Chemotherapy mediates intestinal injury via p53/p53 upregulated modulator of apoptosis (PUMA) signaling pathway.

OBJECTIVE: The aim of this study was to investigate the potential mechanism and signaling pathway involved in chemotherapy-induced intestinal mucosal injury (CIMI), which is a common physiopathological problem in patients with cancer. METHODS: For the in vivo experiment, mice received intraperitoneal injection of 5-fluorouracil (5-FU) at a dose of 75 mg/kg/day for 1, 3 or 5 days. Villus height and crypt depth of the small intestine, cell apoptosis and proliferation were then examined to determine the extent of CIMI. The expressions of Akt, p53, PUMA and p21 were evaluated both in vivo in mice models and in vitro in the IEC-6 and HCT116 cell lines. RESULTS: After 5-FU therapy both the intestinal villus height (275.93 µm vs 164.52 µm, P < 0.001) and crypt depth (64.13 µm vs 42.48 µm, P < 0.001) were decreased. The apoptotic index was greatly increased from 0.32% to 15.84% (P < 0.001) and proliferation was suppressed (63.58% vs 39.15%, P < 0.001). Additionally, p53 expression was significantly increased in the intestinal crypt along with the expressions of PUMA and p21. Western blot showed that the administration of 5-FU induced p53/PUMA-mediated apoptosis and upregulated p21 expression to suppress cell proliferation. CONCLUSION: Chemotherapy might mediate intestinal injury via p53/PUMA-mediated apoptotic signaling and the suppression of proliferation in response to p21.

Tumor necrosis factor-α mediates JNK activation response to intestinal ischemia-reperfusion injury.

AIM: To investigate whether tumor necrosis factor-α (TNF-α) mediates ischemia-reperfusion (I/R)-induced intestinal mucosal injury through c-Jun N-terminal kinase (JNK) activation. METHODS: In this study, intestinal I/R was induced by 60-min occlusion of the superior mesenteric artery in rats followed by 60-min reperfusion, and the rats were pretreated with a TNF-α inhibitor, pentoxifylline, or the TNF-α antibody infliximab. After surgery, part of the intestine was collected for histological analysis. The mucosal layer was harvested for RNA and protein extraction, which were used for further real-time polymerase chain reaction, enzyme-linked immunosorbent assay and Western blotting analyses. The TNF-α expression, intestinal mucosal injury, cell apoptosis, activation of apoptotic protein and JNK signaling pathway were analyzed. RESULTS: I/R significantly enhanced expression of mucosal TNF-α at both the mRNA and protein levels, induced severe mucosal injury and cell apoptosis, activated caspase-9/caspase-3, and activated the JNK signaling pathway. Pretreatment with pentoxifylline markedly downregulated TNF-α at both the mRNA and protein levels, whereas infliximab pretreatment did not affect the expression of TNF-α induced by I/R. However, pretreatment with pentoxifylline or infliximab dramatically suppressed I/R-induced mucosal injury and cell apoptosis and significantly inhibited the activation of caspase-9/3 and JNK signaling. CONCLUSION: The results indicate there was a TNF-α-mediated JNK activation response to intestinal I/R injury.

Primary duodenal NK/T-cell lymphoma with massive bleeding: A case report.

Primary natural killer/T-cell (NK/T-cell) lymphoma of the gastrointestinal tract is a very rare disease with a poor prognosis, and the duodenum is quite extraordinary as a primary lesion site. Here, we describe a unique case of a primary duodenal NK/T-cell lymphoma in a 26-year-old man who presented with abdominal pain and weight loss. Abdominal computed tomography scan demonstrated a hypodense tumor in the duodenum. Because of massive upper gastrointestinal tract bleeding during hospitalization, the patient was examined by emergency upper gastrointestinal endoscopy. Under endoscopy, an irregular ulcer with mucosal edema, destruction, necrosis, a hyperplastic nodule and active bleeding was observed on the duodenal posterior wall. Following endoscopic hemostasis, a biopsy was obtained for pathological evaluation. The lesion was subsequently confirmed to be a duodenal NK/T-cell lymphoma. The presenting symptoms of primary duodenal NK-/T-cell lymphoma in this patient were abdominal pain and gastrointestinal bleeding, and endoscopy was important for diagnosis. Despite aggressive treatments, the prognosis was very poor.

