Preoperative short- vs. long-course chemoradiotherapy with delayed surgery for locally advanced rectal cancer.

PURPOSE: To compare the clinical outcomes between short-course chemoradiotherapy (CRT) and long-course CRT with delayed surgery in locally advanced rectal cancer patients. RESULTS: From 2010 to 2015, 19 patients were treated with short-course CRT and 53 patients were treated with LCRT. The sphincter-saving rate (89.5% vs. 94.3%, short-course CRT vs. long-course CRT), pathologic complete remission (21.1% vs. 13.2%), downstaging (47.4% vs. 26.4%), and treatment complications including anastomotic site leakage, bowel adhesion, and hematologic toxicity associated with short-course CRT were not significantly different from those associated with long-course CRT. 2-year overall survival was 90.0% and 91.2% (p = 0.448), respectively. METHODS AND MATERIALS: 72 patients with stage cT3-4N0-2M0 rectal cancer participated in a multicenter study. Short-course CRT treatment was as follows: a total of 25 Gy of radiotherapy was delivered in 5 equal doses with intensity modulated radiation therapy. Chemotherapy was consisted of Leucovorin 400 mg/m2 administered by bolus injection on day 1 and 5-Fluouracil 1200 mg/m2 given by continuous infusion on days 1 and 2. An additional three cycles of chemotherapy were administered before the surgery. Long-course CRT treatment was as follows: a total of 50.4 Gy of radiotherapy was delivered in 28 equal doses. Chemotherapy consisted of a bolus injection of 5-Fluouracil + Leucovorin during the first and last week of radiotherapy. Surgery was performed 6-8 weeks after completion of radiotherapy in both groups. CONCLUSIONS: Preoperative short-course CRT is an effective and safe modality. It is clinically comparable to long-course CRT in locally advanced rectal cancer.

Protective Effects of Genipin on Gastrointestinal Disorders.

Genipin, an aglycone of geniposide, is a major component of gardeniae fructus, and has been used to treat jaundice, various inflammatory disorders, and liver disease, and has also been used as a natural cross-linking agent. The authors conducted several experiments to evaluate the protective effects of genipin on gastrointestinal disorders, such as, gastritis and gastric ulcers. Genipin showed inhibitory effects against HCl·ethanol-induced acute gastritis and indomethacin-induced gastric ulcers in rats and increased prostaglandin E2 (PGE2) in AGS gastric cancer cell. Genipin had significant effects on aggressive factors, acid-neutralization, and gastric secretion, and inhibited H+/K+-ATPase (a proton pump), which secretes gastric acid. The results obtained indicate that genipin has significant gastroprotective effects and might be useful for treating and preventing gastric lesions.

Gastroprotective Activities of Sennoside A and Sennoside B via the Up-Regulation of Prostaglandin E2 and the Inhibition of H(+)/K(+)-ATPase.

Sennoside A (erythro) and sennoside B (threo) are dianthrone glycosides and diastereomers. We investigated their abilities to prevent the gastric lesions associated with diseases, such as, gastritis and gastric ulcer. To elucidate their gastroprotective effects, the inhibitions of HCl•EtOH-induced gastritis and indomethacin-induced gastric ulcers were assessed in rats. It was observed that both sennoside A and sennoside B increased prostaglandin E2 (PGE2) levels and inhibited H(+)/K(+)-ATPase (proton pump). In a rat model, both compounds reduced gastric juice, total acidity and increased pH, indicating that proton pump inhibition reduces gastric acid secretion. Furthermore, sennoside A and B increased PGE2 in a concentration-dependent manner. In a gastric emptying and intestinal transporting rate experiment, both sennoside A and sennoside B accelerated motility. Our results thus suggest that sennoside A and sennoside B possess significant gastroprotective activities and they might be useful for the treatment of gastric disease.

Apoptosis-Inducing Activity of Marine Sponge Haliclona sp. Extracts Collected from Kosrae in Nonsmall Cell Lung Cancer A549 Cells.

