Mechanisms of thrombin-Induced myometrial contractions: Potential targets of progesterone

Intrauterine bleeding during pregnancy is a major risk factor for preterm birth. Thrombin, the most abundant coagulation factor in blood, is associated with uterine myometrial contraction. Here, we investigated the molecular mechanism and signaling of thrombin-induced myometrial contraction. First, histologic studies of placental abruption, as a representative intrauterine bleeding, revealed that thrombin was expressed within the infiltrating hemorrhage and that thrombin receptor (protease-activated receptor 1, PAR1) was highly expressed in myometrial cells surrounding the hemorrhage. Treatment of human myometrial cells with thrombin resulted in augmented contraction via PAR1. Thrombin-induced signaling to myosin was then mediated by activation of myosin light chain kinase- and Rho-induced phosphorylation of myosin light chain-2. In addition, thrombin increased prostaglandin-endoperoxidase synthase-2 (PTGS2 or COX2) mRNA and prostaglandin E2 and F2α synthesis in human myometrial cells. Thrombin significantly increased the mRNA level of interleukine-1β, whereas it decreased the expressions of prostaglandin EP3 and F2α receptors. Progesterone partially blocked thrombin-induced myometrial contractions, which was accompanied by suppression of the thrombin-induced increase of PTGS2 and IL1B mRNA expressions as well as suppression of PAR1 expression. Collectively, thrombin induces myometrial contractions by two mechanisms, including direct activation of myosin and indirect increases in prostaglandin synthesis. The results suggest a therapeutic potential of progesterone for preterm labor complicated by intrauterine bleeding

Expression of MMP-2, MMP-9 and TIMP-1 in the Wall of Abdominal Aortic Aneurysms

An impaired mechanism of regulatory feedback by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) has been implicated in the development of abdominal aortic aneurysms (AAAs). This study examined the pathogenesis of AAAs with respect to pathological characteristics and expressions of MMP-2, MMP-9 and TIMP-1. Their expressions were evaluated by immunohistochemistry, competitive polymerase chain reaction (PCR) and Western blotting in a total of 23 consecutive AAAs. The AAA specimens were obtained by surgery, while control specimens were obtained at autopsy. Specimens consisted of 6 patients with small-diameter AAAs (30?45 mm), 17 with medium-large-diameter AAAs (> 45 mm) and 11 controls (17?25 mm). Immunohistochemistry showed MMP-2- and TIMP-1-positive cells mainly in the intima, and MMP-9-positive cells in the intima and adventitia. Competitive PCR showed a significantly higher expression of MMP-2 messenger RNA (mRNA) in the small-diameter AAAs, and higher expressions of MMP-9 mRNA in the small-diameter and medium-large-diameter AAAs than in the controls. The mRNA levels significantly correlated between TIMP-1 and MMP-9, and between MMP-2 and MMP-9 in the AAAs, especially in the medium-large-diameter AAAs. Western blotting revealed the expression of MMPs and TIMP-1 variably in all the specimens examined. These results indicated that MMP-2 and MMP-9 might act cooperatively and play a crucial role in the development of AAAs, and that TIMP-1 inhibits MMP-9 in the AAAs, especially in those medium-large-diameter AAAs

Genotoxic Stress Abrogates Renewal of Melanocyte Stem Cells by Triggering Their Differentiation

SummarySomatic stem cell depletion due to the accumulation of DNA damage has been implicated in the appearance of aging-related phenotypes. Hair graying, a typical sign of aging in mammals, is caused by the incomplete maintenance of melanocyte stem cells (MSCs) with age. Here, we report that irreparable DNA damage, as caused by ionizing radiation, abrogates renewal of MSCs in mice. Surprisingly, the DNA-damage response triggers MSC differentiation into mature melanocytes in the niche, rather than inducing their apoptosis or senescence. The resulting MSC depletion leads to irreversible hair graying. Furthermore, deficiency of Ataxia-telangiectasia mutated (ATM), a central transducer kinase of the DNA-damage response, sensitizes MSCs to ectopic differentiation, demonstrating that the kinase protects MSCs from their premature differentiation by functioning as a “stemness checkpoint” to maintain the stem cell quality and quantity

Cancer of Unknown Primary Site:A Review of 28 Cases and the Efficacy of Cisplatin/Docetaxel Therapy at a Single Institute in Japan

We evaluated the efficacy and toxicity of cisplatin/docetaxel (CDDP/TXT) chemotherapy and identified prognostic factors in Japanese patients with cancer of unknown primary site (CUP). Twenty-eight consecutive patients seen at a single institute were reviewed retrospectively. Sixteen patients were treated with TXT 80mg/m2, followed by CDDP 75mg/m2. The overall response rate to CDDP/TXT treatment was 62.5%, with a median survival time (MST) of 22.7 months. Common adverse reactions were myelosuppression and hyponatremia. The MST of all 28 patients with CUP was 8.3 months, and the 1-year overall survival rate was 45.6%. Univariate analysis identified 5 prognostic factors:performance status, liver involvement, bone involvement, pleural involvement, and lymph node involvement. In conclusion, CDDP/TXT chemotherapy is effective with tolerable toxicity in patients with CUP. Japanese patients with CUP might be chemosensitive and may survive longer