Serum KL-6 and the mortality of patients with connective tissue disease-associated interstitial lung disease: A meta-analysis.

Connective tissue disease-associated interstitial lung disease (CTD-ILD) is an important underlying cause of morbidity and mortality in patients with CTD. Serum Krebs von den Lungen-6 (KL-6) is an immune factor which has been related to the severity of ILD. This systematic review and meta-analysis aimed to evaluate the association between serum KL-6 and mortality of patients with CTD-ILD. Longitudinal studies relevant to the aim of the meta-analysis were retrieved by search of electronic databases including PubMed, Web of Science, and Embase. A random-effects model was used to combine the data by incorporating the influence of between-study heterogeneity. Fifteen cohorts involving 1737 patients with CTD-ILD were included. During a mean follow-up of 35.3 months, 430 (24.8%) patients died. Compared to those with a lower KL-6 at admission, patients with a higher KL-6 were associated with a higher mortality risk during follow-up (risk ratio: 2.18, 95% confidence interval: 1.66 to 2.87, P < 0.001; I2 = 20%). Subgroup analysis showed a significant association in studies from Asian countries, but not in those from non-Asian countries; in studies with cutoff of KL-6 derived in receiver operating characteristic (ROC) curve analysis, but not in those derived from other methods; in studies with multivariate analysis, but not in those with univariate analysis (P for subgroup difference all < 0.05). The association was not significantly affected by different CTDs or methods for measuring serum KL-6. In conclusion, a high serum KL-6 may be a risk factor of increased mortality in patients with CTD-ILD.

Anti-inflammatory activity of 4,4'-dihydroxy-alpha-truxillic acid.

The oral anti-inflammatory activity of 4,4'-dihydroxy-alpha-truxillic acid (1) was compared with that of two other nonsteroidal anti-inflammatory drugs, loxoprofen sodium (LOX) and diclofenac sodium (DIC). The activity of 1 against the inflammatory pain response induced by formalin was comparable to that of LOX, but weaker than that of DIC. In the monosodium urate (MSU)-induced acute inflammatory model, 1 showed stronger anti-inflammatory activity than both LOX and DIC. The ED50 value for 1 was 4.5 micromol/kg, while the values for LOX and DIC were 65 and 25 micromol/kg, respectively. Otherwise, the oral single-dose toxicity of 1 was investigated in both sexes of Sprague-Dawley rats administered once at a dose of 2000 mg/kg. 1 showed no death, clinical signs, changes in body weight or pathological findings related to the treatment. In addition, no mutagenicity was observed in the reverse mutation assay. Furthermore, 1 did not show any ulcerogenic activity at doses ranging from 30 to 300 mg/kg in rat. Thus, 1 might be considered to be an effective anti-inflammatory agent with no deleterious adverse effect.

Antinociceptive activities of alpha-truxillic acid and beta-truxinic acid derivatives.

Our recent study demonstrated that the dimeric structure of alpha-truxillic acid derivatives played an important role in the expression of their anti-inflammatory activities. In the present report, to investigate the correlation between the structure and anti-inflammatory activity, alpha-truxillic acid (1) and its derivatives (2-6), beta-truxinic acid (7) and its derivatives (8-10) were prepared, and their activities were evaluated in the formalin test. All compounds showed only weak or no activities against the neurogenic pain response, but demonstrated significant activities against the inflammatory pain response induced by formalin. The highest anti-inflammatory activities were observed for alpha-truxillic acid (1) and its derivative 4,4'-dihydroxy-alpha-truxillic acid (2). In addition, alpha-truxillic acid (1) and its derivative, alpha-truxillic acid bis(p-nitrophenyl)ester (5), showed higher anti-inflammatory activities than beta-truxinic acid (7) and the corresponding derivative (10). Furthermore, free carboxylic acids (1, 2) showed higher activities than their dimethyl esters (3, 4) and bis(p-nitrophenyl)ester (5). These results confirmed that the alpha-formation of dimeric structure and the free carboxylic acid were also important for the expression of anti-inflammatory activities. Otherwise, 4,4'-dichloro-beta-truxinic acid (8) had higher activity than its parent compound 7; furthermore, 1,3-dibenzoyl-2,4-di(4-chlorophenyl)cyclobutane (6) also showed strong anti-inflammatory activity. These results suggested that substituents in the phenyl groups were also important for the expression of anti-inflammatory activity. In order to gain information about their activity intensity, the anti-inflammatory activities of 2 and 4,4'-dichlorolated derivatives (6, 8) were compared with that of indomethacin (a nonsteroidal anti-inflammatory drug) in the formalin test. As a result, compounds 2, 6 and 8 showed stronger anti-inflammatory activities than indomethacin. These results suggested that alpha-truxillic acid and beta-truxinic acid derivatives might be developed into a new type of anti-inflammatory drug.

