clinicaltrials.gov Identifier: NCT01045330.

Andrographis paniculata (Burm. f.) Nees (Acanthaceae) is a medicinal plant used in many countries. Its major constituents are diterpenoids, flavonoids and polyphenols. Among the single compounds extracted from A. paniculata, andrographolide is the major one in terms of bioactive properties and abundance. Among the andrographolide analogues, 14-deoxy-11,12-didehydroandrographolide is immunostimulatory, anti-infective and anti-atherosclerotic; neoandrographolide is anti-inflammatory, anti-infective and anti-hepatotoxic; 14-deoxyandrographolide is immunomodulatory and anti-atherosclerotic. Among the less abundant compounds from A. paniculata, andrograpanin is both anti-inflammatory and anti-infective; 14-deoxy-14,15-dehydroandrographolide is antiinflammatory; isoandrographolide, 3,19-isopropylideneandrographolide and 14-acetylandrographolide are tumor suppressive; arabinogalactan proteins are anti-hepatotoxic. The four flavonoids from A. paniculata, namely 7-Omethylwogonin, apigenin, onysilin and 3,4-dicaffeoylquinic acid are anti-atherosclerotic.

Previous studies showed that the ethyl acetate (EtOAc) fraction of Andrographis paniculata (AP) possessed anti-inflammatory activity. This study further isolated these active compounds from bioactivity-guided chromatographic fractionation and identified eight pure compounds. Reporter gene assay indicated that 5-hydroxy-7,8-dimethoxyflavone (1), 5-hydroxy-7,8-dimethoxyflavanone (2), a mix of beta-sitosterol (3a) and stigmasterol (3b), ergosterol peroxide (4), 14-deoxy-14,15-dehydroandrographolide (5), and a new compound, 19-O-acetyl-14-deoxy-11,12-didehydroandrographolide (6a), significantly inhibited the transcriptional activity of NF-kappaB in LPS/IFN-gamma stimulated RAW 264.7 macrophages (P < 0.05). The two most abundant compounds, 14-deoxy-11,12-didehydroandrographolide (7) and andrographolide (8), had less inhibitory activity but exerted greater inhibitory activity by hydrogenation, oxidation, or acetylation to become four derived compounds, 9, 10, 11, and 12. All of the compounds significantly decreased TNF-alpha, IL-6, macrophage inflammatory protein-2 (MIP-2), and nitric oxide (NO) secretions from LPS/IFN-gamma stimulated RAW 264.7 cells. Compounds 5, 11, and 12 exerted the strongest inhibitory effect on NF-kappaB-dependent transactivation in the RAW 264.7 cell, with IC(50) values of 2, 2.2, and 2.4 microg/mL, respectively, providing encouraging results for bioactive compound development.

Interleukin-6 (IL-6) is a multifunctional cytokine that is associated with the disease status and outcomes of gastric cancer. Nonetheless, the underlying mechanism of how IL-6 promotes the spread of gastric cancer is still unclear. In this study, we used a modified Boyden chamber assay to test the invasion ability of different gastric cancer cell lines. Liposome-mediated transfection was used to introduce an IL-6 expression vector into AGS cells, and the transfectants were further examined for the expression of active RhoA and phosphorylated Src using a pull-down assay and coimmunoprecipitation/Western blot analysis. Furthermore, RhoA expression in gastric adenocarcinoma specimens was investigated immunohistochemically. We documented that IL-6 could promote AGS cell motility and invasiveness, and inhibition of RhoA expression by dominant negative RhoA, C3 transferase, or dominant negative Src expressing plasmids could effectively decrease the invasiveness of IL-6 transfectants. We also documented an interaction between active RhoA and phosphorylated-Src following IL-6 treatment. Gastric cancers displaying high expression of RhoA are highly correlated with aggressive lymph node metastasis, more advanced tumor stage, histologically diffuse type and poorer survival. In conclusion, IL-6 induces AGS gastric cancer cell invasion via activation of the c-Src/RhoA/ROCK signaling pathway and RhoA expression could be used as a prognostic factor in patients with gastric adenocarcinoma. ' 2007 Wiley-Liss, Inc.Key words: interleukin-6; Rho-A; Src; Rho-kinase; gastric cancer Gastric cancer is one of the most common malignancies throughout the world, 1 and the incidence rates show substantial variation internationally, with highest rates in Japan, China and eastern Asia.2-4 About 90% of stomach tumors are adenocarcinomas, which can be subdivided into 2 histologic types: (i) well-differentiated or intestinal type adenocarcinoma and (ii) undifferentiated or diffuse-type adenocarcinoma. Infection with Helicobacter pylori, atrophic gastritis and intestinal metaplasia or dysplasia are identified as important steps in the pathogenesis of gastric cancer, 5 but the precise molecular mechanisms of this progression remain largely unknown. Because invasion and lymphatic metastasis is a frequent event in human gastric cancer, partial or complete gastrectomy with lymphadenectomy is the only potentially curative therapy for gastric cancer. Although surgery carries a high cure rate for early stage cancers, the 5-year survival rate for all patients is only about 20%. Death from gastric cancer is mainly due to recurrent disease (40-60% relapse rate in prospective studies), 6,7 where the most common form is loco-regional recurrence.

