TU-100 exerts a protective effect against bacterial translocation by maintaining the tight junction.

PURPOSE: We previously reported that TU-100 suppresses irinotecan hydrochloride (CPT-11)-induced inflammatory cytokines and apoptosis. However, the mechanism underlying this effect has not been fully elucidated. The aim of this study was to further clarify the mechanism of CPT-11-induced bacterial translocation (BT) and the effect of TU-100 on BT. METHODS: Cell cytotoxicity was assessed in vitro by a WST-8 assay. For the in vivo experiments, rats were randomly divided into 3 groups: the control group, the CPT-11 group (250 mg/kg i.p. for 2 days), and the CPT-11 and TU-100 co-treated group (1000 mg/kg, p.o. for 5 days). All of the rats were sacrificed on day 6 and their tissues were collected. RESULTS: CPT-11 and TU-100 co-treatment improved CPT-11 the related cytotoxicity in vitro. All CPT-11-treated rats developed different grades of diarrhea and BT was observed in 80% of the rats. CPT-11 caused a significant increase in the expression of TLR4, IL-6, TNF-α, IL-1ß and caspase-3 mRNAs in the large intestine. The expression of tight junction (TJ) marker mRNAs (occludin, claudin-1 and 4, and ZO-1) was significantly decreased in comparison to the control group. TU-100 co-treatment significantly reversed diarrhea, BT, and the expression of TLR2, IL-6, TNF-α, IL-1ß and caspase-3, and improved the expression of occludin, claudin-4 and ZO-1. CONCLUSIONS: TU-100 can suppress the adverse effects associated with CPT-11 and improve the function of the TJ. It is possible that this occurs through the TLR pathway.

Effect of Kampo medicine "Dai-kenchu-to" on microbiome in the intestine of the rats with fast stress.

PURPOSE: Diversity of gut microbiome has been recently reported to be lost in inflammatory bowel disease. We have previously reported that the Dai-kenchu-to (DKT) prevented the bacterial translocation through suppression of cytokine and apoptosis in rat's fast stress model. The aim of this study was to evaluate the effect of DKT on maintenance of microbial diversity in rat's intestine with inflammation. METHOD: Wister rats were received the fast stress for 5 days. In DKT group, rats were administered with DKT (300 mg/kg/day) during the fast stress (DKT-group). The gut microbiomes were analyzed at before- and after- fast stress, and the effect of DKT for on microbial diversities of the gut were evaluated by the PCR-clone library method targeting the 16 S ribosomal RNA gene. RESULT: In Control-group, Erysipelotrichaceae increased to 86% in after fast stress, OTU of before-fast stress was 111 and after fast stress was only 9 (changing rate: 58%). The diversity of microbiome was severely decreased. On the other hand, in DKT-group, diversity of microbiome was kept after fast stress (Lachnospiraceae: Ruminococcaceae: Coriobacteriales 54%, 22%, 5%), Operational taxonomic units of before fast stress was 52 and after fast stress was 55 (changing rate: 6%). Family Lachnospiraceae which includes butyrate-producing Clostridia (Clostridium IV and XIVa). CONCLUSION: DKT prevented the reduction of diversity of microbiome in rat's fast stress model. Our data suggested the new anti-inflammatory mechanism of DKT through gut microbiome.

The effects of the Kampo medicine (Japanese herbal medicine) "Daikenchuto" on the surgical inflammatory response following laparoscopic colorectal resection.

PURPOSES: The inflammatory response after surgery is associated with various postoperative complications. The aim of the present prospective study was to evaluate the effects of Daikenchuto (DKT) (a Japanese herbal medicine) on the inflammatory response in patients following laparoscopic colorectal resection. METHODS: Thirty patients who underwent laparoscopic colectomy for colorectal carcinoma were divided into two groups: a DKT intake group (D group, n = 15) and a control group (C group, n = 15). The D group took 7.5 g/day of DKT from the day after surgery until the 7th postoperative day. The body temperature, heart rate, WBC count, lymphocyte count, C-reactive protein (CRP) level, ß-D: -glucan level and Candida index were compared between the two groups. RESULTS: The patients' mean age in the D group was significantly younger than that in the C group. D3 lymph node dissection was performed more often in the D group. The time until first flatus was significantly shorter in the D group (1.8 ± 0.5 days) than in the C group (2.7 ± 0.5 days). The CRP level was significantly lower in the D group (4.6 ± 0.6 mg/dl) than in the C group (8.3 ± 1.1 mg/dl) on the 3rd postoperative day. CONCLUSIONS: Postoperative DKT administration significantly suppressed the CRP level and shortened the time until first flatus. DKT administration also significantly suppressed postoperative inflammation following surgery for colorectal cancer.

Kampo medicine "Dai-kenchu-to" prevents CPT-11-induced small-intestinal injury in rats.

