PLXND1/SEMA3E Promotes Epithelial-Mesenchymal Transition Partly via the PI3K/AKT-Signaling Pathway and Induces Heterogenity in Colorectal Cancer.

Colorectal cancer (CRC) is a major cause of cancer-related deaths. Metastasis is enhanced through epithelial-mesenchymal transition (EMT), a process primarily induced by the transforming growth factor beta (TGF-ß)-mediated canonical Smad pathway. This study focused on plexin D1 (PLXND1), a chemoreceptor for the ligand SEMA3E to mechanosensory, showing that PLXND1 induces EMT via activation of the PI3K/AKT pathway in CRC cells. The findings showed that PLXND1-knockdown decreases cell migration and invasion significantly, and that the binding of p61-SEMA3E to the PLXND1 enhances the invasiveness and migration through EMT. Furin inhibitor suppresses EMT, decreasing cell migration and invasion. Furin cleaves full-length SEMA3E and converts it to p61-SEMA3E, suggesting that furin inhibitors block PLXND1 and p61-SEMA3E binding. Furin is a potential therapeutic target for the purpose of suppressing EMT by inhibiting the binding of p61-SEMA3E to PLXND1. In vivo experiments have shown that PLXND1-knockdown suppresses EMT. Mesenchymal cells labeled with ZEB1 showed heterogeneity depending on PLXND1 expression status. The high-expression group of PLXND1 in 182 CRC samples was significantly associated with poor overall survival compared with the low-expression group (P = 0.0352, median follow-up period of 60.7 months) using quantitative real-time polymerase chain reaction analysis. Further research is needed to determine whether cell fractions with a different expression of PLXND1 have different functions.

Sarcopenia hinders the decline in disease activity after surgery for people with Crohn's disease: Preliminary results.

OBJECTIVES: Surgical treatment is an important option for inducing remission in Crohn's disease (CD); indeed, the longer the disease duration, the higher the cumulative surgical rate. Previous studies have shown that the pathogenesis of Crohn's disease is associated with sarcopenia, a condition of reduced skeletal muscle mass. Here, we investigated the effect of preoperative sarcopenia on postoperative disease activity. METHODS: This retrospective study included 56 patients with CD with medical records who met our inclusion criteria. Sarcopenia was diagnosed based on the psoas muscle mass index derived from computed tomography images, with predetermined cutoff values of <6.36 cm2/m2 for men and <3.92 cm2/m2 for women. We performed univariate and multivariate analyses to identify factors associated with sarcopenia. RESULTS: Of the 56 participants, nine (16%) had sarcopenia. The rate of preoperative treatment with biological drugs was significantly lower in the sarcopenia group than the non-sarcopenia group. In addition, the operation time was significantly longer, and hemorrhage occurred more often, in the sarcopenia group than in the non-sarcopenia group. Postoperatively, the CD activity index at 6 mo had significantly decreased in the non-sarcopenia group (P = 0.01) but not in the sarcopenia group (P = 0.20). Univariate and multivariate analyses showed that a low total serum protein level was significantly associated with sarcopenia. CONCLUSION: Our results suggest that to maximize the effect of surgical treatment for CD, an appropriate nutritional intervention should be performed before surgery, or surgery should be postponed until after the patient recovers from sarcopenia.

Sanguisorba officinalis L. derived from herbal medicine prevents intestinal inflammation by inducing autophagy in macrophages.

Disturbed activation of autophagy is implicated in the pathogenesis of inflammatory bowel disease. Accordingly, several autophagy-related genes have been identified as Crohn's disease susceptibility genes. We screened the autophagy activators from a library including 3,922 natural extracts using a high-throughput assay system. The extracts identified as autophagy activators were administered to mice with 2% dextran sodium sulfate (DSS). Among the autophagy inducers, Sanguisorba officinalis L. (SO) suppressed DSS-induced colitis. To identify the mechanism by which SO ameliorates colitis, epithelial cell and innate myeloid cells-specific Atg7-deficient mice (Villin-cre; Atg7f/f and LysM-cre; Atg7f/f mice, respectively) were analyzed. SO-mediated inhibition of colitis was observed in Villin-cre; Atg7f/f mice. However, SO and a mixture of its components including catechin acid, ellagic acid, gallic acid, and ziyuglycoside II (Mix4) did not suppressed colitis in LysM-cre; Atg7f/f mice. In large intestinal macrophages (Mφ) of Atg7f/f mice, SO and Mix4 upregulated the expression of marker genes of anti-inflammatory Mφ including Arg1, Cd206, and Relma. However, these alterations were not induced in LysM-cre; Atg7f/f mice. These findings indicate that SO and its active components ameliorate DSS-induced colitis by providing intestinal Mφ with anti-inflammatory profiles via promotion of Atg7-dependent autophagy.

Safety of Emulsifying Lipid Formulation Containing Omega-3 Polyunsaturated Fatty Acids for Patients with Crohn's Disease.

