Systematic review of randomized controlled trials of traditional Chinese medicine treatment of non-acute bronchial asthma complicated by gastroesophageal reflux.

OBJECTIVE: To assess the effectiveness and safety of Traditional Chinese Medicine (TCM) treatment of non-acute bronchial asthma complicated by gastroesophageal reflux. METHODS: We searched databases from MEDLINE, Cochrane Library, CNKI, VIP, CBM, Wanfang Data, and TCM Database Systems. All randomized, controlled trials (RTCs) of TCM treatment of non-acute asthma complicated by gastroesophageal reflux were included. Data were independently collected by two reviewers. The standards for assessing quality described in the Cochrane Handbook for Systematic Reviews of Interventions were used to evaluate articles. Meta-analyses were conducted using Rev- Man 5.0.17 software. Heterogeneity was assessed, and a corresponding effects model was used to merge and analyze results. Indexes used to evaluate curative effects were: clinical efficacy, symptom scores, pulmonary function values, and adverse incidents. Effectiveness was indicated using risk ratio (RR) or mean difference (MD), and 95% confidence intervals (CIs) were calculated. RESULTS: Six RCTs were included, involving 304 patients with non-acute asthma complicated by gastroesophageal reflux. The treatment groups received Chinese drugs alone or TCM combined with standard Western medical treatment, and the control groups received standard Western medical treatment alone. Standard Western medical treatment included anti-inflammatory drugs and bronchodilators for asthma, and drugs to promote gastric peristalsis and inhibit gastric acid production for gastroesophageal reflux. Methodological quality was low in all six RCTs. Two RCTs showed that clinical efficacy was higher in the treatment group than in the control group (RR: 1.43, 95%CI: 1.10 to 1.87 vs RR: 1.51, 95% CI: 1.09 to 2.08). One RCT showed that the asthma score was lowered more effectively in the treatment group than in the control group (MD:-1.10, 95% CI:-2.04 to-0.16). Two RCTs showed that the gastroesophageal reflux score was reduced more effectively in the treatment group than in the control group (RR:-3.70, 95% CI:-4.30 to 3.10 vs RR:-5.30, 95% CI:-6.32 to -4.28). One RCT showed that some pulmonary function values were improved more effectively in the treatment group than in the control group (P < 0.05). No differences were seen in the various indexes between groups in the other RCTs. No adverse reactions, dropout rates, or follow-up rates were reported in any of the RCTs. CONCLUSIONS: The clinical symptoms of non-acute asthma complicated by gastroesophageal reflux can be improved by some Chinese drugs. Curative effects can be increased by combining the use of TCM with Western medicine. Because of the small quantity and low quality of research reported to date, it is necessary to conduct further RCTs to confirm these results. The results of this systematic review indicate that the quality of future clinical trials should be improved by including larger patient numbers, correctly randomizing patients into study groups, using blinding methods to measure and assess outcomes, and using accepted indexes to evaluate curative effects.

NF-kappaB down-regulates expression of the B-lymphoma marker CD10 through a miR-155/PU.1 pathway.

Cell-surface protein CD10 is a prognostic marker for diffuse large B-cell lymphoma (DLBCL), where high expression of CD10 is found in the germinal center B-cell (GCB) subtype and CD10 expression is low or absent in the activated B-cell (ABC) subtype. As compared with the GCB subtype, patients with ABC DLBCL have a poorer prognosis after standard treatment, and ABC tumor cells have higher NF-κB activity. Herein, we show that increased expression of the NF-κB target micro-RNA miR-155 is correlated with reduced expression of transcription factor PU.1 and CD10 in several B-lymphoma cell lines. Moreover, electromobility shift assays and luciferase reporter assays indicate that PU.1 can directly activate expression from the CD10 promoter. Expression of a DLBCL-derived mutant of the adaptor CARD11 (a constitutive activator of NF-κB) in the GCB-like human BJAB cell line or v-Rel in the chicken DT40 B-lymphoma cell line causes reduced expression of PU.1. The CARD11 mutant also causes a decrease in CD10 levels in BJAB cells. Similarly, overexpression of miR-155, which is known to down-regulate PU.1, leads to reduced expression of CD10 in BJAB cells. Finally, we show that CD10 expression is reduced in BJAB cells after treatment with the NF-κB inducer lipopolysaccharide (LPS). Additionally, miR-155 is induced by LPS treatment or expression of the CARD11 mutant in BJAB cells. These results point to an NF-κB-dependent mechanism for down-regulation of CD10 in B-cell lymphoma: namely, that increased NF-κB activity leads to increased miR-155, which results in decreased PU.1, and consequently reduced CD10 mRNA and protein.

PKA independent and cell type specific activation of the expression of caudal homeobox gene Cdx-2 by cyclic AMP.

Cdx-2 is a transactivator for the proglucagon gene in pancreatic and intestinal endocrine cells. Cdx-2 is also expressed in differentiated intestinal epithelia of nonendocrine origin. Cdx-2-/- mice are embryonic lethal, while Cdx-2+/- mutants show multiple malfunctions including the formation of intestinal polyps. Within the polyps, the remaining wild type Cdx-2 allele ceases its expression, while the expression of both Cdx-2 and proglucagon in the endocrine cells remains unaltered, indicating that Cdx-2 could be haplo-insufficient for nonendocrine cells, but not for proglucagon producing endocrine cells. We propose that mechanisms underlying Cdx-2 expression and auto-regulation [Xu F, Li H & Jin T (1999), J Biol Chem274, 34310-34316] differ in these two types of cells. We show here that forskolin and cAMP upregulate Cdx-2 expression in proglucagon producing cells, but not in colon cancer cells and primary intestinal cell cultures. It is unlikely that the activation is mainly mediated by PKA, because the activation was observed in a PKA deficient cell line. Co-transfecting a dominant negative Ras expression plasmid substantially repressed the Cdx-2 promoter, in contrast to a previous finding that Ras is a negative factor for Cdx-2 expression in colon cancer cells. Furthermore, forskolin activated ERK1/2 phosphorylation in the endocrine cells, and attenuation of ERK1/2 phosphorylation by its inhibitor is associated with attenuated Cdx-2 expression. Finally, an Epac pathway specific cAMP analogue stimulated both ERK1/2 phosphorylation and Cdx-2 expression. Taken together, our observations suggest that Cdx-2 expression is regulated by the second messenger cAMP, cell-type specifically, via the Epac pathway.