ABSTRACT
Smads are signal transducers for the members of the TGF-beta superfamily. Of these Smads, Smad4 is essential for TGF-beta signaling. The purpose of this study was to elucidate Smad4 expression and localization in 65 gastric adenomas, 49 intestinal-type and 39 diffuse type of gastric adenocarcinomas (including 12 cases of fresh frozen tissue) using Real-time RT-PCR and immunohistochemistry. Real-time RT-PCR showed that intestinal type gastric adenocarcinomas have higher Smad4 mRNA expression than diffuse type gastric adenocarcinomas. Immunohistochemical stain for Smad4 revealed that expression of Smad4 was significantly lower in diffuse-type gastric adenocarcinoma than intestinal-type gastric adenocarcinomas. Also, higher Smad4 protein expression in intestinal type gastric adenocarcinomas than overall gastric adenoma was noted. The rate of reduced Smad4 expression was higher in advanced gastric cancer than early gastric cancer. These results suggest that Smad4 might play different roles in human gastric carcinogenesis, especially between intestinal type and diffuse type of gastric adenocarcinoma.
Subject(s)
Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Adenoma/genetics , Adenoma/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Trans-Activators/genetics , Trans-Activators/metabolism , Adenocarcinoma/pathology , Adenoma/pathology , Adult , Aged , Base Sequence , Female , Gastric Mucosa/metabolism , Gene Expression , Humans , Immunohistochemistry , Male , Middle Aged , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Smad4 Protein , Stomach Neoplasms/pathology , Transforming Growth Factor beta/metabolismABSTRACT
The present study was conducted to explore the potential role of proteasome pathway in NSAIDs-induced apoptosis. We employed sulindac as a NSAID, and chose the lactacystin for inhibition of proteasome activity. Assessment of apoptosis and proteasome activity assay were undertaken. We demonstrated that sulindac treatment resulted in a decrease of proteasome activity, and that the co-treatment of a proteasome inhibitor lactacystin potentiated the extent of sulindac-induced apoptosis in HT-29 cells by augmentation of the decrease in proteasome activity. Elucidation of the mechanism underlying the regression of colon cancers by combinations of sulindac and lactacystin seems to be an immediate challenge for the near future.
Subject(s)
Acetylcysteine/analogs & derivatives , Acetylcysteine/pharmacology , Apoptosis/drug effects , Multienzyme Complexes/antagonists & inhibitors , Sulindac/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Apoptosis/physiology , Carcinoma/drug therapy , Carcinoma/enzymology , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Colonic Neoplasms/enzymology , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Drug Synergism , HT29 Cells , Humans , Multienzyme Complexes/metabolism , Proteasome Endopeptidase Complex , Reaction Time/drug effects , Reaction Time/physiologyABSTRACT
The proteolysis of alphaII-spectrin by calpain may be physiologically involved with synaptic remodeling, long-term potentiation, and memory formation. Calpain activation may also mediate neuronal apoptosis, responses to hypoxic insult, and excitotoxic injury. Surprisingly little is known of the activity of these calpain-mediated processes in the adult human brain. Using an antibody that specifically recognizes calpain-cleaved alphaII-spectrin, we have mapped the topographic distribution of the major alphaII-spectrin break-down product (alphaII-bdp1) in six adult brains examined post-mortem. All brains were from patients without evident neurological disease. Focally positive alphaII-bdp1 was consistently detected in the neuropil of the cortical gray matter, in occasional pyramidal neurons, and in rare reactive astrocytes in the cerebral cortex and hippocampus. Cerebellar Purkinje cells were more frequently, and more intensely, immunopositive. In all fields, staining was most intense in the soma and dendrites of neurons. There was no correlation of the frequency of positive cells with the postmortem interval or clinical condition. While these findings do not rigorously exclude contributions from postmortem calpain activation, they do suggest that a low-level of calpain processing of alphaII-spectrin is likely to be a constitutive process in the adult human brain.
Subject(s)
Brain/enzymology , Calpain/metabolism , Peptide Hydrolases/metabolism , Spectrin/metabolism , Adult , Aged , Calpain/analysis , Female , Humans , Hydrolysis , Male , Middle Aged , Spectrin/analysisABSTRACT
Aging is associated with altered immune responses including dysregulation of cytokine production. Of cytokines, interleukin-1 (IL-1) family has been primarily involved with central nervous system. To evaluate the age-related different response of IL-1 family following peripheral administration of lipopolysaccharide (LPS), immunohistochemical study of IL-1beta and IL-1 receptor expression was performed on Sprague-Dawley rat brain. Experimental animals were divided into four groups; saline-treated young (3-5 months) and old (over 24 months), and LPS-treated young and old groups. After intraperitoneal (i.p.) injection of LPS, three to five rats within each group were killed at 1, 2, 4, 8 and 16 hr. After fixation in 4% neutral buffered formalin, the brain slices were paraffin-embedded. Immunohistochemical staining using labelled streptavidin biotin was performed. The results showed that IL-1beta immunoreactivity was seen in the endothelial cell of pons in both LPS-treated young and old rats, with slightly longer persistency in old group. IL-1RI immunoreactivity appeared initially in the neurons of cerebral cortex in LPS-treated old group, compared with predominantly the cerebellum in LPS-treated young group. In conclusion, our study shows that there is age-related, different neuronal localization of IL-1RI expression at different points of time after LPS treatment.
Subject(s)
Brain Chemistry/drug effects , Interleukin-1/analysis , Lipopolysaccharides/toxicity , Age Factors , Animals , Gene Expression Regulation/drug effects , Immunohistochemistry , Interleukin-1/genetics , Male , Rats , Rats, Sprague-Dawley , Receptors, Interleukin-1/analysisABSTRACT
The term myxosarcoma is currently not used in standard classification for soft tissue tumors, but restricted to cardiac tumors. Primary cardiac myxosarcoma is a very rare disease and is difficult to differentiate from myxoma clinically and pathologically. We report a case of left atrial myxosarcoma with widespread systemic metastasis in a 21-yr-old male. The patient presented with sudden onset of intermittent dyspnea and orthopnea. Echocardiography showed a mobile, pedunculated tumor, 7.5x5x2 cm in size, at left atrium. Histologically, the excised tumor showed an amorphous finely fibrillar and mucinous stroma, in which irregular cords and clusters of lepidic cells and large stellate cells with plump vesicular nuclei resembled the usual type of cardiac myxoma were noted. And it showed focally cellular area with great nuclear pleomorphism and frequent mitoses. The patient received combination chemotherapy, peripheral blood stem cell collection transplantation and operations for systemic metastases in the brain, skeletal muscle and lung. He is alive at present 37 months after initial diagnosis and has no more new metastatic lesion.