Patients with acute pancreatitis are liable to suffer from PUD. PUD is associated with severe acute pancreatitis according to the APACHE II score, and treatment for PUD should be considered for patients with severe acute pancreatitis.

Laryngeal and hypopharyngeal squamous cell carcinomas (LHSCCs) are common head and neck cancers with a high propensity for lymph node (LN) and lung metastasis. Here, we report that LHSCCs express high levels of functional CXCR4 receptors, native for chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). Primary tumor immunohistochemistry from LHSCC patients has revealed significant expression of CXCR4 and CXCL12. Greater expression of CXCR4 but not that of CXCL12 is correlated with LN and distant metastasis. Reverse transcription-polymerase chain reaction and western blots have demonstrated that CXCR4 messenger RNA (mRNA) and protein were expressed in LHSCC cell lines as well, but failed to detect CXCL12 mRNA expression. CXCL12 treatment enhanced extracellular signal-regulated kinase (ERK) pathway activation and the motility/invasiveness of LHSCC cell lines, which were blocked by treatment with a CXCR4 antagonist (AMD3100) and a specific MEK inhibitor (U0126). Results show that the mRNA and protein levels of matrix metalloproteinase (MMP)-13, but not MMP-2 or MMP-9, were elevated in HEp-2 cells in response to CXCL12. Again, U0126 almost inhibited the induction of MMP-13 in HEp-2 cells by stimulating CXCL12. The transcriptional factor, c-Jun, a downstream factor of ERK pathway, was found to be readily phosphorylated and translocated to the nucleus after 10 min of exposure to CXCL12. Blockage of c-Jun activity by transfection with c-jun antisense oligodeoxynucleotide significantly decreased CXCL12-induced MMP-13 expression and cell invasion. CXCL12 seems to enhance LHSCC cell invasion through paracrine-activated CXCR4, which triggers ERK/c-Jun-dependent MMP-13 upregulation.

Purpose: Cysteine-rich 61 (Cyr61/CCN1) is involved in many different types of tumor development and progression. Nonetheless, the role of Cyr61 in human gastric cancer has not yet been fully characterized. Experimental design: We addressed the issue by immunohistochemical staining of 81 gastric adenocarcinoma specimens. Liposome-mediated transfection was used to introduce a Cyr61 expression vector into gastric cancer AGS cell lines. Transfectants were tested in invasion assay by a Boyden chamber. Furthermore, a cyclooxygenase-2 (COX-2) reporter assay and gel mobility shift assay were done to investigate the potential signal pathway of Cyr61. Results: Patients with gastric adenocarcinoma whose tumor displayed high expression of Cyr61 correlated well with aggressive lymph node metastasis, more advanced tumor stage, histologic diffuse type, and early recurrence. Stable transfection of Cyr61 into the AGS cell line strongly enhanced its invasive activity. The overexpression of Cyr61into AGS cells significantly increased the expression of COX-2 mRNA, protein, and enzymatic activity. Gel mobility shift assays further showed that the nuclear factor-nB (NF-nB) pathway was evidently activated in Cyr61-expressing AGS cells. Function-neutralizing antibody to avh3 but not avh5 effectively suppressed Cyr61-mediated NF-nB activation, COX-2 gene expression, and cell invasiveness. Conclusions: Cyr61may contribute to the malignant progression of gastric cancer by promoting tumor cell motility/invasion through up-regulation of the functional COX-2 via an integrin avh3/ NF-nB-dependent pathway.

Danggui, also known as Angelica sinensis (Oliv.) Diels (Apiaceae), has been used in Chinese medicine to treat menstrual disorders. Over 70 compounds have been isolated and identified from Danggui. The main chemical constituents of Angelica roots include ferulic acid, Z-ligustilide, butylidenephthalide and various polysaccharides. Among these compounds, ferulic acid exhibits many bioactivities especially anti-inflammatory and immunostimulatory effects; Z-ligustilide exerts anti-inflammatory, anti-cancer, neuroprotective and anti-hepatotoxic effects; n-butylidenephthalide exerts anti-inflammatory, anti-cancer and anti-cardiovascular effects.