[Omega-6 polyunsaturated fatty acid promotes colon carcinogenesis].

OBJECTIVE: To investigate whether ω-6 polyunsaturated fatty acid promotes colon carcinogenesis through downregulation of P53-dependent growth inhibition. METHODS: Colon carcinogenesis was induced by injection of azoxymethane (AOM) intraperitoneally. Experimental animals were randomly divided into four groups, receiving regular diet and intraperitoneal injection of normal saline(control group), high ω-6 polyunsaturated fatty acid diet with intraperitoneal injection of normal saline(Corn oil group), regular diet with intraperitoneal injection of AOM(AOM group), or high ω-6 polyunsaturated fatty acid diet with intraperitoneal injection of AOM (Corn oil+AOM group). Aberrant crypt focis (ACFs) were observed after methylene blue staining and enumerated. Colonic mucosa PCNA and P53 expressions were assessed by RT-PCR and Western blotting, and location of P53 in the colon crypt focis was determined by immunohistochemical staining. RESULTS: Amounts of ACFs was 1.2±0.3 in the control group, 1.3±0.4 in the Corn oil group, 41.0±4.8 in the AOM group, and 73.3±9.9 in the Corn oil+AOM group, the differences were statistically significant(P<0.05). The expression of P53 in normal crypt focis was higher than that in ACFs. High ω-6 polyunsaturated fatty acid dietary significantly promoted AOM-induced colon PCNA expression, and enhanced AOM-mediated P53 inhibition in colon mucosa. CONCLUSION: High ω-6 polyunsaturated fatty acid diet can enhance AOM-induced inhibition of P53 in colon mucosa, resulting in overexpression of PCNA, formation of ACF, and carcinogenesis in the colon.

Glucose metabolism disorders in cancer patients in a Chinese population.

BACKGROUND: Characteristics of glucose metabolism disorders (GMDs) in different cancers and the contributory role of GMDs in developing cancers are still not so clear. METHODS: Two thousand four hundred and five patients with malignancy who had been hospitalized in the First Affiliated Hospital of Jinan University were pooled as case group. Two thousand and sixteen non-cancer people who finished health examinations in the Affiliated Yangcheng Hospital of Guangzhou Medical College were enrolled as control group. We compared glucose metabolism among patients with different kinds of malignancy. Based on logistic regression models, we analyzed factors that affect the development of carcinoma. RESULTS: (1) Among 2,408 malignancy patients, the total prevalence of diabetes mellitus (DM) and impaired fasting glucose (IFG) reached 28.0%. Pancreatic cancer, lymphoma, liver cancer, leukemia, and colorectal cancer showed most striking hyperglycemia. (2) Leukemia and esophageal cancer accounting for 12.5% and 12.1%, respectively, were the most likely to suffer from hypoglycemia. (3) Older cancer patients seem to be more vulnerable to hyperglycemia, while the younger tend to be more likely to develop hypoglycemia. (4) High level of fasting plasma glucose (FPG) was associated with lung cancer, breast cancer, leukemia, lymphoma, thyroid cancer, bladder cancer, and pancreatic cancer. Patients with DM increased risks for developing colorectal cancer, liver cancer, esophageal cancer, thyroid cancer, cervical cancer, and pancreatic cancer. CONCLUSIONS: GMDs are frequent events in malignancy patients. Hyperglycemia and hypoglycemia are found in the same kinds or different kinds of cancers, and the incidence of hyperglycemia is higher than that of hypoglycemia. Characteristics of GMDs were dissimilar in different cancers and different ages. Hyperglycemia was a risk factor for many cancers.