Nanodrug Delivery Systems in Antitumor Immunotherapy.

Cancer has become one of the most important factors threatening human health, and the global cancer burden has been increasing rapidly. Immunotherapy has become another clinical research hotspot after surgery, chemotherapy, and radiotherapy because of its high efficiency and tumor metastasis prevention. However, problems such as lower immune response rate and immune-related adverse reaction in the clinical application of immunotherapy need to be urgently solved. With the development of nanodrug delivery systems, various nanocarrier materials have been used in the research of antitumor immunotherapy with encouraging therapeutic results. In this review, we mainly summarized the combination of nanodrug delivery systems and immunotherapy from the following 4 aspects: (a) nanodrug delivery systems combined with cytokine therapy to improve cytokines delivery in vivo; (b) nanodrug delivery systems provided a suitable platform for the combination of immune checkpoint blockade therapy with other tumor treatments; (c) nanodrug delivery systems helped deliver antigens and adjuvants for tumor vaccines to enhance immune effects; and (d) nanodrug delivery systems improved tumor treatment efficiency and reduced toxicity for adoptive cell therapy. Nanomaterials chosen by researchers to construct nanodrug delivery systems and their function were also introduced in detail. Finally, we discussed the current challenges and future prospects in combining nanodrug delivery systems with immunotherapy.

Chuanxiong improves angiogenesis via the PI3K/AKT/Ras/MAPK pathway based on network pharmacology and DESI-MSI metabolomics.

Introduction: Chuanxiong, a traditional Chinese medicine, has been proved to treat a variety of cardiovascular and cerebrovascular diseases by promoting angiogenesis. However, the mechanisms of Chuanxiong's pro-angiogenesis is currently unknown. This study aimed to uncover the effect and mechanisms of Chuanxiong promoting angiogenesis in vivo and in vitro. Methods: First, potential targets were predicted by network pharmacology analysis, and PPI network was established and the pathways were enriched. Then, the chorioallantoic membrane test on quails was applied to assess the proangiogenic effects in vivo. As well, to evaluate the effects in vitro, real-time PCR, western blot analysis, the scratch test, and the tube formation experiment were used. Subsequently, the major metabolic pathways were analyzed using non-targeted metabolomics. Results: As a result of network pharmacological analysis, 51 collective targets of Chuanxiong and angiogenesis were identified, which are mainly associated with PI3K/AKT/Ras/MAPK pathway. And the biological verification results showed that Chuanxiong could increase the vessel numbers and vessel area in qCAM models. Meanwhile, Chuanxiong contributed to HUVEC proliferation, tube formation, migration, by encouraging scratch healing rates and boosting tube branch points. In addition, the levels of VEGFR2, MAPK and PI3K were elevated compared to the control group. The western blot analysis also confirmed Chuanxiong could promote an increase in AKT, FOXO1 and Ras. Furtheremore, metabolomic results showed that the proangiogenic effect of Chuanxiong is associated with glycine, serine and threonine metabolism. Discussion: In conclusion, this study clarified that Chuanxiong could promote angiogenesis in vivo and in vitro via regulating PI3K/AKT/Ras/MAPK pathway.

Design and synthesis of novel anti-multidrug-resistant staphylococcus aureus derivatives of glycyrrhetinic acid by blocking arginine biosynthesis, metabolic and H2S biogenesis.

With the soaring number of multidrug-resistant bacteria, it is imperative to develop novel efficient antibacterial agents and discovery new antibacterial pathways. Herein, we designed and synthesized a series of structurally novel glycyrrhetinic acid (GA) derivatives against multidrug-resistant Staphylococcus aureus (MRSA). The in vitro antibacterial activity of these compounds was evaluated using the microbroth dilution method, agar plate coating experiments and real-time growth curves, respectively. Most of the target derivatives showed moderate antibacterial activity against Staphylococcus aureus (S. aureus) and MRSA (MIC = 3.125-25 µM), but inactivity against Escherichia coli (E. Coli) and Pseudomonas aeruginosa (P. aeruginosa) (MIC > 200 µM). Among them, compound 11 had the strongest antibacterial activity against MRSA, with an MIC value of 3.125 µM, which was 32 times and 64 times than the first-line antibiotics penicillin and norfloxacin, respectively. Additionally, transcriptomic (RNA-seq) and quantitative polymerase chain reaction (qPCR) analysis revealed that the antibacterial mechanism of compound 11 was through blocking the arginine biosynthesis and metabolic and the H2S biogenesis. Importantly, compound 11 was confirmed to have good biocompatibility through the in vitro hemolysis tests, cytotoxicity assays and the in vivo quail chicken chorioallantoic membrane (qCAM) experiments. Current study provided new potential antibacterial candidates from glycyrrhetinic acid derivatives for clinical treatment of MRSA infections.

Immunometabolism at the service of traditional Chinese medicine.

To enhance therapeutic efficacy and reduce adverse effects, ancient practitioners of traditional Chinese medicine (TCM) prescribe combinations of plant species/animal species and minerals designated "TCM formulae" developed based on TCM theory and clinical experience. TCM formulae have been shown to exert curative effects on complex diseases via immune regulation but the underlying mechanisms remain unknown at present. Considerable progress in the field of immunometabolism, referring to alterations in the intracellular metabolism of immune cells that regulate their function, has been made over the past decade. The core context of immunometabolism is regulation of the allocation of metabolic resources supporting host defense and survival, which provides a critical additional dimension and emerging insights into how the immune system and metabolism influence each other during disease progression. This review summarizes research findings on the significant association between the immune function and metabolic remodeling in health and disease as well as the therapeutic modulatory effects of TCM formulae on immunometabolism. Progressive elucidation of the immunometabolic mechanisms involved during the course of TCM treatment continues to aid in the identification of novel potential targets against pathogenicity. In this report, we have provided a comprehensive overview of the benefits of TCM based on regulation of immunometabolism that are potentially applicable for the treatment of modern diseases.