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  • br Fig The flow cytogram of NK cells among

    2020-08-12


    Fig. 8. The flow cytogram of NK Cobimetinib among peripheral blood and spleen of each group. A. The proportion of NK cells among peripheral blood was significantly higher in HD-E and MD-E group than others (P < 0.01). B. The proportion of NK cells among spleen cells was also significantly higher in comparison of LD-E, CE, and NS group (P < 0.05). NS: normal saline; CI: Cinobufacini Injection; CE: control emulsion; LD-E: low-dose emulsion; MD-E: middle-dose emulsion; HD-E: high-dose emulsion.
    significantly increased red blood cells, hemoglobin, white blood cells and platelet by activating hematopoietic function. In addition, HD-E and MD-E significantly increased the ratio of lymphocyte, meanwhile, reduced the ratio of neutrophil (Fig. 10A). However, the obvious side effects on liver function were also observed. The level of ALT and AST were significantly higher in HD-E group than other groups (Fig. 10B). 
    4. Discussion
    Anti-cancer researches of traditional Chinese medicine (TCM) have been progressing greatly with the development and guidance of con-temporary evidence-based medicine [14]. Constituent manufacture of TCM is vital for its modernization. Arteannuin and its derivation
    Table 3 The content of IFN-γ and IgG1 in serum and the splenic cell supernatant.
    Group IFN-γ (ng/mL)
    Serum
    Splenic cell supernatant
    Serum Splenic cell supernatant
    NS: normal saline; CI: Cinobufacini Injection; CE: control emulsion; LD-E: low-dose emulsion; MD-E: middle-dose emulsion; HD-E: high-dose emulsion.
    extracted from abrotanum are currently the most effective drugs to treat malaria, which is a successful case of constituent TCM [28]. In the first part of our study, we collected 22 fractions of bufadienolides se-parated and purified from the skin of Bufo bufo gargarizans Cantor (toad skin) based on the theory of constituent TCM. We haven't seen similar articles concerning such quantities of antitumor fractions of bufadie-nolides published domestically or internationally.
    The skin of Bufo bufo gargarizans Cantor is a well-known TCM toad widely used in China. Toad skins consist of epidermis and dermis. The epidermis, exuviate of toad skins, possess little effective constituent, while the dermis containing venom gland and mucous gland is the es-sential constituent. CI (Cinobufacini Injection), also known as Huachansu, is the aqueous extract from the skins and parotid venom glands of Bufo bufo gargarizans Cantor. It has been officially approved
    Fig. 9. The hematological examination of each group. A. HD-E and MD-E significantly increased red blood cells. B. HD-E and MD-E significantly increased he-moglobin. C. HD-E and MD-E significantly increased white blood cells. D. HD-E and MD-E significantly increased platelet. NS: normal saline; CI: Cinobufacini Injection; CE: control emulsion; LD-E: low-dose emulsion; MD-E: middle-dose emulsion; HD-E: high-dose emulsion.
    Fig. 10. The ratio of lymphocyte and neutrophil and the level of ALT and AST of each group. A. HD-E and MD-E significantly increased the ratio of lymphocyte and reduced the ratio of neutrophil. B. ALT and AST were significantly higher in HD-E group than other groups. NS: normal saline; CI: Cinobufacini Injection; CE: control emulsion; LD-E: low-dose emulsion; MD-E: middle-dose emulsion; HD-E: high-dose emulsion.
    by the Chinese Food and Drug Administration since 1991 [29]. The antitumor mechanism of Cinobufacini includes inhibiting tumor cell proliferation, inducing differentiation and apoptosis, influencing au-tophagy-related genes expressing, EKR path, NA+-K+-ATPase and so on [30–34]. It may also alleviate paclitaxel-induced peripheral neuro-pathic pain and promote therapeutic Cobimetinib efficacy of chemotherapy [33]. However, due to technical limitations, certain aqueous crude extract of toad exuviates applied in clinic have limited effects and serious adverse reactions [18]. It's known that the skins of toad Bufo bufo gargarizans Cantor is rich in bufadienolides, peptides and alkaloids [17]. Recently, bufadienolides have been shown to have the best antitumor activity with less adverse reaction for the treatment of liver and gastric cancers, compared to other components [35]. Bufadienolides, a C-24 steroid with a α-2-pyrone ring at its C-17 position, contain bufalin, cinobu-fagin, resibufogenin and telocinobufagin [17,36]. Previous studies showed that some fractions of bufadienolides such as resibufogenin have antitumor effect as well as toxicity and other side effects [17,18]. Our study aimed to screen constituents of bufadienolides with higher efficacy and lower toxicity and confirm its effects in lymphatic che-motherapy for CRC in a lymphatic metastatic model.
    During the procedure of dissolving constituents, constituent 1–3 were totally dissolved in physiological saline and constituent 4–22 had to dissolve within DMSO. We found both inhibition effect and promo-tion effect in 22 constituents in vitro. The water-soluble constituent 1–3 and liposoluble constituent 21 and 22 had little antitumor effect and even promoted the growth of tumor cells. On the contrary, most of the liposoluble constituents, 4–20, obviously inhibited the tumor cells, especially the intermediate constituents such as 11. Meanwhile, CIK cells were inhibited by the intermediate constituents but were unin-hibited or promoted by the ambilateral constituents. It thus indicated that both concentration and physical property of constituents were concerned with the effects on tumor cells and CIK cells. This result might explain why Cinobufacini, water-soluble medicament of toad skin, had limited antitumor effects and severe side effects in clinical practice.