Quantitative determination of incarvillateine in Incarvillea sinensis by solid phase extraction and high performance liquid chromatography.

Method for rapid quantitative analysis of incarvillateine in Incarvillea sinensis by high-performance liquid chromatography (HPLC) has been developed. The sample preparation involves solid phase extraction (SPE) with a mixed-mode reversed-phase and cation-exchange cartridge. The linear calibration range for incarvillateine was 0.002-0.5 mg/ml. The limit of detection was 0.35 microg/ml (S/N=3). Intra- and interday precisions were less than 0.36% (n=6) and 1.61% (n=18), respectively. The recovery of incarvillateine was 97.61-102.44% with the relative standard deviation (RSD) ranging from 0.63 to 1.93% (n=3). This method was proposed as a simple, rapid and accurate method for quantitative determination of incarvillateine content in various samples of Incarvillea sinensis collected from different areas of China.

Pharmacological study on the novel antinociceptive agent, a novel monoterpene alkaloid from Incarvillea sinensis.

To determine the antinociceptive mechanism of incarvillateine (INCA), the opiate antagonists nor-binaltorphimine (nor-BNI), beta-funaltrexamine (beta-FNA) and naltrindole (NTI) were pretreated prior to its injection in a formalin test. The antinociceptive effect of INCA was antagonized by nor-BNI (kappa-receptor antagonist) and beta-FNA (mu-receptor antagonist), while NTI (delta-receptor antagonist) did not influence its effect. Furthermore, the antinociceptive effect of INCA was blocked by theophylline (THEO), an adenosine-receptor antagonist. These results suggested that the antinociceptive effect arose from the activation of mu-, kappa-receptors and adenosine-receptor.

Anti-inflammatory activities of alpha-truxillic acid derivatives and their monomer components.

The anti-inflammatory activities of alpha-truxillic acid (1) and 4,4'-dihydroxy-alpha-truxillic acid (2) as well as their monomer components (E)-cinnamic acid (3) and (E)-p-coumaric acid (4) were evaluated in the formalin test. alpha-Truxillic acid (1) and its derivative 4,4'-dihydroxy-alpha-truxillic acid (2) exhibited significant activity against inflammatory pain response, while their monomer components (E)-cinnamic acid (3) and (E)-p-coumaric acid (4) did not show any activity against either neurogenic or inflammatory pain responses induced by formalin in mice. These results suggested that the dimeric structure might play an important role for the expression of anti-inflammatory activity. Furthermore, in order to gain information on their potencies, their anti-inflammatory activities were compared with that of incarvillateine (5) which contains the same dimeric structure and showed more potent antinociceptive activity than morphine in the formalin test. The activities of alpha-truxillic acid (1) and 4,4'-dihydroxy-alpha-truxillic acid (2) at the dose of 40 mg/kg against inflammatory pain response were equal to that of incarvillateine at doses of 20 mg/kg.

A monoterpene alkaloid from incarvillea sinensis.

A novel monoterpene alkaloid, named incarvillateine E, possessing three moles of incarvilline moieties, has been obtained from the aerial parts of Incarvillea sinensis LAM. (Bignoniaceae). On the basis of spectroscopic evidence, the structure of incarvillateine E has been characterized.