Theophylline enhances melanogenesis in B16F10 murine melanoma cells through the activation of the MEK 1/2, and Wnt/β-catenin signaling pathways.
茶碱通过激活 MEK 1/2 和 Wnt/β-catenin 信号通路增强 B16F10 鼠黑色素瘤细胞的黑素生成。
- 作者列表："Huang HC","Yen H","Lu JY","Chang TM","Hii CH
:Theophylline is a kind of methyl xanthine, which has been suggested to inhibit the activity of phosphodiesterase and increase the intracellular level of cyclic adenine monophosphate (cAMP). Theophylline has also been reported to increase the length and complexity of the dendritic process in melanocytes. However, the mode of action of theophylline in melanogenesis has never been reported. In this study, the effects of theophylline on melanogenesis were evaluated spectrophotometrically by the mushroom tyrosinase activity assay and by the determination of the intracellular tyrosinase activity and melanin content. The expression levels of melanogenesis-related proteins were analyzed by Western blot. The results indicated that theophylline (100-500 μM) effectively enhanced melanogenesis in the B16F10 murine melanoma cells. Moreover, theophylline increased the protein expression levels of microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein 1 (TRP-1), and the level of phosphorylated extracellular regulated protein kinase (p-ERK) and phosphorylated glycogen synthase kinase-3β (p-GSK3β) were also increased. In summary, the results revealed that theophylline promoted melanogenesis in B16F10 cells by upregulating the mitogen-activated protein kinase kinase 1 (MEK 1/2) and Wnt/β-catenin signaling pathways.
: 茶碱是甲基黄嘌呤的一种，已被建议抑制磷酸二酯酶的活性，增加环腺嘌呤一磷酸 (cAMP) 的细胞内水平。茶碱也有报道增加黑素细胞树突过程的长度和复杂性。然而，茶碱在黑素生成中的作用方式从未被报道。在本研究中，通过分光光度法测定蘑菇酪氨酸酶活性和细胞内酪氨酸酶活性和黑色素含量，评价了茶碱对黑素生成的影响。通过 Western blot 分析黑素生成相关蛋白的表达水平。结果表明，茶碱 (100-500 μ m) 可有效增强 B16F10 鼠黑色素瘤细胞的黑素合成。此外，茶碱增加小眼畸形相关转录因子 (MITF) 、酪氨酸酶和酪氨酸酶相关蛋白 1 (TRP-1) 的蛋白表达水平, 磷酸化细胞外调节蛋白激酶 (p-ERK) 和磷酸化糖原合成酶激酶 3 β (p-gsk3 β) 水平也升高。总之，结果揭示茶碱通过上调丝裂原活化蛋白激酶激酶 1 (MEK 1/2) 和 Wnt/β-catenin 信号通路促进 B16F10 细胞黑素生成。
METHODS::In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.
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METHODS::Several studies have indicated that cancer-associated fibroblasts (CAFs) could promote cancer progression in many malignancies. However, the mechanism by which CAFs promote the growth and metastasis of lung cancer remains poorly defined. In the present study, CAFs and normal fibroblasts (NFs) were isolated from human lung cancer and adjacent tissue. The data showed that the conditional medium (CM) of CAFs could increase the proliferation, migration and invasion of lung cancer cells. Vascular cell adhesion molecule-1 (VCAM-1) showed a higher expression in CAF-CM than NF-CM, and blocking VCAM-1 in CAF-CM attenuated the proliferation and invasion of cancer cells. Further, the results showed that VCAM-1 secreted from CAFs activated AKT and MAPK signaling via receptor α4β1 integrin (very-late antigen (VLA)-4) in lung cancer cells. Moreover, CAFs promoted VCAM-1 expression and tumor growth in vivo. Additionally, bioinformatics analysis indicated a positive correlation on the CAF marker protein alpha-smooth muscle actin (α-SMA) and VCAM-1 expression, which was associated with a poor prognosis in lung cancer patients. These findings demonstrate that the VCAM-1 secreted from CAFs enhances growth and invasion by activating the AKT and MAPK signaling of lung cancer cells.