A cross-linked macropore hydrogel based on M1 macrophage lysate and alginate regulates tumor-associated macrophages for the treatment of melanoma.

Pro-inflammatory M1 macrophages possess the ability to change the immunosuppressive tumor microenvironment by releasing various inflammatory factors simultaneously, which can effectively inhibit tumor progression and relapse. Promoting macrophage polarization towards M1 may be an effective way to treat Melanoma. However, the risk of cytokine storm caused by the proliferation and excessive activation of M1 macrophages greatly limits it as a biosafety therapeutic strategy in anti-tumor immunotherapy. Therefore, how to engineer natural M1 macrophage to a biocompatible biomaterial that maintains the duration time of tumor suppressive property duration time still remains a huge challenge. To achieve this goal, we developed an injectable macroporous hydrogel (M1LMHA) using natural M1 macrophage lysates and alginate as raw materials. M1LMHA had excellent biocompatibility, adjustable degradation rate and could sustainably release varieties of natural inflammatory factors, such as tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), and interleukin-12 (IL-12), etc. M1LMHA could repolarize anti-inflammatory M2 macrophages to M1 macrophages by the synergistic effect of released tiny inflammatory factors via the NF-κB pathway. This study supported that M1LMHA might be an effective and safe tool to activate tumor-associated immune cells, improving the efficiency of anti-tumor immunotherapy.

The Apoptosis of Liver Cancer Cells Promoted by Curcumin/TPP-CZL Nanomicelles With Mitochondrial Targeting Function.

The mitochondrion is one of the most important cellular organelles, and many drugs work by acting on mitochondria. Curcumin (Cur)-induced apoptosis of HepG2 in liver cancer cells is closely related to the function of inhibiting mitochondria. However, the mitochondrion-targeting curcumin delivery system was rarely been reported. It is important to develop a high-efficiency mitochondrion-targeting curcumin vector that can deliver curcumin into mitochondria directly. Here, a special mitochondrion-targeting delivery system based on triphenylphosphine bromide (TPP)-chitosan-g-poly-(N-3-carbobenzyloxy-l-lysine) (CZL) with TPP functional on the surface is designed to perform highly efficient mitochondria-targeting delivery for effective liver cancer cell killing in vitro. The TEM images showed that the nanomicelles were spherical; the results of fluorescence test showed that TPP-CZL nanomicelles could promote the cellular uptake of drugs and finally targeted to the mitochondria. The results of cell survival rate and Hoechst staining showed that curcumin/TPP-CZL nanomicelles could promote the apoptosis of liver cancer cells. Curcumin/TPP-CZL nanomicelles could significantly reduce the mitochondrial membrane potential, increase the expression of pro apoptotic protein Bcl-2, and reduce the expression of antiapoptotic Bax protein, and these results were significantly better than curcumin/CZL nanomicelles and curcumin. It is a potential drug delivery system with high efficiency to target mitochondria of liver cancer cells.

Saikosaponin-A induces apoptosis of cervical cancer through mitochondria- and endoplasmic reticulum stress-dependent pathway in vitro and in vivo: involvement of PI3K/AKT signaling pathway.

Cervical cancer causes considerable mortality in women worldwide. Saikosaponin-A, a triterpenoid glycoside isolated from Bupleurum falcatum, has been proven to exert anti-cancer property. In this study, we evaluated the possibility of saikosaponin-A on cervical cancer in vitro and in vivo. The results showed that saikosaponin-A induced cell death and altered cellular morphology dose-dependently. Saikosaponin-A significantly induced apoptosis in HeLa cells, confirmed by Hoechst 33,342 staining and flow cytometry. Sequentially, saikosaponin-A triggered the mitochondrial-mediated apoptosis demonstrated by deficiency of MMP, induction of Bax/Bcl-2 ratio, leakage of cytochrome c to cytoplasm, and activation of caspase-3. Moreover, ER stress also participated in the apoptosis induced by saikosaponin-A in HeLa cells as indicated by the upregulation of GPR78, CHOP and caspase-12 expression. Furthermore, HeLa cells showed increased expressions of p-PI3K and p-AKT in response to saikosaponin-A treatment. Additionally, saikosaponin-A could inhibit HeLa tumor growth in nude mice and induce apoptosis, reflected by the induction of TUNEL and the expression of cytochrome c, caspase-3 and CHOP confirmed by immunohistochemistry. These findings at least to a certain extent suggested that saikosaponin-A triggered apoptosis through both mitochondrial pathway and ER stress pathway and inhibiting PI3K/Akt signaling, thereby contributing to against cervical cancer. This work provides a new understanding of saikosaponin-A on therapeutic application in treatment of cancer, which has the potential to be a promising candidate therapeutic agent for cervical cancer patients.

Elucidation of the Mechanisms and Molecular Targets of Shuanglian Decoction for the Treatment of Hepatocellular Carcinoma Based on Network Pharmacology.

Shuanglian decoction (SLD) is traditionally used to treat hepatocellular carcinoma (HCC) in the clinical practice of traditional Chinese medicine. However, its mechanisms of action and molecular targets for the treatment of HCC are not clear. The active compounds of SLD were collected and their targets were identified. HCC-related targets were obtained by analyzing the differentially expressed genes between HCC patients and healthy individuals. Protein-protein interaction (PPI) data were then obtained and PPI networks of SLD putative targets and HCC-related targets were visualized and merged to identify the candidate targets for SLD against HCC. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis were carried out. The gene-pathway network was constructed to screen the key target genes. In total, 35 active compounds and 31 targets of SLD were identified. In total, 245 differentially expressed genes with P values <0.005 and |log2 (fold change)| > 1 were identified between HCC patients and control groups, and 68 target genes associated with HCC were finally identified. Twenty-one pathways including cellular senescence, p53 signaling pathway, and cell cycle were significantly enriched. CYP3A4 was the core gene and other several genes including CYP1A2, PPP3CA, PTGS2, CCCNB1, and CDK1 were the key genes in the gene-pathway network of SLD for the treatment of HCC. The results indicated that SLD's effects against HCC may relate to the regulation of an antioxidant function through specific biological processes and related pathways. This study demonstrates the application of network pharmacology in evaluating mechanisms of action and molecular targets of complex herbal formulations.