these findings by RCTs is recommended.

Simvastatin has beneficial effect on pulmonary artery hypertension by inhibiting NF-κB expression.

Whether Simvastatin has beneficial effect on pulmonary artery hypertension (PAH) remains unclear. This study aimed to explore the effect of simvastatin on PAH and the underlying mechanism. Male SD rats were randomized into three groups: control group, PAH model group, and treatment group with the intervention of the Simvastatin (n = 10, each group). Rat PVSMCs were isolated from pulmonary artery, cultured in vitro, and subjected to different treatment with PDGF, and/or Simvastatin or parthenolide. The mean pulmonary arterial pressure (mPAP), endomembrane proliferation in the pneumono-arteriole, and scores of the average angiemphraxis (VOS) were measured. The expression of NF-κB at mRNA and protein levels in the artery and PVSMCs was evaluated by fluorescent quantitative PCR, immunohistochemistry, and Western blot. Our results showed that mPAP, endomembrane proliferation in the pneumono-arteriole and VOS increased significantly in PAH model group compared with control group (P < 0.05). NF-κB expression was significantly higher in PAH model group than control group (P < 0.05), and also higher in the stimulated PVSMCs than control PVSMCs (P < 0.05). With the intervention of simvastatin, mPAP, endomembrane proliferation in the pneumono-arteriole and VOS decreased dramatically, compared with model group (P < 0.05). NF-κB expression was significantly decreased in both the artery and PVSMCs (P < 0.05). In conclusion, our study provides experimental evidence that NF-κB plays an important role in the occurrence of pulmonary artery hypertension and Simvastatin has beneficial effect on pulmonary artery hypertension by inhibiting the expression of NF-κB.