SMAD and p38 MAPK Signaling Pathways Independently Regulate α1(I) Collagen Gene Expression in Unstimulated and Transforming Growth Factor-β-stimulated Hepatic Stellate Cells

The hepatic stellate cell (HSC) is the predominant cell type responsible for excess collagen deposition during liver fibrosis. Both transforming growth factor-beta (TGF-beta), the most potent fibrogenic cytokine for HSCs, which classically activates Smad signaling, and p38 MAPK signaling have been shown to influence collagen gene expression; however, the relative contribution and mechanisms that these two signaling pathways have in regulating collagen gene expression have not been investigated. The aim of this study was to investigate the relative roles and mechanisms of both Smad and p38 MAPK signaling in alpha1(I) collagen gene expression in HSCs. Inhibiting either p38 MAPK or Smad signaling reduced alpha1(I) collagen mRNA expression in untreated or TGF-beta-treated HSCs, and when both signaling pathways were simultaneously inhibited, alpha1(I) collagen gene expression was essentially blocked. Both signaling pathways were found to independently and additively increase alpha1(I) collagen gene expression by transcriptional mechanisms. TGF-beta treatment increased alpha1(I) collagen mRNA half-life, mediated by increased stability of alpha1(I) collagen mRNA through p38 MAPK signaling but not through Smad signaling. In conclusion, both p38 MAPK and Smad signaling independently and additively regulate alpha1(I) collagen gene expression by transcriptional activation, whereas p38 MAPK and not Smad signaling increased alpha1(I) collagen mRNA stability

Suppression of Interferon-induced Oligo-2\u27, 5\u27-adenylate Synthetase Induction in Human Hepatoma Cell Line, Li-7

Induction of oligo-2\u27, 5\u27-adenylate synthetase (2-5AS) activity by interferon (IFN) was investigated in a human hepatoma cell line, Li-7 cells. Little induction of 2-5AS activity by IFN was demonstrated in Li-7 cells in comparison with other types of cell lines including Ramos, NC-37, FL, Co-3. Furthermore, failure to induce 2-5AS was much clearer in old-cultured cells. Cell growth inhibition by IFN was demonstrated in only high titers of IFN (>10? IU/ml), in which the enzyme had one hundred fold higher activity than that of untreated cells. Poor induction of 2-5AS was in part the result of some inhibitor presented in cellular extracts of Li-7 cells and the decreased level of 2-5AS mRNA transcription

Changing trends in the risk factors for second primary malignancies after autologous stem cell transplantation for multiple myeloma before and after the introduction of proteasome inhibitors and immunomodulatory drugs

The incidence of second primary malignancies (SPM) in long-term survivors of multiple myeloma (MM) is increasing because of increased life expectancy. We retrospectively analyzed the risk factors for SPM in patients with MM after autologous stem cell transplantation (ASCT) before and after the introduction of proteasome inhibitors and immunomodulatory drugs (IMiDs). In total, 2,340 patients newly diagnosed with MM who underwent ASCT between 1995 and 2016 were enrolled in this study. Forty-three patients developed SPM (29 solid, 12 hematological, and 2 unknown tumors), with cumulative incidence rates of 0.8% and 2.5% at 24 and 60 months, respectively. The cumulative incidence rates of hematological and solid SPM at 60 months were 0.8% and 1.8%, respectively. The overall survival (OS) rate at 60 months after ASCT was 62.9% and the OS rates after the diagnosis of SPM at 24 months were 72.2% for hematological SPM and 70.9% for solid SPM. Multivariate analysis revealed that the use of IMiDs (P=0.024) and radiation (P=0.002) were significant independent risk factors for SPM. The probabilities of developing SPM and death due to other causes (mainly MM) at 60 months were 2.5% and 36.5%, respectively, indicating that the risk of SPM was lower than that of death from MM. Furthermore, SPM between the pre-novel and novel agent eras (ASCT between 2007 and 2016) groups significantly increased (1.9% vs. 4.3% at 60 months; P=0.022). The early occurrence of SPM after ASCT should be monitored cautiously

<原著>二酸化炭素気腹で抑制される豚の門脈血流量はドパミン投与によって回復する

Portal venous blood flow (PVF), hepatic arterial blood flow (HAF) and systemic arterial pressure (SAP) were examined after dopamine (DA) injection into the jugular vein under carbon dioxide pneumoperitoneum in pigs. When intraabdominal pressure (IAP) was increased by 12 mmHg, PVF and HAF were reduced, but SAP was unchanged. When IAP was kept at 12 mmHg, the injection of DA at 10 μg/kg/min for 2 min produced an increase in PVF without causing any change in HAF or SAP. The response in PVF was dose-dependent. When IAP was increased to 16 mmHg, PVF response was diminished, and no change in HAF or SAP was seen at the same dose of DA. These observations suggest that DA is effective in increasing PVF under enhanced IAP conditions, but such circulatory improvement due to the agent would be prominent when IAP is below 12 mmHg.豚を用いて二酸化炭素気腹下でドパミンの頸静脈投与が門脈血流量, 肝動脈血流量, 体血圧に対する影響を調へた腹腔内圧を 12 mmHg まで高めると, 門脈と肝動脈血流量は減少したが, 体血圧には変化を認めなかった. 腹腔内圧を 12 mmHg で維持した状態で, ドパミン 10 μg/kg/min で2分間の投与は肝動脈血流量と体血圧に変化を与えることなく, 門脈血流量を増加させた. こうしたドパミンによる門脈血流量反応は用量依存性を示した. 腹腔内圧 16 mmHg では同用量のドパミンの投与で, 門脈血流量反応は低下したが, 肝動脈血流量と体血圧には変化を認めなかった. これらの観察から, ドパミンは腹腔内圧上昇時に肝門脈血流量を増加させること, しかしそうしたドパミンの肝循環改善効果は腹腔内圧 12 mmHg 以下で顕著であることを導いた