Although various anticancer drugs have been developed for the treatment of nonsmall cell lung cancer, chemotherapeutic efficacy is still limited. Natural products such as phytochemicals have been screened as novel alternative materials, but alternative funds such as marine bioresources remain largely untapped. Of these resources, marine sponges have undergone the most scrutiny for their biological activities, including antiinflammatory, antiviral, and anticancer properties. However, the biological mechanisms of the activities of these marine sponges are still unclear. We investigated the anticancer activity of marine sponges collected from Kosrae in Micronesia and examined their mechanisms of action using nonsmall cell lung cancer A549 cells as a model system. Of 20 specimens, the Haliclona sp. (KO1304-328) showed both dose- and time-dependent cytotoxicity. Further, methanol extracts of Haliclona sp. significantly inhibited cell proliferation and cell viability. A549 cells treated with Haliclona sp. demonstrated induced expression of c-Jun N-terminal kinase (JNK), p53, p21, caspase-8, and caspase-3. The percentage of apoptotic cells significantly increased in A549 cultures treated with Haliclona sp. These results indicate that Haliclona sp. induces apoptosis via the JNK-p53 pathway and caspase-8, suggesting that this marine sponge is a good resource for the development of drugs for treatment of nonsmall cell lung cancer.

Anti-tumor effect of Cordyceps militaris in HCV-infected human hepatocarcinoma 7.5 cells.

Cordyceps extract has been reported to have various pharmacological activities including an anti-cancer effect. We investigated the inhibitory effect of Cordyceps militaris on hepatitis C virus-infected human hepatocarcinoma 7.5 cells (J6/JFH1-huh 7.5 cells). The huh7.5 cells with or without HCV infection were treated with various concentrations of ethanol extract of Cordyceps militaris (CME) for 48 h and the cytotoxicity was measured by CCK-8 assay. Both J6/JFH1-huh7.5 cells and huh7.5 cells were highly susceptible to CME. To examine the molecular mechanisms of the inhibitory effect on huh7.5 cells, the effect of CME on cell apoptosis was measured using flow cytometry and the expressions of p53, Bim, Bax, PARP, (cleaved) caspase-9, and (cleaved) caspase- 3 in huh 7.5 cells were detected by western blot assays. CME significantly increased early apoptosis and up-regulated the expression of Bim, Bax, cleaved PARP, cleaved caspase 9 and cleaved caspase-3. We also found the decrease of HCV Core or NS3 protein by CME in HCV-infected huh 7.5 cells.

Genipin as a novel chemical activator of EBV lytic cycle.

Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that causes acute infection and establishes life-long latency. EBV causes several human cancers, including Burkitt's lymphoma, nasopharyngeal and gastric carcinoma. Antiviral agents can be categorized as virucides, antiviral chemotherapeutic agents, and immunomodulators. Most antiviral agents affect actively replicating viruses, but not their latent forms. Novel antiviral agents must be active on both the replicating and the latent forms of the virus. Gardenia jasminoides is an evergreen flowering plant belonging to the Rubiaceae family and is most commonly found growing wild in Vietnam, Southern China, Taiwan, Japan, Myanmar, and India. Genipin is an aglycone derived from an iridoid glycoside called geniposide, which is present in large quantities in the fruit of G. jasminoides. In this study, genipin was evaluated for its role as an antitumor and antiviral agent that produces inhibitory effects against EBV and EBV associated gastric carcinoma (EBVaGC). In SNU719 cells, one of EBVaGCs, genipin caused significant cytotoxicity (70 µM), induced methylation on EBV C promoter and tumor suppressor gene BCL7A, arrested cell-cycle progress (S phases), upregulated EBV latent/lytic genes in a dose-dependent manner, stimulated EBV progeny production, activated EBV F promoter for EBV lytic activation, and suppressed EBV infection. These results indicated that genipin could be a promising candidate for antiviral and antitumor agents against EBV and EBVaGC.

Protective Effect of Liriodendrin Isolated from Kalopanax pictus against Gastric Injury.

