Anti-Neuroinflammatory Effects of Arecae pericarpium on LPS-Stimulated BV2 Cells.

Arecae pericarpium (AP), the fruit peel of the betel palm, is a traditional Oriental herbal medicine. AP is used to treat various diseases and conditions, such as ascites, edema, and urinary retention, in traditional Korean medicine. Recent studies have demonstrated its anti-obesity and antibacterial effects; however, its anti-neuroinflammatory effects have not yet been reported. Therefore, we investigated the anti-neuroinflammatory effects of AP on lipopolysaccharide (LPS)-stimulated mouse microglia in this study. To determine the anti-neuroinflammatory effects of AP on BV2 microglial cells, we examined the production of nitric oxide (NO) using Griess assay and assessed the mRNA expression levels of inflammatory mediators, such as inducible NO synthase (iNOS) and cyclooxygenase (COX)-2, and pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α, using a real-time reverse transcription-polymerase chain reaction. Furthermore, we determined the levels of mitogen-activated protein kinases and IκBα via Western blotting to understand the regulating mechanisms of AP. AP treatment decreased NO production in LPS-stimulated BV2 cells. Additionally, AP suppressed the expression of iNOS and COX-2 and the production of pro-inflammatory cytokines. AP also inhibited the activation of p38 and nuclear factor-kappa B (NF-κB) in LPS-stimulated BV2 cells. Therefore, AP exerts anti-neuroinflammatory effects via inactivation of the p38 and NF-κB pathways.

Reappraisal of the Lymphatic Drainage System of the Distal Rectum: Functional Lymphatic Flow into the Presacral Space and Its Clinical Implication in Rectal Cancer Treatment.

Understanding the source and route of pelvic metastasis is essential to developing an optimal strategy for controlling local and systemic diseases of rectal cancer. This study aims to delineate the distribution of lymphatic channels and flow from the distal rectum. In fresh-frozen cadaveric hemipelvis specimens, the ligamentous attachment of the distal rectum to the pelvic floor muscles and the presacral fascia were evaluated. Using indocyanine green (ICG) fluorescence imaging, we simultaneously evaluated the gross anatomy of the lymphatic communication of the distal rectum. We also investigated the lymphatic flow in the pelvic cavity intraoperatively in rectal cancer patients who underwent radical rectal resection with total mesorectal excision (TME). In fresh cadavers, multiple small perforating lymphovascular branches exist in the retrorectal space, posteriorly connecting the mesorectum to the presacral fascia. The lymphatic flow from the distal rectum drains directly into the presacral space through the branches. In patients who underwent TME for rectal cancer, intraoperative ICG fluorescence signals were seen in the pelvic sidewalls and the presacral space. This anatomical study demonstrated that the lymphatic flow from the distal rectum runs directly to the pelvic lateral sidewalls and the presacral space, suggesting a possible route of metastasis in distal rectal cancer.

Assessment of the 4-week repeated-dose oral toxicity and genotoxicity of GHX02.

Herbal medicines are widely utilized for disease prevention and health promotion. GHX02 consists of mixtures including Gwaruin (Trichosanthes kirilowii), Haengin (Prunus armeniaca), Hwangryeon (Coptis japonica) and Hwangkeum (Scutellaria baicalensis). It has been purported to have therapeutic effectiveness in cases of severe bronchitis. Non-clinical safety testing comprised a single-dose oral toxicity study and a 28-day repeated-dose oral toxicity study with a 14-day recovery period, and genotoxicity was assessed by a bacterial reverse mutation test, in vitro chromosomal aberration test, in vivo mouse bone marrow micronucleus test and single cell gel electrophoresis assay (comet assay). In the single-dose oral toxicity study, the approximate lethal dosage is estimated to be higher than 5000 mg/kg in rats. Thus, the dosage levels were set at 0, 1250, 2500 and 5000 mg/kg/day in the 28-day repeated-dose oral toxicity study, and 10 male rats and 10 female rats/dose were administered GHX02. No clinical signs of toxicological significance were recorded in any animal during the dosing and the observation period in the single-dose study. The no-observed-adverse-effect level of GHX02 was 5000 mg/kg/day when administered orally for 28 days to male and female Sprague-Dawley rats. Despite increases in the frequencies of cells with numerical chromosomal aberration in the in vitro test, the increases were not considered relevant to the in vivo genetic risk. Except for the increase of in vitro numerical chromosomal aberration, clear negative results were obtained from other genetic toxicity studies.

