Dimethyl Fumarate Alleviates Dextran Sulfate Sodium-Induced Colitis, through the Activation of Nrf2-Mediated Antioxidant and Anti-inflammatory Pathways.

Oxidative stress and chronic inflammation play critical roles in the pathogenesis of ulcerative colitis (UC) and inflammatory bowel diseases (IBD). A previous study has demonstrated that dimethyl fumarate (DMF) protects mice from dextran sulfate sodium (DSS)-induced colitis via its potential antioxidant capacity, and by inhibiting the activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. This study aims to clarify the nuclear factor erythroid 2-related factor 2/antioxidant responsive element (Nrf2/ARE) pathway pharmacological activation and anti-inflammatory effect by DMF, through focusing on other crucial antioxidant enzymes and inflammatory mediator, including glutamate-cysteine ligase catalytic subunit (GCLC), glutathione peroxidase (GPX) and cyclooxygenase-2 (COX-2), in a DSS-induced colitis mouse model. The oral administration of DMF attenuated the shortening of colons and alleviated colonic inflammation. Furthermore, the expression of key antioxidant enzymes, including GCLC and GPX, in the colonic tissue were significantly increased by DMF administration. In addition, protein expression of the inflammatory mediator, COX-2, was reduced by DMF administration. Our results suggest that DMF alleviates DSS-induced colonic inflammatory damage, likely via up-regulating GCLC and GPX and down-regulating COX-2 protein expression in colonic tissue

Sidedness of CRC on tumor immunity

Background Clinical and molecular characteristics differ between right-sided and left-sided colorectal cancer (CRC). This study aimed to clarify the correlation between CRC sidedness and tumor immunity. Methods A total of 102 patients who underwent curative colectomy for stage II/III CRC were included in this study. The expression of programmed cell death (PD)-1, PD1-ligand 1 (PD-L1), forkhead box P3 (Foxp3), transforming growth factor (TGF)-β, and indoleamine-pyrrole 2,3-dioxygenase (IDO) were examined using immunohistochemistry and the relationships between sidedness and several prognostic factors were examined. Results Clinicopathological factors were not significantly different between right- and left-sided CRC. The tumor immunity-related molecule PD-L1 was more highly expressed in right-sided than in left-sided CRC (62.9% vs. 30.6%, p<0.01). No significant difference was found in overall survival (OS) and disease-free survival (DFS) by sidedness. PD-1 and Foxp3 expression were significant prognostic factors for OS. Lymph node metastasis (N), lymphatic invasion (ly), and PD-L1 expression were significant prognostic factors for DFS. In right-sided CRC, IDO-positive patients had a poor OS (p<0.05), and IDO was the only independent prognostic indicator for OS. N and venous invasion were identified as independent prognostic indicators for DFS. In left-sided CRC, univariate analysis identified PD-1, PD-L1, and Foxp3 expression as significant predictors of poor OS. Multivariate analysis confirmed PD-L1 expression as an independent prognostic indicator. N, ly, and PD-L1 expression levels were identified as significant predictors of poor DFS. Conclusions The prognostic factors were IDO in right-sided CRC and PD-L1 and Foxp3 in left-sided CRC. These findings indicated that tumor immunity might play different roles depending upon sidedness. Tumor location may be an important factor to consider when assessing immune response and therapeutic decisions in CRC patients

Anastomotic recurrence after delta method

Delta-shaped anastomosis is nowadays an increasingly performed reconstruction method in laparoscopic distal gastrectomy for early gastric cancer. To date, anastomotic recurrence at the delta-shaped anastomotic site has not been reported. Surgery for this disease is more complicated than anastomotic recurrence at the site of conventional Billroth-I anastomosis. A 68-year-old female was referred to our institute with early gastric cancer on the posterior wall of the antrum. She underwent laparoscopic distal gastrectomy with delta-shaped Billroth-I anastomosis. Follow-up gastrofiberscopy 16 months after the operation revealed suspected anastomotic recurrence, and gastric biopsy revealed signet-ring cell carcinoma. Open total gastrectomy with reconstruction with the Roux-en-Y method was performed. At the distal part of the previous anastomosis, an adequate length of the duodenum was dissected from the pancreas. Then, the duodenum was transected 3 cm distal to the anastomosis using a linear stapler. The patient recovered well and was discharged on postoperative day 14. The patient is alive without re-recurrence 3 years postoperatively. We successfully treated a patient with anastomotic recurrence of gastric cancer after delta-shaped anastomosis. Adequate resection of the duodenal stump was performed without any residual tumor or injury to the pancreas

