Interferon-α enhances biological defense activities against oxidative stress in cultured rat hepatocytes and hepatic stellate cells

Oxidative stress has been implicated as a cause of hepatic fibrosis, and hepatic stellate cells (HSCs), which are the most important collagen-producing cell types, have been reported to be activated by lipid peroxidation products. Antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) provide a defense system that plays a critical role in protecting the cell from free radical damage, particularly lipid peroxidation. To elucidate the antioxidant activity of interferon-α (IFN-α), the effects of IFN-α on rat hepatocytes undergoing oxidative stress and HSCs in primary culture as well as isolated rat liver mitochondria were examined. IFN-α was observed to dose-dependently increase the immunoreactive protein levels of copper, zinc-and manganese-dependent SOD as well as the enzyme activities of GPx, and decrease the lipid peroxidation product levels and oxidative burst both in stressed hepatocytes and activated HSCs GPx activities, however, were not detected in the latter cells. IFN-α also inhibited HSC activation and lipid peroxidation in liver mitochondria. These findings suggest that IFN-α may enhance biological defense activities against oxidative stress and function as a potent fibrosuppressant by protecting hepatocytes and hepatic stellate cells from lipid peroxidation in vivo

Cガタカンエン ウイルス ジゾク カンセン カンジャ ノ カンセンイカ ニオケル ジョセイ ホルモン ノ ヤクワリ

The most common cause of hepatic fibrosis is chronic hepatitis C virus infection, the characteristic feature of which is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which in turn activates hepatic stellate cells (HSCs). HSCs are also thought to be the primary target cells for inflammatory stimuli, and produce extracellular matrix components. Clinical observations and death statistics support the view that chronic hepatitis C appears to progress more rapidly in men than in women, and cirrhosis is predominately a disease of men and postmenopausal women. It should be noted in this respect that estradiol (E2) is a potent endogenous antioxidant. Our studies showed that E2 suppressed hepatic fibrosis in hepatic fibrosis models, and attenuated HSC activation in primary culture. Recently, variant estrogen receptors (ERs) were found to be expressed to a greater extent in male patients with chronic liver disease than in female subjects. We also demonstrated decreased levels of ERs in postmenopausal women and cirrhotic patients of both genders. The present review summarizes our current knowledge of the biological functions of E2 and ER status as it relates to fibrogenesis in the liver

Interaction between human osteosarcoma and mesenchymal stem cells via an interleukin-8 signaling loop in the tumor microenvironment

Abstract Background Osteosarcoma (OS) is the representative primary malignant bone tumor with the highest incidence. It is known that malignant phenotypes of OS, such as proliferation, invasion, and metastasis, are significantly influenced not only by characteristics of the tumor itself, but also by the surrounding microenvironment. In other words, OS is considered to utilize cells in the vicinity of the tumor by changing the characteristics of these cells. Direct intercellular contact is believed to be important for this phenomenon. In the present study, we hypothesized that an interaction mediated by a humoral factor, requiring no cellular contact, might play a significant role in the progression of OS. Methods We developed a new co-culture model, using OS cells and mesenchymal stem cells (MSCs) without cellular contact, and found that both cell types expressed IL-8 at a high level, and FAK in OS cells was phosphorylated leading to an increase in the metastatic potential of the tumor in the co-culture condition. Results It was revealed that OS cells formed a loop of signal cross-talk in which they released IL-8 as a paracrine factor, stimulating MSCs to express IL-8, and received IL-8 released by MSCs to accelerate IL-8 expression in OS cells. Administration of anti-IL-8 antibody resulted in the inhibition of FAK expression, its downstream signaling, and the invasive potential of the OS cells, resulting in decrease in metastatic lesions. Conclusion The present study might lead not only to the clarification of a new molecular mechanism of invasion and metastasis of OS, but also to the development of a new therapeutic strategy of blocking IL-8 in OS

A meta-analysis of randomized controlled trials that compare standard doxorubicin with other first-line chemotherapies for advanced/metastatic soft tissue sarcomas.

ObjectiveThe standard treatment for patients with advanced/metastatic soft tissue sarcomas (ASTS) is systemic chemotherapy with doxorubicin. A previous meta-analysis of 8 randomized controlled trials (RCTs) demonstrated the superiority of single-agent doxorubicin over doxorubicin-based combination chemotherapy for ASTS. However, meta-analyses of all RCTs that compare doxorubicin to other single-agent or combination regimens as first-line treatments for ASTS are lacking. We conducted a systematic review and meta-analysis to evaluate the efficacy and toxicity of current primary treatments for ASTS.MethodsEligible studies were RCTs of first-line chemotherapies for ASTS comparing doxorubicin alone to other single agents or to combination therapies (experimental arm). Data from studies reporting hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS) were pooled. Other time-to-event endpoints were extracted from the studies based on Kaplan-Meier estimates, and pooled odds ratios (OR) and 95% CI were calculated.ResultsTwenty-seven eligible RCTs comprising 6156 patients were identified. Overall, the 1-year OS (OR 0.88, 95% CI 0.79-0.99, P = 0.03) was significantly improved in the experimental arm over the doxorubicin-only arm; however, there was no significant difference in 2-year OS (OR 0.87, 95% CI 0.73-1.03, P = 0.11) or OS (HR 0.97, 95% CI 0.91-1.03, P = 0.28) between the two groups. PFS and other time-to-event endpoints were not significantly different between the two treatment arms. While incidences of overall severe adverse events were not significantly different (OR 1.20, 95% CI 0.88-1.65, P = 0.26), severe nausea/vomiting was significantly more frequent in the experimental arm (OR 1.90, 95% CI 1.27-2.83, P = 0.002).ConclusionThe efficacies of doxorubicin-only and experimental arm regimens were similar, although toxicities were more frequent in the experimental arms. Hence, doxorubicin monotherapy remains suitable as a standard first-line regimen for ASTS