Tumor Homing Reactive Oxygen Species Nanoparticle for Enhanced Cancer Therapy.

Multifunctional nanoparticles that carry chemotherapeutic agents can be innovative anticancer therapeutic options owing to their tumor-targeting ability and high drug-loading capacity. However, the nonspecific release of toxic DNA-intercalating anticancer drugs from the nanoparticles has significant side effects on healthy cells surrounding the tumors. Herein, we report a tumor homing reactive oxygen species nanoparticle (THoR-NP) platform that is highly effective and selective for ablating malignant tumors. Sodium nitroprusside (SNP) and diethyldithiocarbamate (DDC) were selected as an exogenous reactive oxygen species (ROS) generator and a superoxide dismutase 1 inhibitor, respectively. DDC-loaded THoR-NP, in combination with SNP treatment, eliminated multiple cancer cell lines effectively by the generation of peroxynitrite in the cells (>95% cell death), as compared to control drug treatments of the same concentration of DDC or SNP alone (0% cell death). Moreover, the magnetic core (ZnFe2O4) of the THoR-NP can specifically ablate tumor cells (breast cancer cells) via magnetic hyperthermia, in conjunction with DDC, even in the absence of any exogenous RS supplements. Finally, by incorporating iRGD peptide moieties in the THoR-NP, integrin-enriched cancer cells (malignant tumors, MDA-MB-231) were effectively and selectively killed, as opposed to nonmetastatic tumors (MCF-7), as confirmed in a mouse xenograft model. Hence, our strategy of using nanoparticles embedded with ROS-scavenger-inhibitor with an exogenous ROS supplement is highly selective and effective cancer therapy.

The Effect of Biofeedback Therapy on Anorectal Function After the Reversal of Temporary Stoma When Administered During the Temporary Stoma Period in Rectal Cancer Patients With Sphincter-Saving Surgery: The Interim Report of a Prospective Randomized Controlled Trial.

We evaluated the effect of biofeedback therapy (BFT) on anorectal function after stoma closure when administered during the interval of temporary stoma after sphincter-preserving surgery for rectal cancer.Impaired anorectal function is common after lower anterior resections, though no specific treatment options are currently available to prevent this adverse outcome.Fifty-six patients who underwent neoadjuvant chemoradiation therapy after sphincter-preserving surgery with temporary stoma were randomized into 2 groups: group 1 (received BFT during the temporary stoma period) and group 2 (did not receive BFT). To evaluate anorectal function, anorectal manometry was performed in all patients and subjective symptoms were evaluated using the Cleveland Clinic Incontinence Score. The present study is a report at 6 months after rectal resection.Forty-seven patients, including 21 in group 1 and 26 in group 2, were evaluated by anorectal manometry. Twelve patients (57.1%) in group 1 and 13 patients (50%) in group 2 were scored above 9 points of Cleveland Clinic Incontinence Score, which is the reference value for fecal incontinence (P = 0.770). With time, there was a significant difference (P = 0.002) in the change of mean resting pressure according to time sequence between the BFT and control groups.BFT during the temporary stoma interval had no effect on preventing anorectal dysfunction after temporary stoma reversal at 6 months after rectal resection. However, BFT might be helpful for maintaining resting anal sphincter tone (NCT01661829).

Anti-cancer activity of Ginger (Zingiber officinale) leaf through the expression of activating transcription factor 3 in human colorectal cancer cells.