In this study, we investigated the inhibitory activities on gastritis and gastric ulcer using liriodendrin which is a constituent isolated from Kalopanax pictus. To elucidate its abilities to prevent gastric injury, we measured the quantity of prostaglandin E2 (PGE2) as the protective factor, and we assessed inhibition of activities related to excessive gastric acid be notorious for aggressive factor and inhibition of Helicobacter pylori (H. pylori) colonization known as a cause of chronic gastritis, gastric ulcer, and gastric cancer. Liriodendrin exhibited higher PGE2 level than rebamipide used as a positive control group at the dose of 500 µM. It was also exhibited acid-neutralizing capacity (10.3%) and H(+)/K(+)-ATPase inhibition of 42.6% (500 µM). In pylorus-ligated rats, liriodendrin showed lower volume of gastric juice (4.38 ± 2.14 ml), slightly higher pH (1.53 ± 0.41), and smaller total acid output (0.47 ± 0.3 mEq/4 hrs) than the control group. Furthermore liriodendrin inhibited colonization of H. pylori effectively. In vivo test, liriodendrin significantly inhibited both of HCl/EtOH-induced gastritis (46.9 %) and indomethacin-induced gastric ulcer (46.1%). From these results, we suggest that liriodendrin could be utilized for the treatment and/or protection of gastritis and gastric ulcer.

Inhibitory Activities of Palmatine from Coptis chinensis Against Helicobactor pylori and Gastric Damage.

Helicobacter pylori (H. pylori) is the most important factor of gastric disease in clinical practice. Moreover, smoking, stress and a poor diet may be additive factors for gastric damage. With these factors, increasing infection of H. pylori triggers gastritis, gastric ulcers and gastric cancer. To develop a new protective agent, we are concerned with plant-derived extract. The extract of Coptis chinensis (C. chinensis) and its constituents were investigated to assess their protective activities against gastric damage. The C. chinensis extract showed a scavenging effect against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radicals, inhibition of H. pylori colonization and antiulcerogenic activities in rat. In particular, palmatine derived from C. chinensis was found to be the novel protective agent. It is better than the C. chinensis extract, berberine, a well-known constituent of C. chinensis. We suggest that palmatine from the root cortex of C. chinensis may be a good candidate for the development of new pharmaceuticals to prevent gastric disease.

Anti-Helicobacter pylori and antiulcerogenic activities of the root cortex of Paeonia suffruticosa.

In this study, we evaluated the gastric protective activities of mokdanpi in vitro. Further, we used experimental ulcer models to identify the active ingredients of mokdanpi. As a preliminary evaluation of mokdanpi ethanolic extract and its ingredients, we assessed its radical scavenging activities. In addition, its antimicrobial activity against Helicobacter pylori (H. pylori) was investigated. The antiulcerogenic activity of the active ingredients was evaluated in pylorus-ligated rats, an HCl/ethanol-induced and an absolute ethanol-induced ulcer model. We confirmed the scavenging effect of the ethanolic extract of mokdanpi and its ingredients against 2,2-diphenyl-1-picrylhydrazyl, nitric oxide and superoxide radicals, and we demonstrated that mokdanpi could inhibit the colonization of H. pylori. In an HCl-ethanol-induced ulcer model, gallic acid and catechin (100 mg/kg) inhibited 40.6% and 41.7% of gastric lesions, respectively. Catechin (100 mg/kg) significantly reduced (p<0.05) the gastric secretion induced by pylorus ligature in rats in comparison to the control group. Gallic acid (100 mg/kg) significantly increased (p<0.05) the mucus contents in an ethanol-induced ulcer model. The antioxidant ingredients (catechin and gallic acid) present in mokdanpi play a major role in antiulcerogenic activity, and demonstrate novel activity against H. pylori.

Genipin, a constituent of Gardenia jasminoides Ellis, induces apoptosis and inhibits invasion in MDA-MB-231 breast cancer cells.

