Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice.

Leptin acts on its receptor (ObR) in the hypothalamus to inhibit food intake and energy expenditure. Leptin and ObR are also expressed in the gastrointestinal tract; however, the physiological significance of leptin signaling in the gut remains uncertain. Suppressor of cytokine signaling 3 (SOCS3) is a key negative feedback regulator of ObR-mediated signaling in the hypothalamus. We now show that gastrointestinal epithelial cell-specific SOCS3 conditional knockout (T3b-SOCS3 cKO) mice developed gastric tumors by enhancing leptin production and the ObRb/signal transducer and activator of transcription 3 (STAT3) signaling pathway. All T3b-SOCS3 cKO mice developed tumors in the stomach but not in the bowels by 2 months of age, even though the SOCS3 deletion occurred in both the epithelium of stomach and bowels. The tumors developed in the absence of the inflammatory response and all cKO mice died within 6 months. These tumors displayed pathology and molecular alterations, such as an increase in MUC2 (Mucin 2, oligomeric mucus/gel-forming) and TFF3 (trefoil factor 3), resembling human intestinal-type gastric tumors. Administration of antileptin antibody to T3b-SOCS3 cKO mice reduced hyperplasia of gastric mucosa, which is the step of the initiation of gastric tumor. These data suggest that SOCS3 is an antigastric tumor gene that suppresses leptin overexpression and ObRb/STAT3 hyperactivation, supporting the hypothesis that the leptin/ObRb/STAT3 axis accelerates tumorigenesis and that it may represent a new therapeutic target for the treatment of gastric cancer.

Effects of volatile and intravenous anesthetics on the uptake of GABA, glutamate and dopamine by their transporters heterologously expressed in COS cells and in rat brain synaptosomes.

Although the neurotransmitter uptake system is considered a possible target for the presynaptic action of anesthetic agents, observations are inconsistent concerning effects on the transporter and their clinical relevance. The present study examined the effects of volatile and intravenous anesthetics on the uptake of GABA, glutamate and dopamine in COS cells heterologously expressing the transporters for these neurotransmitters and in the rat brain synaptosomes. Halothane and isoflurane, but not thiamylal or thiopental, significantly inhibited uptake by COS cell systems of GABA, dopamine and glutamic acid in a concentration-dependent manner within clinically relevant ranges for anesthesia induced by these agents. Similarly, in synaptosomes halothane and isoflurane but not thiopental significantly suppressed the uptake of GABA and glutamic acid, respectively. These results do not support the hypothesis that volatile and intravenous anesthetics exert their action via specific inhibition of GABA uptake to enhance inhibitory GABAergic neuronal activity. Rather, they suggest that presynaptic uptake systems for various neurotransmitters including GABA may be the molecular targets for volatile anesthetic agents.

Mice deficient in Th1- and Th2-type cytokines develop distinct forms of hapten-induced colitis.

BACKGROUND & AIMS: Most experimental models for inflammatory bowel disease in mice are associated with production of interferon (IFN)-gamma and other proinflammatory cytokines. We hypothesized that T-helper 2 (Th2)-type cells could also contribute to the colitis and cause inflammation different than that mediated by Th1-type cells. METHODS: Trinitrobenzene sulfonic acid (TNBS)-induced colitis in C57BL/6 background mice genetically deficient in interleukin (IL)-12 p40 (IL-12(-/-)), IFN-gamma (IFN-gamma(-/-)), or IL-4 (IL-4(-/-)) was examined in comparison with control mice (C57BL/6(+/+)). RESULTS: C57BL/6(+/+), IFN-gamma(-/-), and IL-12(-/-) mice developed patterns of colitis characterized by distortion of crypts, loss of goblet cells, and mononuclear cell infiltration with fibrosis of the mucosal layer. IL-4(-/-) mice had greater mortality than other groups because of penetrating ulcers; however, survivors developed milder lesions that were limited to focal acute ulceration. Colonic CD4(+) T cells from normal, IFN-gamma(-/-), or IL-12(-/- )mice produced both IL-4 and IL-5. CONCLUSIONS: In TNBS colitis, Th1-like cytokine responses induce fatal, acute, transmural, and focal types of lesions, whereas Th2-like cytokine responses play a significant role in the diffuse atrophic changes in crypts and the mucosal layer that occur in the late stages of this disease.

