Pancreatic cancer has remained a major cause of cancer-related deaths. A hallmark of pancreatic cancer is extensive stromal reactions, resulting in a unique tumor microenvironment, especially the involvement of macrophages. These tumor-educated cells limit the efficacy of chemotherapy. Therefore, it is necessary to identify an effective treatment strategy. In this study, we aimed to explore the anti-tumor and immunomodulatory effects of osthole on pancreatic cancer. We found that osthole suppressed Panc 02 cell migration and proliferation and induced apoptosis as shown in vitro. Osthole also attenuated the development of pancreatic cancer in mice by inhibiting tumor-infiltrating M2 macrophages in our study. Additionally, osthole inhibited the polarization of primary bone marrow cells into M2 macrophages and inhibited the expression of MRC1 , CCL22 and TGF-β in the M2 polarization process in vitro. Detection of the related signaling pathways revealed that osthole exerted immunomodulatory effects on M2 macrophages by down-regulating p-STAT6 and the p-ERK1/2-C/EBP β axis. These results indicated that osthole has effective anti-tumor and immunomodulatory effects on pancreatic cancer.
Yue Luo,Zhouyuan Yang,Xin Zhao,Donghai Li,Qianhao Li,Yang Wei,Luyao Wan,Meng Tian,Pengde Kang
Osteonecrosis is a devastating orthopedic disease in clinic that generally occurs in the femoral head associating with corticosteroid use up to 49 % in patients. In particular, glucocorticoids induced osteonecrosis of the femoral head is closely related to the local immune response that characterized by abnormal macrophage activation and inflammatory cell infiltration at the necrotic site, forming a pro-inflammatory microenvironment dominated by M1 macrophages, and thus leads to failure of bone repair and regeneration. Here, we report a bone regeneration strategy that constructs an immune regulatory biomaterial platform using an injectable thiolated hyaluronic acid hydrogel with lithium-doped nano-hydroxyapatite (Li-nHA@Gel) delivery for osteonecrosis treatment. Li-nHA@Gel achieved a sustain and longterm release of Li ions, which might enhance M2 macrophage polarization through the activation of the JAK1/STAT6/STAT3 signaling pathway, and the following induced pro-repair immune microenvironment mediated the enhancement of the osteogenic and angiogenic differentiation. Moreover, both in vitro and in vivo studies indicated that Li-nHA@Gel enhanced M2 macrophage polarization, osteogenesis, and angiogenesis, and thus promoted the bone and blood vessel formation. Taken together, this novel bone immunomodulatory biomaterial platform that promotes bone regeneration by enhancing M2 macrophage polarization, osteogenesis, and angiogenesis could be a promising strategy for osteonecrosis treatment.
Effective treatment of malignant glioma still remains a formidable challenge due to lack of the effective BBB-permeable drugs and efficient brain delivery methods, and the pharmacotherapy options are very limited. Therefore, to develop an effective therapeutic strategy is a pressing need. In this work, a noncytotoxic drug combination (i.e., simvastatin and fenretinide) was revealed to be potent for treating glioma, which was co-encapsulated into a TPGS-TAT-embedded lactoferrin nanoparticle system for achieving brain-targeted biomimetic delivery via the LRP-1 receptor. It was shown that the lactoferrin nanoparticle repolarized the tumor-associated macrophages from the M2 phenotype to M1 via regulating the STAT6 pathway, as well as induced the ROS-mediated mitochondrial apoptosis by inhibiting the Ras/Raf/p-Erk pathway in the glioma cells. The antiglioma efficacy was further demonstrated in both the subcutaneous and orthotopic glioma models. The repolarization of tumor-associated macrophages not only prompted the ROS generation but also induced the innate immunity (e.g., antitumor cytokine release). This delivery and therapeutic strategy provides a novel modality for the glioma treatment.
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