Genipin, a constituent of Gardenia jasminoides Ellis, is used in the treatment of hepatic disorders and inflammatory diseases in traditional medicine. Although mounting evidence suggests an anti-tumor activity of genipin in several cancer cell systems, the inhibitory effect of genipin on the growth of breast cancer cells has not been reported yet. The present study aimed to investigate the anti-proliferative activity of genipin in MDA-MB-231 human breast cancer cells. Herein, we showed that genipin efficiently induced apoptosis in MDA-MB-231 cells by the down-regulation of Bcl-2, up-regulation of Bax and proteolytic activation of caspase-3. Activation of JNK and p38 MAPK also increased by genipin. Importantly, genipin significantly inhibited invasive and migratory phenotypes of MDA-MB-231 cells. Taken together, this study demonstrates that genipin induces apoptosis and inhibits invasive/migratory abilities of highly invasive MDA-MB-231 human breast cancer cells, suggesting a potential application of genipin as a chemopreventive agent that may prevent or alleviate metastatic breast cancer.

Inhibitory Effects of 4-Guanidinobutyric Acid against Gastric Lesions.

This study examined the inhibitory effects of 4-guanidinobutyric acid (4GBA), an alkaloid, against gastric lesions by assessing the inhibition of Helicobacter pylori (H. pylori) and gastric cancer cells. Acute and chronic gastritis were also observed using HCl/ethanol (EtOH) and indomethacin-induced gastric lesion models, respectively. 4GBA inhibited the growth of H. pylori in a dose dependent manner, and showed acid-neutralizing capacity. In the pylorus ligated rats, 4GBA decreased the volume of gastric secretion and gastric acid output slightly, and increased the pH. 4GBA at a dose of 100 mg/kg reduced the size of HCl/EtOH-induced gastric lesions (70.8%) and indomethacin-induced gastric lesions (38.8%). The antigastritic action of 4GBA might be associated with the acid-neutralizing capacity, anti-H. pylori action, and decreased volume of gastric secretion. These results suggest that 4GBA might be useful in the treatment and/or protection of gastritis.

Anti-gastric actions of eugenol and cinnamic acid isolated from Cinnamomi Ramulus.

We investigated the evidence of gastric protection for ulcer and gastritis by Cinnamomi Ramulus (Cinnamomum cassia Blume, Geiji, CR) extract and its several constituents. CR ethanolic extract showed the potent antioxidant activity and cytotoxicity of Helicobacter pylori (H. pylori) and acid-neutralizing capacity. Especially, eugenol exerted a significant antioxidant activity and inhibited the colonization of H. pylori. In vivo test, eugenol and cinnamic acid significantly inhibited HCl/ethanol-induced gastric lesions and increased the mucus content though they didn't inhibit gastric secretion effectively. Taken together, eugenol and cinnamic acid, which were isolated from CR, exhibited the antioxidant activity in vitro and protective effect against gastric damage in vivo through stimulation of mucus secretion and so on. It suggested that they are useful as the neutraceuticals for gastritis.

Synthesis and mechanistic studies of a mitomycin dimer containing an eight-membered cyclic disulfide.

Dimeric DNA alkylating agents have drawn significant interest because these compounds are expected to provide at least two reactive sites and as a result, generate enhanced levels of DNA interstrand cross-link (DNA ISC) adducts compared to their monomeric agents. We report the synthesis and mechanistic studies of a novel mitomycin dimer, 7-N,7'-N'-(1″,2″-dithiocanyl-3″,8″-dimethylenyl)bismitomycin C (8) connected by an eight-membered cyclic disulfide. Mitomycins require prior activation (i.e., transformation to a good electrophile) for DNA adduction and therefore, 8 was aimed to undergo facile nucleophilic activation and produce enhanced levels of DNA ISC. At the core of this function lies a cyclic disulfide in 8. It was expected that disulfide cleavage by an appropriate nucleophile would successively produce two thiols that may trigger activation of two mitomycin rings in a dimer through intramolecular cyclization to quinine rings. Compound 8 was synthesized from mitomycin A (1) and the key intermediate, cyclic disulfide (11), along with the reference diol mitomycin 7-N,7'-N'-(2″,7″-dihydroxy-1″,8″-octanediyl)bismitomycin C (23) which does not contain the disulfide unit. We found that 8 underwent significantly enhanced nucleophilic activation in the presence of Et(3)P compared with 23, and that the disulfide unit in 8 played a key role for the nucleophilic activation. Based on these findings, we proposed a mechanism for nucleophilic activation of 8. We further demonstrated that 8 generated much higher levels of DNA ISC (94%) compared with 23 (4%) and 2 (3%) in the presence of Et(3)P (and L-DTT) leading to the conclusion that 8 is more efficient for DNA ISC processes than 23 and 2 due to the role of disulfide unit.

