Fuwen Luo

Chemopreventive effects of aspirin at a glance

Experimental, epidemiological, and clinical data from the last two decades have each supported the hypothesis that aspirin possesses anticancer properties, and that its use may also reduce the lifetime probability of developing or dying from a number of cancers. Aspirins ability to act on multiple key metabolic and signaling pathways via inhibition of the cyclooxygenase (COX) enzyme, as well as through COX-independent mechanisms, makes it particularly relevant in the fight against cancer. A growing body of evidence indicates that aspirin may not only reduce cancer risk, but also prevent metastasis and angiogenesis while slowing the rate of mutation-inducing DNA damage. These emerging benefits of aspirin are offset to some extent by the known risks of treatment, such as cardiovascular events and gastrointestinal bleeding. However, it has been shown that pre-treatment risk assessment of individual patients and the use of proton pump inhibitors or Helicobacter pylori eradication therapy concomitantly with aspirin treatment can reduce these potential risks. Thus, the significant benefits of aspirin treatment, coupled with recent data concerning its risks, may prove to tip the balance in favor of aspirin use in cancer prevention.

Lactobacillus rhamnosus induced epithelial cell apoptosis, ameliorates inflammation and prevents colon cancer development in an animal model.

BACKGROUND/AIM Probiotics have been suggested as prophylactic measure in colon carcinogenesis. This study aimed at determining the potential prophylactic activity of Lactobacillus rhamnosus GG CGMCC 1.2134 (LGG) strain on colorectal carcinogenesis via measuring its effect on Nuclear factor kappa B (NFκB) inflammatory pathway and apoptosis. MATERIALS AND METHODS 64 Sprague Dawley rats were grouped into four as follows; Group 1 (Healthy control), Group 2 (LGG), Group 3 (cancer control Dimethyl hydrazine (DMH)) and Group 4 (LGG+DMH). LGG was administered orally to LGG and LGG+DMH groups. Colon carcinogenesis was chemically induced in LGG+DMH and DMH groups by weekly injection of 40mg/kg DMH. Animals were sacrificed after 25 weeks of experiment and tumor characteristics assessed. The change in expression of NFκB-p65, COX-2, TNFα, Bcl-2, Bax, iNOS, VEGFα, β-catenin, Casp3 and p53 were evaluated by western blotting and qRT-PCR. RESULTS LGG treatment significantly reduced tumor incidence, multiplicity and volume in LGG+DMH treatment group compared to DMH cancer control group. Also, LGG treatment reduced the expression of β-catenin and the inflammatory proteins NFκB-p65, COX-2 and TNFα; the anti-apoptotic protein Bcl-2, but increased the expression of the pro-apoptotic proteins Bax, casp3 and p53 compared with DMH group. CONCLUSION LGG have a potential protection effect against colon carcinogenesis; inducing apoptosis and ameliorating inflammation, and may hold a promise as bio-therapeutic dietary agent.

The protective effects of curcumin on experimental acute liver lesion induced by intestinal ischemia-reperfusion through inhibiting the pathway of NF-κB in a rat model.

Objective. In this study, we investigated the protective effect and mechanism of curcumin on a rat model of intestinal ischemia/reperfusion (I/R), which induces an acute liver lesion. Methods. Curcumin was injected into rats in the curcumin groups through left femoral vein. The same volume of vehicle (0.9% normal saline) was injected into sham and I/R groups. Blood and liver tissue were gathered for serological and histopathological determination. Results. Intestinal I/R led to severe liver injury manifested as a significant increase in serum AST and ALT levels; all of those were reduced by treatment with curcumin. Simultaneously, the activity of SOD in liver decreased after intestinal I/R, which was increased by curcumin treatment. On the other hand, curcumin reduced MPO activity of liver tissue, as well as serum IL-6 and TNF-α levels observably. This is in parallel with the decreased level of liver intercellular cell adhesion molecule-1 (ICAM-1) and nuclear factor-κB (NF-κB) expression. Conclusion. Our findings suggest that curcumin treatment attenuates liver lesion induced by intestinal I/R, attributable to the antioxidative and anti-inflammatory effect via inhibition of the NF-κB pathway.