Effect of DMF on liver I/R

AIM To investigate the hypothesis that treatment with dimethyl fumarate (DMF) may ameliorate liver ischemia/reperfusion injury (I/RI). METHODS Rats were divided into 3 groups: sham, control (CTL), and DMF. DMF (25 mg/kg, twice/d) was orally administered for 2 d before the procedure. The CTL and DMF rats were subjected to ischemia for 1 h and reperfusion for 2 h. The serum alanine aminotransferase (ALT) and malondialdehyde (MDA) levels, adenosine triphosphate (ATP), NO × metabolites, anti-oxidant enzyme expression level, anti-inflammatory effect, and anti-apoptotic effect were determined. RESULTS Histological tissue damage was significantly reduced in the DMF group (Suzuki scores: sham: 0 ± 0; CTL: 9.3 ± 0.5; DMF: 2.5 ± 1.2; sham vs CTL, P < 0.0001; CTL vs DMF, P < 0.0001). This effect was associated with significantly lower serum ALT (DMF 5026 ± 2305 U/L vs CTL 10592 ± 1152 U/L, P = 0.04) and MDA (DMF 18.2 ± 1.4 μmol/L vs CTL 26.0 ± 1.0 μmol/L, P = 0.0009). DMF effectively improved the ATP content (DMF 20.3 ± 0.4 nmol/mg vs CTL 18.3 ± 0.6 nmol/mg, P = 0.02), myeloperoxidase activity (DMF 7.8 ± 0.4 mU/mL vs CTL 6.0 ± 0.5 mU/mL, P = 0.01) and level of endothelial nitric oxide synthase expression (DMF 0.38 ± 0.05-fold vs 0.17 ± 0.06-fold, P = 0.02). The higher expression levels of anti-oxidant enzymes (catalase and glutamate-cysteine ligase modifier subunit and lower levels of key inflammatory mediators (nuclear factor-kappa B and cyclooxygenase-2 were confirmed in the DMF group. CONCLUSION DMF improved the liver function and the anti-oxidant and inflammation status following I/RI. Treatment with DMF could be a promising strategy in patients with liver I/RI

TAPP with liquid-injection and gauze dissection

Purpose : This report describes a novel technique for trans-abdominal pre-peritoneal (TAPP) inguinal hernia repair using liquid injection and gauze dissection. Methods : Twenty-five cases underwent TAPP inguinal hernia repair with liquid-injection and gauze dissection. Before the initial peritoneal incision, liquid injection was performed percutaneously into the pre-peritoneal space at the outside of the internal inguinal ring and the inside of the seminal duct. Especially, at the inside of the seminal duct, the liquid was injected into the space between the superficial and deep lobe of pre-peritoneal fascia. Gauze was effectively used to dissect this liquid-injected space. Results : In comparison with the cases of inguinal hernia repair without liquid-injection and gauze dissection, the cases who underwent TAPP inguinal hernia repair with liquid-injection and gauze dissection experienced shorter operation times and no complications or recurrence. Conclusions : TAPP inguinal hernia repair with liquid-injection and gauze dissection appears to be a safe and feasible procedure

Desmoid-type fibromatosis in abdomen

Background : Desmoid-type fibromatosis is a very rare disease that has no characteristic image findings, so it is often difficult to differentiate from gastrointestinal stromal tumor (GIST). A case of desmoid-type fibromatosis that was difficult to differentiate from GIST is reported. The decisive factor in the diagnosis was positive nuclear immunostaining for β-catenin nucleus. Case presentation : A man is his 30s had no significant past medical history, including no abdominal surgery. A medical check-up found a large tumor in the right lateral abdomen. After some examinations, a preoperative diagnosis of GIST was made, and open ileocecal resection was performed. However, the final diagnosis based on the pathological findings was desmoid-type fibromatosis. Conclusions : We should consider desmoid-type fibromatosis when we find a large abdominal mass, but it may be difficult to diagnose based only on imaging findings. Immunohistochemical examination of the specimen may make the diagnosis

Pre-operative weight loss program

Background : The aim of this study was to investigate the influence of obesity and the usefulness of a pre-operative weight loss program (PWLP) for obese patients undergoing laparoscopic gastrectomy (LG) for gastric cancer (GC). Materials and Methods : Study1 : 219 patients who underwent laparoscopic distal gastrectomy (LDG) for GC were divided into 2 groups : body mass index (BMI) ≧ 28 and BMI < 28kg / m2. The influence of BMI in LG surgery was investigated. Study2 : The BMI ≧ 28 kg / m2 patients with a planned LG (n = 8) undertook a PWLP including calorie restriction and exercise. The effects of this program were evaluated. Results : Study1 : The BMI ≧ 28kg / m2 group showed significantly longer operation times, more blood loss and a higher frequency of post-operative complications than that of the BMI < 28kg / m2 group. Study 2 : The patients achieved a weight loss of 4.2%. The visceral fat area (VFA) was significantly decreased by 10.6%, whereas skeletal muscle mass was unaffected. The PWLP group showed shorter operation times, less blood loss and a lower frequency of post-operative complications compared with that of the BMI ≧ 28kg / m2 group. Conclusion : Obesity is an important risk factor and a pre-operative weight loss program is useful for obese patients undergoing a LG