Isolation and tandem mass fragmentations of an anti-inflammatory compound from Aralia elata.

One-step isolation of a saponin from Aralia elata was undertaken using high-speed countercurrent chromatography coupled with evaporative light scattering detection. A triterpenoid saponin, elatoside F, was purified with 96.8% purity using a two-phase-system comprising chloroform-methanol-water-isopropanol. The yield was 35.0 mg from 348.2 mg of the enriched saponin fraction. In vitro anti-inflammatory study demonstrated that elatoside F inhibited lipopolysaccharide-induced nitric oxide production, as well as nuclear factor kappaB activation, in a dose-dependent manner. Two types of mass ionization technique were compared on elatoside F to investigate characteristic fragmentation patterns. MALDI-TOF tandem mass spectrometric fragmentation patterns of sodiated ions provided structural information on glycosidic cleavages and on extensive cross-ring cleavages. Electrospray ionization multiple-stage tandem mass fragmentation of both sodiated and lithiated ions could provide information on glycosidic cleavages. All observed tandem mass fragmentation spectra provided valuable elatoside F structural information when unknown samples from crude extracts are under screening by mass spectrometry.

Gardenia jasminoides Ellis ethanol extract and its constituents reduce the risks of gastritis and reverse gastric lesions in rats.

In this study we investigated the effects of Gardenia jasminoides Ellis (GJE) extract and its constituents, such as ursolic acid and genipin, on gastritis in rats and the growth of human gastric cancer cells. The GJE extract, ursolic acid and genipin showed the acid-neutralizing capacities, the antioxidant activities, and the inhibitory effects on the growth of Helicobacter pylori (H. pylori), which are almost equivalent to positive control compounds. In addition, the GJE extract and ursolic acid had cytotoxic activity against AGS and SUN638 gastric cancer cells. The genipin and ursolic acid inhibited significant HCl/ethanol-induced gastric lesions. Taken together, GJE extract and its constituents might have antigastritic activities, associated with the antioxidant activities, acid-neutralizing capacities, and anti-H. pylori action. Also, we could suggest that genipin and ursolic acid may be useful for the treatment and/or protection of gastritis.

Protective effects of neohesperidin and poncirin isolated from the fruits of Poncirus trifoliata on potential gastric disease.

The effects of Poncirus trifoliata (P. trifoliata) (Ponciri Fructus, PF) extract and its constituents such as neohesperidin and poncirin on gastritis in rats and human gastric cancer cells were investigated. The PF 70% ethanol extracts (1 g) showed approximately 11.38% of acid-neutralizing capacities and cytotoxicity (IC50=85.39 microg/mL) against human AGS gastric cancer cells. In addition, neohesperidin exhibited antioxidant activity (IC50=22.31 microg/mL) in the 1,1-diphenyl-2-picryldydrazyl (DPPH) radical-scavenging assay. Neohesperidin (50 mg/kg) and poncirin (100 mg/kg) significantly inhibited 55.0% and 60.0% of HCl/ethanol-induced gastric lesions, respectively, and increased the mucus content. In pylorus ligated rats, neohesperidin (50 mg/kg) significantly decreased the volume of gastric secretion and gastric acid output, and increased the pH. From these results, it could be suggested that neohesperidin and poncirin isolated from PF may be useful for the treatment and/or protection of gastritis.

Co-contamination of Aflatoxins with Ochratoxin A and Zearalenone in Thuja orientalis Semen.