MG132 Alleviates Liver Injury Induced by Intestinal Ischemia/Reperfusion in Rats: Involvement of the AhR and NFκB Pathways

BACKGROUND MG132 is a potent antioxidant and has been reported to play a protective role in ischemia/reperfusion (I/R) of many organs. Recent studies have shown that the Aryl hydrocarbon receptor (AhR) may play a beneficial role in I/R of many organs and an AhR agonist has been implicated in an anti-inflammatory role. MG132 might function as an AhR agonist through proteasome inhibition, possibly through the inhibition of NFκB. Herein, we hypothesized that MG132 may play a protective role in liver injury induced by intestinal I/R and we analyzed the expression behavior of AhR and NFκB to determine whether the two factors play a role in intestinal I/R. MATERIALS AND METHODS Thirty-two Sprague-Dawley rats were divided into four groups: control, I/R, MG132 control, and MG132 pretreatment. The I/R and MG132 pretreatment groups were subjected to mesenteric arterial ischemia for 1 h and reperfusion for 3 h. The control and MG132 control groups underwent surgical preparation including isolation of the superior mesenteric artery (SMA) without occlusion. The MG132 control and MG132 pretreatment groups were subjected to intraperitoneal administration of 0.5 mg/kg MG132 30 min before surgery. We collected serum specimens to measure TNF-α, IL-6, liver tissue levels of malondialdehyde (MDA), AhR, and cyp1a2; NFκB, IκBα, and ICAM-1 were also tested. Histologic changes of liver and intestine were subsequently evaluated. RESULTS Compared with the control group, significant increases in MDA, NFκB, and ICAM-1 levels were accompanied by decreases in AhR, cyp1a2, and IκBα expression in the liver in the I/R group, which is consistent with liver and intestinal tissue injury. MG132 blocked the alterations of the indicators above. There were no changes in the MG132 control group compared with the control group in the indicators above. CONCLUSIONS This study demonstrated that MG132 has a significant effect in protection against liver injury induced by intestinal I/R, which may be due to modulation of the AhR and NFκB pathways.

Reviewing the Management of Obstructive Left Colon Cancer: Assessing the Feasibility of the One-stage Resection and Anastomosis After Intraoperative Colonic Irrigation

Micro‐Abstract Around 20% of patients with colorectal cancer present with acute colonic obstruction as the first sign of colon cancer. Traditionally, a multi‐stage approach was favored but, given the large amount of non‐reversal of stoma, the single‐stage primary resection and anastomosis after colonic irrigation is becoming more popular. We concluded that it can be done after our analysis at our institution. Background: The management of obstructive left colon cancer (OLCC) remains debatable with the single‐stage procedure of primary colonic anastomosis after cancer resection and on‐table intracolonic lavage now being supported. Patients and Methods: Patients with acute OLCC who were admitted between January 2008 and January 2015 were distributed into 5 different groups. Group ICI underwent emergency laparotomy for primary anastomosis following colonic resection and intraoperative colonic lavage; Group HP underwent emergency Hartmanns Procedure; Group CON consisted of patients treated by conservative management with subsequent elective open cancer resection; Group COL were colostomy patients; and Group INT consisted of patients who had interventional radiology followed by open elective colon cancer resection. The demographics of the patients and comorbidity, intraoperative data, and postoperative data were collected, with P < .05 as significant. Results: There were 4 deaths in 138 cases (2.90%). There was only 1 patient who had anastomotic leakage (5.56%) in Group ICI, compared with none in Group HP and Group COL, 1 case in Group INT (7.69%), and 2 cases in Group CON (6.06%) (P > .05). Group INT and Group CON, when compared to the three surgical groups, Groups ICI, Group COL, and Group HP, individually, were statistically significant for the duration of surgery (P < .05). Conclusions: Primary anastomosis following colonic resection after irrigation can be safely performed in selected patients, with the necessary surgical expertise, with no increased risk in mortality, anastomotic leakage, and other postoperative complications.

Splenic abscess owing to cancer at the splenic flexure: A case report and comprehensive review.