Development of a frameless and armless stereotactic neuronavigation system with ultrasonographic registration.

OBJECTIVE: We have developed a frameless stereotactic neuronavigation system that allows navigation during neurosurgical procedures through an image formed from integrating ultrasonography and preoperative magnetic resonance (MR) imaging and/or x-ray computed tomography. METHODS: The system consists of a ultrasound imaging scanner, a workstation with an image capture board, and an ultrasonic tracking sensor with a 5-MHz ultrasonographic transducer. The ultrasonic tracking sensor measures the position and orientation of the ultrasonographic transducer. The oblique plane of the MR/computed tomographic image corresponding to the ultrasound image is then displayed on the workstation monitor. A three-dimensional computer graphic representation of the integrated image is also reported as a preliminary test. For the patient-image registration, the coordinates of digitized and imaged markers on a specifically developed reference frame are used. The reference frame is noninvasive because it is not bolted but only fastened to the patient's head with silicon. RESULTS: Based on the findings from the clinical application of the system in three cases, the system was advantageous because of the surgical procedures could be controlled by intraoperative ultrasonography as well as by preoperative MR/computed tomographic images. Missing parts in the ultrasonogram were supplemented with preoperative MR/computed tomographic images. At other times, spatial positioning and visualization by ultrasonography were useful for identifying anatomical objects in the image. CONCLUSION: This preliminary study of the frameless integration of ultrasonography into stereotactic space demonstrated its clinical usefulness. We believe that the concept of pre- and intraoperative image-guided surgery presented here will find increasing use in the future.

[Cytotoxicity of Corylifoliae fructus. I. Isolation of the effective compound and the cytotoxicity].

The ethanol extract of Psoraleae Fructus (Psoralea corylifolia L.) was found to have cytotoxic activity against L929-cells in cell culture. The active compound was isolated by column chromatography on silica gel and identified as bakuchiol by means of spectral evidence. The cytotoxic activity of bakuchiol in cell culture was observed in short time and found to be unreversible. The mechanism of the cytotoxic activity was considered to be due to an injury of cell membrane from electron microscopic observation and hemolytic activity.

[Cytotoxicity of corylifoliae fructus. II. Cytotoxicity of bakuchiol and the analogues].

Bakuchiol is a major component of Corylifoliae Fructus (Psoralea corylifolia L.) and has been clarified to have cytotoxic activity. The chemical structure-cytotoxic activity relationship of bakuchiol was investigated by means of cytotoxic activity of synthesized analogues of bakuchiol and phenol. It was proved that an alkyl group was necessary for cytotoxic activity. But the double bonds in the unsaturated hydro-carbon group exerted but little influence on the cytotoxic activity. The cytotoxic activity of bakuchiol was the strongest as compared with that of the analogues examined.

Alterations of the plasma selenium concentrations and the activities of tissue peroxide metabolism enzymes in streptozotocin-induced diabetic rats.

The activity of aortic glutathione peroxidase, a selenium-dependent enzyme, significantly decreased in rats 4 and 8 months after the injection of streptozotocin (STZ). Catalase activity was shown to occur at low levels in rat aorta and was not influenced by the diabetic state. Superoxide dismutase activity was less than detectable. The activity of selenium-dependent glutathione peroxidase in kidney, but not in lung and liver, increased in diabetic rats. Catalase and superoxide dismutase activities in the kidney were not altered. The plasma lipid peroxide value increased in diabetic rats. The selenium content in plasma of diabetic rats increased markedly while the increase in plasma glutathione peroxidase activities was insignificant. The observed abnormalities in plasma of STZ rats were improved by insulin treatment. The defects in glutathione peroxidase in the diabetic rat aorta were restored by insulin treatment. These results may suggest that the capacity of the antioxidative defense system in the aorta decreased in the diabetic state, and this may help clarify the mechanism of the pathogenesis of endothelial dysfunction associated with diabetes.