Korea is representative of a country that consumes herbal medicines; most of the herbal medicines circulating in South Korea have been imported from developing countries in Southeast Asia, such as China and Indonesia. Recently, domestic hygiene and safety are issues that have come to the forefront, because herbal medicines currently in circulation could possibly contain contaminants or residues. Furthermore, the appearance or discovery of harmful new species due to environmental and industrial developments is becoming a social problem. Therefore, it may be necessary to consider and investigate these matters on a continual basis. Recently, mycotoxin contaminations in such foods as cereals, nuts, and powdered red pepper have been reported. They have become a problematic issue; the possibility of contamination in herbal medicines has also been considered. Nevertheless, recognition of and research into mycotoxin contamination in herbal medicines has been scarce because herbal medicine is used in only a few nations. In this research, we identified contamination by aflatoxin which is known to be the most potent mutagenic, carcinogenic, and teratoge-nic mycotoxin in Thujae Semen, a herbal medicine. We also found co-contaminations involving other mycotoxins, including ochratoxin A and zeraleanone.

Suppressive effects on the biosynthesis of inflammatory mediators by Aralia elata extract fractions in macrophage cells.

The aim of this study is to elucidate the anti-inflammatory effects of Aralia elata extract fractions (AEEFs). A. elata-ethyl acetate fraction (AEEF) had the strongest antioxidant activity. A. elata-chloroform fraction (AECF) and A. elata-butanol fraction (AEBF) inhibited potently LPS-induced nitrite production from RAW 264.7 macrophage cells. The inhibition of nitric oxide (NO) production by AEEFs was partially due to chemical scavenge of NO and the suppression of inducible NOS (iNOS) transcription level in LPS-induced macrophage cells. In addition, AEEFs inhibited significantly the biosynthesis of Prostaglandin E(2) (PGE(2)), and cyclooxygenase-2, which regulates the synthesis of PGE(2), was attenuated partially by the treatment of AEEFs in LPS-induced macrophage cells. Also, A. elata-methanolic extract (AEME) suppressed remarkably IL-1ß and IL-6 level to the basal (more than 99% inhibition) in concentration-dependant manners. Its anti-inflammatory actions might be related with inhibition of NF-κB activation in LPS-stimulated macrophage cells. It is concluded that AEEFs may be useful as a functional food material and an alternative medicine for the relief and retardation of immunological inflammatory responses.

Potential analgesic and anti-inflammatory activities of Panax ginseng head butanolic fraction in animals.

The present study reports the potential anti-rheumatoid activity of Panax ginseng head part. P. ginseng-head part BuOH fraction (PGHB) was safe in acute toxicity (LD(50)>5000mg/kg) and inhibited the partially acetic acid-induced writhes (approximately 32%, P<0.05) in mice. PGHB (500mg/kg) inhibited the acetic acid-induced extravasation of Evan's blue dye in mice by approximately 20.6% (P<0.05), and was similar to the suppressive effect of ibuprofen (27.7%) as a positive control drug. Also, PGHB reduced the carrageenan-induced paw edema at 3h after oral administration, and suppressed the production of serum IL-6 in CIA mice. This suggests that PGHB has potential analgesic and anti-inflammatory activities, and will be the supporting evidence for the potential anti-rheumatoid activity of Korean P. ginseng-head.

Mechanism of apoptosis induced by apigenin in HepG2 human hepatoma cells: involvement of reactive oxygen species generated by NADPH oxidase.

Although plant-derived flavonoids have been reported to have anti-cancer activities, the exact mechanism of these actions is not completely understood. In this study we investigated the role for reactive oxygen species (ROS) as a mediator of the apoptosis induced by apigenin, a widespread flavonoid in plant, in HepG2 human hepatoma cells. Apigenin reduced cell viability, and induced apoptotic cell death in a dose-dependent manner. In addition, it evoked a dose-related elevation of intracellular ROS level. Treatment with various inhibitors of the NADPH oxidase (diphenylene iodonium, apocynin, neopterine) significantly blunted both the generation of ROS and induction of apoptosis induced by apigenin. These results suggest that ROS generated through the activation of the NADPH oxidase may play an essential role in the apoptosis induced by apigenin in HepG2 cells. These results further suggest that apigenin may be valuable for the therapeutic management of human hepatomas.