Background:The cancer of the splenic flexure of the colon is a rare medical entity with severe morbidity because of its insidious onset. Methods:We present the case of a 59-year-old male patient with dull left upper quadrant pain, leukocytosis, and anemia. A splenic abscess described as an air-fluid level with splenocolic fistula was found on CT scan imaging. Surgery was done for splenic pus drainage. He was again admitted 2 months later for intestinal obstruction. Results:An exploratory laparotomy showed multiple hard, gray liver nodules as well as a hard mass in the small bowel. Owing to extensive adhesions and a late stage of cancer involvement, the splenic flexure tumor was not resected. A loop transverse colostomy was done and a ColoplastTM Colostomy bag placed. We also reviewed the literature-linking colon cancer and splenic abscess with specific attention to the carcinoma of the splenic flexure. As the latter invades through the spleen matter, there is the creation of a splenocolic fistula, which allows the migration of normal gut flora into the spleen. This leads to the formation of the splenic abscess. Conclusion:This is the 13th case report pertaining to invading colonic cancer causing a splenic abscess. Although the treatment for splenic abscesses is shifting from splenectomy to image-guided percutaneous pus drainage, the few reported cases make the proper management of such complication still unclear.

Fish oil alleviates liver injury induced by intestinal ischemia/reperfusion via AMPK/SIRT-1/autophagy pathway

AIM To evaluate whether fish oil (FO) can protect liver injury induced by intestinal ischemia/reperfusion (I/R) via the AMPK/SIRT-1/autophagy pathway. METHODS Ischemia in Wistar rats was induced by superior mesenteric artery occlusion for 60 min and reperfusion for 240 min. One milliliter per day of FO emulsion or normal saline was administered by intraperitoneal injection for 5 consecutive days to each animal. Animals were sacrificed at the end of reperfusion. Blood and tissue samples were collected for analyses. AMPK, SIRT-1, and Beclin-1 expression was determined in lipopolysaccharide (LPS)-stimulated HepG2 cells with or without FO emulsion treatment. RESULTS Intestinal I/R induced significant liver morphological changes and increased serum alanine aminotransferase and aspartate aminotransferase levels. Expression of p-AMPK/AMPK, SIRT-1, and autophagy markers was decreased whereas tumor necrosis factor-α (TNF-α) and malonaldehyde (MDA) were increased. FO emulsion blocked the changes of the above indicators effectively. Besides, in LPS-stimulated HepG2 cells, small interfering RNA (siRNA) targeting AMPK impaired the FO induced increase of p-AMPK, SIRT-1, and Beclin-1 and decrease of TNF-α and MDA. SIRT-1 siRNA impaired the increase of SIRT-1 and Beclin-1 and the decrease of TNF-α and MDA. CONCLUSION Our study indicates that FO may protect the liver against intestinal I/R induced injury through the AMPK/SIRT-1/autophagy pathway.

Macrophages confer resistance to PI3K inhibitor GDC-0941 in breast cancer through the activation of NF-κB signaling

The PI3K pathway is one of the most dysregulated signaling pathways in epithelial cancers and has become an attractive therapeutic target under active preclinical and clinical development. However, recent clinical trial studies revealed that blockade of PI3K activity in advanced cancer often leads to the development of resistance and relapse of the diseases. Intense efforts have been made to elucidate resistance mechanisms and identify rational drug combinations with PI3K inhibitors in solid tumors. In the current study, we found that PI3K inhibition by GDC-0941 increased macrophage infiltration and induced the expression of macrophage-associated cytokines and chemokines in the mouse 4T1 breast tumor model. Using the in vitro co-culture system, we showed that the presence of macrophages led to the activation of NF-κB signaling in 4T1 tumor cells, rendering tumor cells resistant to PI3K inhibition by GDC-0941. Furthermore, we found that Aspirin could block the activation of NF-κB signaling induced by PI3K inhibition, and combined use of GDC-0941 and Aspirin resulted in attenuated cell growth and enhanced apoptosis of 4T1 cells in the in vitro co-culture system with the presence of macrophages. Consistently, the combination treatment also effectively reduced tumor burden, macrophage infiltration and pulmonary metastasis in in vivo 4T1 breast tumor model. Together, our results suggested macrophages in microenvironment may contribute to the resistance of breast cancer cells to PI3K inhibition and reveal a new combination paradigm to improve the efficacy of PI3K-targeted therapy.