BACKGROUND/AIM: The efficacy of omega-3 supplementation by oral capsule for patients with Crohn's disease (CD) remains controversial. We investigated the safety and efficacy of an omega-3 emulsified formulation. PATIENTS AND METHODS: Six patients with CD in remission participated in this open-label clinical trial. Patients ingested one bottle (100 ml) of the test formulation (IMARK S®) daily for 28 days. After a 1-month washout period, patients ingested two bottles of the formulation daily for 28 days. Anthropometric and blood tests were performed before and after each intervention. RESULTS: The omega-3 emulsifying formulation was safe with minimal side-effects. Body weight and body-mass index were not altered; however, CD activity index scores tended to decrease after ingested one bottle of formulation. Blood tests revealed no severe adverse effects. CONCLUSION: Supplementation with an omega-3 emulsifying formulation can be safe and useful for maintaining remission in patients with CD and warrants further studies.

The effect of Clostridium butyricum MIYAIRI on the prevention of pouchitis and alteration of the microbiota profile in patients with ulcerative colitis.

PURPOSE: Ulcerative colitis (UC) is a chronic, relapsing, and refractory disorder of the intestine. Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is the preferred and standard surgical procedure for patients' refractory to medical therapy. Pouchitis is one of the most common long-term complications after IPAA. In the present study, the safety and efficacy of Clostridium butyricum MIYAIRI (CBM) as a probiotic were examined. METHODS: A randomized and placebo-controlled study was performed. Seventeen patients were recruited from 2007 to 2013. Nine tablets of MIYA-BM(®) or placebo were orally administered once daily. The cumulative pouchitis-free survival, pouch condition (using the modified pouch disease activity index), and blood parameters were evaluated. A fecal sample analysis was also performed. RESULTS: Subjects were randomly allocated to receive MIYA-BM or placebo (9 and 8 subjects, respectively). One subject in the MIYA-BM group and four subjects in the placebo group developed pouchitis. No side effects occurred in either group. Characteristic intestinal flora was observed in each group. CONCLUSIONS: Our results suggest that probiotic therapy with CBM achieved favorable results with minimal side effects and might be a useful complementary therapy for the prevention of pouchitis in patients with UC who have undergone IPAA.

Efficacy and Interaction of Antioxidant Supplements as Adjuvant Therapy in Cancer Treatment: A Systematic Review.

Oxidative stress is a key component in carcinogenesis. Although radiation produces reactive oxygen species, some anticancer agents such as alkylating agents, platinum and antitumor antibiotics exert cytotoxicity by generating free radicals. Nonenzymatic exogenous antioxidants such as vitamins, minerals, and polyphenols can quench ROS activity. However, whether antioxidants alter antitumor effects during radiotherapy and some types of chemotherapy remains unclear. In the present study, we reviewed antioxidants as an adjuvant therapy for cancer patients during chemotherapy or radiotherapy. Electronic literature searches were performed to select all randomized controlled clinical trials (RCTs) in which antioxidants were administered to cancer patients along with chemotherapy or radiotherapy. Articles or abstracts written in English were included. In total, 399 reports received primary screening. Duplicated articles and those meeting the exclusion criteria (not RCT, not human, and no oral administration) were excluded. Finally, 49 reports matching the inclusion criteria were included. It was difficult to determine whether antioxidants affect treatment outcomes or whether antioxidants ameliorate adverse effects induced by chemotherapy and radiotherapy. It is desirable to use an evidence-based method to select supplements best suited to cancer patients. Although there are many opinions about risks or benefits of antioxidant supplementation, we could mostly conclude that the harm caused by antioxidant supplementation remains unclear for patients during cancer therapy, except for smokers undergoing radiotherapy.

Review: Evidence-based Clinical Research of Anti-obesity Supplements in Japan.

BACKGROUND: The prevalence of obesity has increased dramatically throughout the world, and weight reduction through lifestyle management is urgently warranted. At present, numerous supplements advertised for their anti-overweight property are available in the Japanese market, but most of these lack proper evidence. Thus, we investigated dietary supplements that have been tested in clinical trials. SEARCH STRATEGY: We researched anti-obesity supplements in the Japanese market using the google search engine in Japanese with the key terms "anti-obesity supplements," "diet supplements," and "weight reduction supplements." RESULTS: We listed 49 companies that supply anti-obesity supplements. Of these, 11 had published clinical evidence of the anti-obesity efficacy of their supplements. These products contain the following active ingredients: Angelica keiskei, bofu-tsusho-san, capsaishin, DHA/EPA, forskohlii, garcinia cambogia, lactoferrin, L-carnitine, oligonol, tea catechin, and yeast hydrolysate. CONCLUSION: We obtained 11 supplements for which clinical evidence was published in medical journals in English. We also found 10 products for which clinical or animal evidence was published in Japanese. We expect that many companies will produce evidence of the efficacy of their products in the near future, thereby validating the use of dietary anti-obesity supplements in Japan.