HIF-1α expression in liver metastasis but not primary colorectal cancer is associated with prognosis of patients with colorectal liver metastasis

Background: The role of hypoxia-inducible factor-1α (HIF-1α) in primary colorectal cancer (CRC) and colorectal liver metastasis (CRLM) has remained unclear. The aim of this study was to investigate HIF-1α expression and its association with prognosis in patients with CRLM with a focus on hepatic stellate cells (HSCs). Methods: Colon cancer cells were cultured in HSC-conditioned medium (CM), and HIF-1α expression and cell migration were analyzed. Seventy-five patients with CRLM who underwent an initial curative hepatectomy were enrolled. We examined HIF-1α expressions and patient prognosis between primary CRCs and the matched liver metastatic specimens. Results: Activated HSCs induced HIF-1α mRNA and protein expression in colon cancer cells (p < 0.01) and promoted cell migration (p < 0.01). The positive rates of HIF-1α expression in primary CRCs and liver metastases were 68.0 and 72.0%, respectively. There were no differences in overall (OS) and disease-free survival (DFS) of HIF-1α expression in primary CRC. However, HIF-1α expression in liver metastasis correlated to poor prognosis in both OS and DFS. Furthermore, patients with HIF-1α positive expression in liver metastasis had poor prognosis. Conclusion: HIF-1α expression in liver metastasis determines poor prognosis of CRLM patients. HSCs might play a key role in aggressive phenotypes of tumor cells

The influence and countermeasure of obesity in laparoscopic colorectal resection

Background: The aim of this study was to investigate the influence of obesity and the usefulness of a preoperative weight loss program (PWLP) for obese patients undergoing laparoscopic colorectal resection (LCR). Methods: Study 1: 392 patients who underwent LCR for colorectal cancer were divided into two groups: those with a body mass index (BMI) ≥25 kg/m2 (n = 113) and those with a BMI <25 kg/m2 (n = 279). The influence of BMI on LCR was investigated. Study 2: Patients with a BMI ≥28 kg/m2 who were scheduled to undergo LCR (n = 7, mean body weight 87.0 kg, mean BMI 33.9 kg/m2) undertook a PWLP including caloric restriction and exercise for 29.6 (15–70) days. The effects of this program were evaluated. Results: Study 1: The BMI ≥25 kg/m2 group had a prolongation of operation time and hospital stay than the BMI <25 kg/m2 group. Study 2: The patients achieved a mean weight loss of 6.9% (−6.0 kg). The mean visceral fat area was significantly decreased by 18.0%, whereas the skeletal muscle mass was unaffected. The PWLP group had a significantly lower prevalence of postoperative complications compared with the BMI ≥25 kg/m2 group. Conclusion: Obesity affected the surgical outcomes in LCR. A PWLP may be useful for obese patients undergoing LCR

Role of Nrf2 in HLC

Generation of hepatocytes from human adipose-derived mesenchymal stem cells (hADSCs) could be a promising alternative source of human hepatocytes. However, mechanisms to differentiate hepatocytes from hADSCs are not fully elucidated. We have previously demonstrated that our three-step differentiation protocol with glycogen synthase kinase (GSK) 3 inhibitor was effective to improve hepatocyte functions. In this study, we investigated the activation of the nuclear factor erythroid-2 related factor 2 (Nrf2) on hADSCs undergoing differentiation to HLC (hepatocyte-like cells). Our three-step differentiation protocol was applied for 21 days (Step 1 : day 1-6, Step2 : day 6-11, Step3 : day 11-21). Our results show that significant nuclear translocation of Nrf2 occurred from day 11 until the end of HLC differentiation. Nuclear translocation of Nrf2 and CYP3A4 activity in the GSK3 inhibitor-treated group was obviously higher than that in Activin A-treated groups at day 11. The maturation of HLCs was delayed in Nrf2-siRNA group compared to control group. Furthermore, CYP3A4 activity in Nrf2-siRNA group was decreased at the almost same level in Activin A-treated group. Nrf2 translocation might enhance the function of HLC and be a target for developing highly functional HLC