JNK (c-Jun NH2 terminal kinase) and p38 during ischemia reperfusion injury in the small intestine.

BACKGROUND: In small intestinal ischemia reperfusion injury, we investigated the pathophysiological role of c-Jun NH2 terminal kinase (JNK) and p38 in order to determine whether the dual inhibition of JNK and p38 was beneficial. METHODS: Ischemia reperfusion injury was induced by clamping the superior mesenteric artery for 30 min in Wistar male rats. The inhibition of JNK and p38 was achieved with LL-Z1640-2 as a novel JNK and p38 dual inhibitor in vivo. Between the non-treatment group (Control group) and the LL-Z1640-2 treatment group (LL-Z group), the following findings were compared; histological damage by hematoxylin and eosin (H. E.) staining, JNK and p38 activation by a kinase assay, the localization of apoptosis using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method, the localization of activated JNK and activated p38 based on immunohistochemistry. RESULTS: The activation of JNK and p38 increased remarkably after reperfusion according to a kinase assay. In immunohistochemistry for activated JNK and activated p38, a remarkable degree of positive staining was revealed in the nucleus of the detached epithelial cells from the tip of villi after reperfusion. In addition, many TUNEL positive cells were observed in the detached epithelial cells where JNK and p38 were activated. Pretreatment of LL-Z1640-2 inhibited the activation of JNK and p38, and also significantly improved the histological damage. CONCLUSIONS: These results suggest that JNK and p38 both play a key role during small intestinal ischemia reperfusion injury through a proapoptotic action on the tip of villi.

[Four cases of gastric cancer with multiple hepatic metastases successfully treated with TS-1 in combination with low-dose cisplatinum].

We treated five cases for multiple hepatic metastases from gastric cancer with a novel combination of TS-1 and low-dose cisplatinum (CDDP). TS-1 was orally administered at 100 mg/body/day every day or only on weekdays, and 10 mg of CDDP was infused once or twice a week. The efficacy was evaluated by body CT after the treatment. The CT showed more than a 60% reduction of hepatic tumors in four patients. The tumor markers, CEA and CA19-9, were reduced to 10%. The response rate was 80%. Adverse reactions of grade 1 anemia were observed in two patients and grade 1 leucopenia in one patient. The liver function normalized in one patient. The hemoglobin level was increased from 6.8 g/dl to 11.8 g/dl in one patient. In conclusion, this combined chemotherapy of TS-1 and low-dose CDDP proved useful for advanced gastric cancer patients with multiple hepatic metastases, in view of its therapeutic efficacy, patients' quality of life and low toxicity.

c-Jun N-terminal kinase activation during warm hepatic ischemia/reperfusion injuries in a rat model.

Ischemia/reperfusion injuries are a major problem in liver resections and transplantations. Tumor necrosis factor-alpha has been widely investigated as a key mediator in the mechanism of ischemia/reperfusion injury. Upstream signal transduction mechanisms for tumor necrosis factor-alpha have not been well documented. Therefore, we assessed c-Jun N-terminal kinase activation during warm hepatic ischemia/reperfusion injuries in a rat model. Male Wistar rats were subjected to 30 minutes of ischemia followed by reperfusion. Hepatic enzymes, histological examinations, microfluorographs, and tumor necrosis factor-alpha protein production (in the serum and liver tissue) were analyzed during the course of reperfusion. c-Jun N-terminal kinase activity was measured by a radioisotope kinase assay. Ischemia/reperfusion injuries were characterized by an elevation in hepatic enzyme, the histological degeneration of hepatocytes, and an increase in the number of nonviable cells. Moreover, increased endothelial-adherent leukocytes and tumor necrosis factor-alpha protein production were also observed. c-Jun N-terminal kinase activity at 60 minutes after reperfusion was 12.4 times higher than the pre-ischemia level. These results suggest that c-Jun N-terminal kinase may play some role in the mechanism of ischemia/reperfusion injuries.