Surrogacy of intermediate endpoints for overall survival in randomized controlled trials of first-line treatment for advanced soft tissue sarcoma in the pre- and post-pazopanib era: a meta-analytic evaluation

Abstract Background Overall survival is the true endpoint for most randomized controlled trials (RCTs) of malignant tumors, whereas progression-free survival (PFS) is considered the most reliable surrogate endpoint for overall survival (OS). The present study aimed to evaluate the correlation between surrogate endpoints and OS in randomized trials of first-line chemotherapy with doxorubicin (DOX), the standard treatment for advanced and metastatic soft tissue sarcomas (ASTS), using a meta-analytic approach. Methods In a systematic review, we identified RCTs of first-line chemotherapy for ASTS that compared single-agent doxorubicin (DOX) with other chemotherapy regimens, and were published in English during January 1974–December 2017. A meta-analysis was performed to evaluate the efficacy of first-line treatments for ASTS. Surrogacy of the intermediate endpoints for OS was investigated using weighted linear regression analysis. Correlation strength was examined using the coefficient of determination (R2). Results Twenty-seven randomized trials, comprising 6156 patients (3371 patients in the experimental arm and 2785 patients in the DOX arm) were identified. The hazard ratios for OS and PFS showed that the efficacy of treatment for ASTS was not significantly different between standard DOX and experimental treatments. The median OS was significantly prolonged in RCTs published after 2012 when pazopanib was approved for treating ASTS. The median PFS, however, did not differ significantly. The correlation between PFS and OS was moderate (R2 = 0.557), but better than that between OS and 3-month PFS, 6-month PFS, and response rate (R2 = 0.200, 0.073, and 0.278, respectively). The correlation between PFS and OS tended to be more favorable in RCTs published after 2012 (R2 = 0.586 and 0.459, respectively). Conclusions The trial-level correlation between PFS and OS was only modest; it tended to be better in RCTs published after 2012. While the effective lines of chemotherapy and the introduction of new drugs prolonged OS but not PFS, PFS is a better surrogate than other intermediate endpoints in the first-line ASTS trials even in the post-pazopanib era. Although this does not negate the need for more reliable surrogate endpoints for OS

c-Myc Represses Tumor-Suppressive microRNAs, let-7a, miR-16 and miR-29b, and Induces Cyclin D2-Mediated Cell Proliferation in Ewing’s Sarcoma Cell Line

<div><p>Myc oncogenic transcription factor is known to inhibit tumor suppressive microRNAs (miRNAs), resulting in greater expression of their target protein related to cell cycle, invasion or anti-apoptotic factors in human cancer cells. To explore possible oncogenic factors in Ewing’s sarcoma (ES), we conducted microarray-based approach to profile the changes in the expression of miRNAs and its downstream mRNAs in five ES cell lines and human mesenchymal stem cells (hMSCs). Three miRNAs, let-7a, miR-16 and miR-29b were significantly down-regulated, whereas c-Myc and cyclin D2 (CCND2) were significantly up-regulated in all tested ES cells compared with hMSCs. To verify that let-7a, miR-16 and miR-29b were the targets of c-Myc in ES cell lines, we transfected siRNA against c-Myc and confirmed the coordinate up-regulation of let-7a, miR-16 and miR-29b through the repression of c-Myc. The ES cells transfected with c-Myc-siRNA and let-7a, miR-16 and miR-29b exhibited the inhibition of the cell cycle progression. The increased expression of let-7a, miR-16 and miR-29b resulted in the reduction of CCND2 protein expression. We also demonstrated that c-Myc-siRNA treatment of ES cells was associated with the decreased expression of CCND2 as a down-stream of three miRNAs. Furthermore, the introduction of let-7a, miR-16 and miR-29b in ES cells could inhibit the c-Myc-mediated up-regulation of CCND2 resulted in the prevention of cell cycle progression. In addition, the transfection of let-7a, miR-16 and miR-29b in ES cells suppressed tumor growth ex vivo treatment. These findings suggests that the up-regulation of c-Myc inhibited the expression of let-7a, miR-16 and miR-29b subsequently induced CCND2 expression in ES cells. The present study might identify a novel oncogenic axis that c-Myc regulates the expression of CCND2 via let-7a, miR-16 and miR-29b, leading to the development new therapeutic targets for ES.</p></div

Cell proliferation assay.

<p>Antiproliferation effect of let-7a (A), miR-16 (B), miR-29b (C) and CCND2-siRNA (D) in ES cells. Error bars represent mean ± S.D. from three independent experiments. Two-tailed Student’s t-test was employed to statistically analyze the results. **<i>p</i> < 0.01</p