Induction of cellular senescence in fibroblasts through ß1-integrin activation by tenascin-C-derived peptide and its protumor effect.

Tenascin-C is upregulated during inflammation and tumorigenesis, and its expression level is correlated with a poor prognosis in several malignancies. Nevertheless, the substantial role of tenascin-C in cancer progression is poorly understood. Previously, we found that a peptide derived from tenascin-C, termed TNIIIA2, acts directly on tumor cells to activate ß1-integrin and induce malignant progression. Here, we show that ß1-integrin activation by TNIIIA2 in human fibroblasts indirectly contributes to cancer progression through the induction of cellular senescence. Prolonged treatment of fibroblasts with TNIIIA2 induced cellular senescence, as characterized by the suppression of cell growth and the induction of senescence-associated-ß-galactosidase and p16INK4a expression. The production of reactive oxygen species and subsequent DNA damage were responsible for the TNIIIA2-induced senescence of fibroblasts. Interestingly, peptide FNIII14, which inactivates ß1-integrin, inhibited fibroblast senescence induced not only by TNIIIA2 but also by H2O2, suggesting that ß1-integrin activation plays a critical role in the induction of senescence in fibroblasts. Moreover, TNIIIA2-induced senescent fibroblasts secreted heparin-binding epidermal growth factor-like growth factor (HB-EGF), which caused preneoplastic epithelial HaCaT cells to acquire malignant properties, including colony-forming and focus-forming abilities. Thus, our study demonstrates that tenascin-C-derived peptide TNIIIA2 induces cellular senescence in fibroblasts through ß1-integrin activation, causing cancer progression via the secretion of humoral factors such as HB-EGF.

Peptide TNIIIA2 Derived from Tenascin-C Contributes to Malignant Progression in Colitis-Associated Colorectal Cancer via ß1-Integrin Activation in Fibroblasts.

Inflammatory bowel diseases increase the risk of colorectal cancer and colitis-associated colorectal cancer (CAC). Tenascin-C, a matricellular protein, is highly expressed in inflammatory bowel diseases, especially colorectal cancer. However, the role of tenascin-C in the development of CAC is not yet fully understood. We previously showed that a peptide derived from tenascin-C, peptide TNIIIA2, induces potent and sustained activation of ß1-integrin. Moreover, we recently reported that peptide TNIIIA2 promotes invasion and metastasis in colon cancer cells. Here, we show the pathological relevance of TNIIIA2-related functional site for the development of CAC. First, expression of the TNIIIA2-containing TNC peptides/fragments was detected in dysplastic lesions of an azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. In vitro experiments demonstrated that conditioned medium from peptide TNIIIA2-stimulated human WI-38 fibroblasts induced malignant transformation in preneoplastic epithelial HaCaT cells. Indeed, these pro-proliferative effects stimulated by peptide TNIIIA2 were abrogated by peptide FNIII14, which has the ability to inactivate ß1-integrin. Importantly, peptide FNIII14 was capable of suppressing polyp formation in the AOM/DSS model. Therefore, tenascin-C-derived peptide TNIIIA2 may contribute to the formation of CAC via activation of stromal fibroblasts based on ß1-integrin activation. Peptide FNIII14 could represent a potential prophylactic treatment for CAC.

Effectiveness of Japanese herbal medicine yokukansan for alleviating psychiatric symptoms after traumatic brain injury.

The Japanese herbal medicine, yokukansan, has been reported to improve behavioral and psychological symptoms of dementia and activities of daily living in patients with dementia. In the present case report, the authors report the effectiveness of yokukansan in treating psychiatric symptoms after traumatic brain injury. An 85-year-old man, who underwent surgery for hepatic portal cholangiocarcinoma, sustained traumatic brain injury after falling from bed as the result of postoperative delirium. He subsequently presented with psychiatric symptoms, showing markedly impulsive and aggressive behavior. Neuroleptics did not alleviate the symptoms. Ultimately, we succeeded in controlling the symptoms, without adverse effects, by giving the patient yokukansan. Yokukansan shows the potential for reducing aggressive and impulsive behavior in dementia as well as in other psychiatric diseases.

[Is the incidence of schizophrenia declining?: an investigation of the examination rates in the psychiatric clinics of a medical school hospital and a general hospital].

PURPOSE: Some researchers in Europe, America and Oceania have recently reported that the incidence of schizophrenia is declining. We investigated changes in the proportion of schizophrenic patients to the total number of patients in two Japanese hospitals during the last decade. SUBJECTS AND METHODS: The subjects were patients who first consulted the psychiatric clinic of Jichi Medical School or the psychiatric clinic of Kamitsuga General Hospital between December 1993 and November 1994 or between December 2003 and November 2004. Both clinics accepted new patients without prior appointments. Patients were classified using ICD-10 criteria (F0-F9, G40). The sex distribution of the patients and the mean age at first contact were compared for the two time periods. The proportion of schizophrenia (F2 in the ICD-10 criteria) to the total number of patients was compared for the two time periods after standardizing the populations with regard to age using the "1985 model population in Japan." RESULTS: A decade ago, 398 patients first contacted the psychiatric clinic of the medical school hospital, compared with 958 patients in the recent investigation. A decade ago, 166 patients first contacted the psychiatric clinic of the general hospital, compared with 407 patients in the recent investigation. No differences in the sex ratios of the two groups were noted. The mean age of the patients visiting the medical school significantly increased by 3.5 years (36.9 to 40.4 years), while that of the patients visiting the general hospital significantly increased by 10.0 years (46.2 to 56.2 years). The proportion of schizophrenia patients in the medical hospital decreased from 8.5% to 6.9%, while that in the general hospital decreased from 11.0% to 5.4%. Only the change in the proportion of schizophrenia patients at the general hospital was significant. CONCLUSION AND DISCUSSION: The facts that the mean age of first-contact patients has risen and that the number of first-contact patients has increased approximately 2.5-fold suggests a change in the composition of first-contact patients in the last decade. We have some reservations regarding the comparison of these two groups. Although the actual number of first-contact patients with schizophrenia increased in both clinics, we found that the proportions of schizophrenia patients decreased in both clinics after standardizing the populations with regard to age. This finding must be investigated in view of other factors, including the overall age distribution of first-contact patients, increases in the proportions of affective disorders and organic mental disorders, and so on.