Background The pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, and interleukin (IL)-17, have been implicated in the pathogenesis of liver fibrosis. In this study, we investigated the role of TNFα and IL-17 towards induction of profibrotic factor, periostin. Methods HepG2 cells were cultured and treated with inflammatory cytokines, TNFα and IL-17. Computational promoter sequence analysis of the periostin promoter was performed to define the putative binding sites for transcription factors. Transcription factors were analyzed by Western blot and Chromatin Immunoprecipitation. Periostin and transcription factor expression analysis was performed by RT-PCR, Western blot, and fluorescence microscopy. Type I collagen expression from fibroblast cultures was analyzed by Western blot and Sircol soluble collagen assay. Results Activation of HepG2 Cells with TNFα and IL-17 enhanced the expression of periostin (3.5 and 4.4 fold, respectively p<0.05) compared to untreated cells. However, combined treatment with both TNFα and IL-17 at similar concentration demonstrated a 13.3 fold increase in periostin (p<0.01), thus suggesting a synergistic role of these cytokines. Periostin promoter analysis and specific siRNA knock-down revealed that TNFα induces periostin through cJun, while IL-17 induced periostin via STAT-3 signaling mechanisms. Treatment of the supernatant from the cytokine activated HepG2 cells on fibroblast cultures induced enhanced expression of type I collagen (>9.1 fold, p<0.01), indicative of a direct fibrogenic effect of TNFα and IL-17. Conclusion TNFα and IL-17 induced fibrogenesis through cJun and STAT-3 mediated expression of profibrotic biomarker, periostin. Therefore, periostin might serve as a novel biomarker in early diagnosis of liver fibrosis.
Pancreatic cancer has one of the highest mortality rates among cancers, and a combination of nab-paclitaxel with gemcitabine remains the cornerstone of first-line therapy. However, major advances are required to achieve improvements in patient outcomes. For this reason, several research groups have proposed supplementing treatment with other therapeutic agents. Ongoing studies are being conducted to find the optimal treatment in a first-line setting. In this work, we used a search strategy to compare studies on the efficacy and safety of nab-paclitaxel with gemcitabine in combination with other therapeutic agents based on the criteria of the Preferred Reporting Items for Systematic Reviews. We found seven studies in different clinical phases that met the inclusion criteria. The seven therapeutic agents were ibrutinib, necuparanib, tarextumab, apatorsen, cisplatin, enzalutamide, and momelotinib. Although these therapeutic agents have different mechanisms of action, and molecular biology studies are still needed, the present review was aimed to answer the following question: which formulations of the nab-paclitaxel/gemcitabine regimen in combination with other therapeutic agents are safest for patients with previously untreated metastatic pancreas ductal adenocarcinoma? The triple regimen is emerging as the first-line option for patients with pancreatic cancer, albeit with some limitations. Thus, further studies of this regimen are recommended.
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