PURPOSE: The key anticancer agent, CPT-11 (irinotecan hydrochloride), induces severe diarrhea clinically. We investigated the effect of a Kampo medicine, Dai-kenchu-to (DKT), on CPT-11-induced intestinal injuries in rats. METHODS: Twenty-four male Wistar rats were divided into three groups: a control group; a CPT-11 group, given CPT-11 150 mg/kg intraperitoneally for 2 days; and a DKT group, given DKT 300 mg/kg orally for 5 days with CPT-11 150 mg/kg intraperitoneally on days 4 and 5. The rats were killed on day 6. RESULTS: Interleukin (IL)-1ß, IL-12, interferon (IFN)-γ, and tumor necrosis factor-α expression in the small intestine of the CPT-11 group was significantly higher than that of the control group. Interleukin-1ß and IFN-γ expression was improved significantly by DKT (P < 0.05). The number and height of jejuna villi, injury score, and apoptosis index in the CPT-11 group were improved significantly by DKT (P < 0.05). CONCLUSIONS: DKT suppressed CPT-11 induced inflammatory cytokines and apoptosis in the intestinal mucosa and maintained the mucosal integrity.

The Kampo medicine, Goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen.

BACKGROUND: Oxaliplatin is now considered a standard treatment for advanced or unresectable colorectal cancer, but its main dose-limiting toxicity is sensory neuropathy. The OPTIMOX (stop and go) approach offers a reasonable strategy, but the preventive agent is not established. It is reported that the Kampo medicine, Goshajinkigan (GJG), has recently been considered an effective agent for the neuropathy of taxanes and for vibration sensation in patients with diabetic neuropathy. The aim of this study was to clarify the efficacy of GJG for peripheral neuropathy associated with oxaliplatin therapy. PATIENTS AND METHOD: From 2007, 45 patients treated with modified FOLFOX6 for non-resectable or recurrent colorectal cancer participated in the study. Twenty-two patients (GJG group) received oral administration of 7.5 g/day of GJG every day during mFOLFOX6 therapy and 23 patients (control group) did not receive GJG. Neuropathy was evaluated during every course according to DEB-NTC (Neurotoxicity Criteria of Debiopharm). RESULTS: The median number of cycles per patient in the GJG group was 13 (range 4-32), and in the control group was 12 (range 4-28). The cumulative dose of oxaliplatin was 1105 mg/m(2) (GJG group) and 1120 mg/m(2) (control group). The incidence of grade 3 peripheral neuropathy in the GJG group was significantly lower than in the control group (p < 0.01, log-rank test). The incidence of grade 3 peripheral neuropathy after 10 courses was 0% in the GJG group and 12% in the control group, and after 20 courses was 33% in the GJG group and 75% in the control group. The percentage of grade 2 and 3 peripheral neuropathy in the GJG group was lower than that in the control group. There were no differences in adverse effects between the two groups except for peripheral neuropathy and influence on tumor response. CONCLUSION: The Kampo medicine, Goshajinkigan, is useful in preventing neuropathy in non-resectable or recurrent colorectal cancer patients treated with a FOLFOX regimen.

Kampo medicine "Dai-kenchu-to" prevents bacterial translocation in rats.

Kampo medicine "Dai-kenchu-to" (DKT) has been used for treatment of ileus. The aim of this study was to evaluate the role of DKT on the bacterial translocation (BT) model in rats. Rats were divided into the following four groups: group 1, receiving only water, and groups 2, 3, and 4, receiving 100, 300, and 1,000 mg/kg/day of DKT. Rats were sacrificed 6 days after the beginning of the fast, and then the mesenteric lymph node was cultured. Inflammatory cytokines, intestinal integrity, and apoptosis were assessed. Incidence of BT in groups 3 (33%) and 4 (16%) was lower than in group 1 (66%). Interferon-gamma expression in groups 2, 3, and 4 was significantly lower than in group 1. Villous height and number of villus in groups 2, 3, and 4 were significantly taller and greater than in group 1. Apoptotic index in groups 2, 3, and 4 was significantly lower than in group 1. This is the first evidence that DKT prevents BT by reducing inflammatory reaction and maintaining intestinal integrity.

Poorly differentiated neuroendocrine cell carcinoma of the rectum: report of a case and literal review.

A 56-year-old man was admitted to our hospital because of anal bleeding. Colonoscopy and barium enema revealed type 4 tumor in the rectum. Biopsy revealed poorly differentiated adenocarcinoma. Low anterior resection with total mesorectal excision and lymph node dissection was performed. In immunohistochemical staining, chromogranin A and synaptophysin were positive at major lesion, and CEA were focal positive. The resected tumor was diagnosed pathologically as neuroendocrine cell carcinoma. The Ki-67 labeling index (LI) was 87.8%, so proliferative activity and potential malignancy was very high. Multiple metastatic tumors appeared in pelvis and lung eight months after operation. Treatment for neuroendocrine cell carcinoma of the rectum was controversial. Surgical resection and adjuvant chemotherapy might be one of the methods for gastrointestinal neruroendocrine cell carcinoma.