BACKGROUND: Ginger leaf (GL) has long been used as a vegetable, tea and herbal medicine. However, its pharmacological properties are still poorly understood. Thus, we performed in vitro studies to evaluate anti-cancer properties of ginger leaf and then elucidate the potential mechanisms involved. METHODS: Cell viability was measured by MTT assay. ATF3 expression level was evaluated by Western blot or RT-PCR and ATF3 transcriptional activity was determined using a dual-luciferase assay kit after the transfection of ATF3 promoter constructs. In addition, ATF3-dependent apoptosis was evaluated by Western blot after ATF3 knockdown using ATF3 siRNA. RESULTS: Exposure of GL to human colorectal cancer cells (HCT116, SW480 and LoVo cells) reduced the cell viability and induced apoptosis in a dose-dependent manner. In addition, GL reduced cell viability in MCF-7, MDA-MB-231 and HepG-2 cells. ATF3 knockdown attenuated GL-mediated apoptosis. GL increased activating transcription factor 3 (ATF3) expressions in both protein and mRNA level and activated ATF3 promoter activity, indicating transcriptional activation of ATF3 gene by GL. In addition, our data showed that GL-responsible sites might be between -318 and -85 region of the ATF3 promoter. We also observed that ERK1/2 inhibition by PD98059 attenuated GL-mediated ATF3 expression but not p38 inhibition by SB203580, indicating ERK1/2 pathway implicated in GL-induced ATF3 activation. CONCLUSIONS: These findings suggest that the reduction of cell viability and apoptosis by GL may be a result of ATF3 promoter activation and subsequent increase of ATF3 expression through ERK1/2 activation in human colorectal cancer cells.

NSAID is inversely associated with asymptomatic gastric ulcer: local health examination data from the Korean National Health Insurance Corporation.

BACKGROUND. Silent peptic ulcer has been considered to be associated with nonsteroidal anti-inflammatory drug (NSAID). The recent studies have reported no relationship between them. AIM. We attempted to investigate an association between asymptomatic peptic ulcer and NSAID in Korean adults. METHODS. The subjects were enrolled from participants visiting Myongji Hospital for health examination program of the Korean National Health Insurance Corporation. The questionnaires were designed to investigate individual medical information and gastroduodenal symptoms. RESULTS. From May 2005 to March 2009, 5459 participants were enrolled and 299 participants were excluded. Of 5160 participants, 3144 (60.9%) participants were asymptomatic and 424 (8.2%) participants had peptic ulcer. Among 3144 asymptomatic participants, NSAID-taking participants had the odds ratio of 1.4 [95% confidence interval (CI): 0.7-2.6, p = 0.339] for the risk of peptic ulcer. Among 424 peptic ulcer patients, 247 (58.3%) were asymptomatic. They had lower prevalence of NSAID use (4.9% vs. 14.7%). The asymptomatic gastric ulcer patients had smaller size and more frequent healing stage than the symptomatic gastric ulcer patients. In multivariable analysis of 424 peptic ulcer patients, NSAID patients had the odds ratio of 0.249 (95%CI: 0.115-0.536, p < 0.05) for asymptomatic peptic ulcer. In subgroup analysis of 284 gastric ulcer patients, NSAID-taking patients had the odds ratio of 0.263 (95% CI: 0.105-0.657, p = 0.004) for asymptomatic peptic ulcer. CONCLUSION. NSAID has an inverse association with asymptomatic patients with gastric peptic ulcer, but has no association with gastroduodenal symptoms in duodenal ulcer patients. These suggest that NSAID may be associated with gastroduodenal symptoms rather than masking symptoms, at least in gastric ulcer patients.

Intractable rectal stricture caused by hot water enema.

Rectal burns caused by hot water enema have been reported only occasionally and the majority of them were treated in a conservative manner. Although intractable rectal stricture caused by rectal burn is rare, it may be treated by endoscopic intervention or surgery. A 52-year-old woman who had used various methods of enema to treat her chronic constipation eventually undertook a hot water enema herself. After that, anal pain and constipation became aggravated prompting her to visit our clinic. Although various nonoperative treatments including endoscopic stenting were performed, her obstructive symptom did not improve and endoscopic findings had not changed. Hence, we performed a laparoscopic proctosigmoidectomy and transanal coloanal anastomosis with ileal diversion to treat the disease, and as a result, her obstructive symptom improved well. Corrective surgery such as resection of involved segment with anastomosis may be beneficial in relieving obstructive symptoms of an intractable rectal stricture caused by hot water enema.