| Objective To investigate the causes to the occurrence of 'stasis toxin theory' in tumors,and to study the therapeutic rule and prescription medication derived from the theory.Studying the pharmacodynamics of Salvia miltiorrhiza synergistic arsenic trioxide for liver cancer treatment under the guidance of 'stasis toxin theory' by molecular biological methods and to explore the mechanism of its action.To prove of the correctness and scientific of 'stasis toxin theory' etiopathological theory by prescription medication studies.Present the findings of the study as a valid complement to the theory.Methods Studies were conducted by means of a combination of theoretical and experimental studies.The theoretical study was taken as a pilot to guide the conduct of the experimental study.Experimental studies are taken as evidence to support the content of theoretical research.1.Theoretical study:The strengths and limitations of 'stasis' and 'poison' as etiological agents in cancer are analyzed by reviewing ancient and present literature,and overall team-related research results.The reasons for the generation of the 'stasis toxin theory' and to elaborate on the meaning and value of 'stasis toxin theory' was also dissected.Based on the theory,the representative therapeutical principle of 'removing stasis' and 'removing toxins' are investigated,and their applicability is analyzed.A better drug compatibility scheme for removing stasis and poison is selected through the theoretical clinical outcomes.Based on the therapeutic rule derived from stasis toxin theory,we enumerate representative drugs involved in the simultaneous treatment of stasis and toxin,demonstrating the theoretical possibility of Salvia miltiorrhiza combined with arsenic trioxide.2.Based on the above theory,we extracted the active components of Salvia miltiorrhiza by multiple methods and matched them with arsenic trioxide.The combination with the best efficacy on liver cancer inhibition and less killing on normal cells was identified.In addition,we established orthotopic and subcutaneous xenograft tumor models by Hep 1-6 and H22 mouse hepatoma cell lines to verify the anti-liver cancer effects of the combination in vitro and in vivo.We drop the focus of our mechanistic studies on macrophage polarization in response to intervention of glucose metabolism.We examined the macrophage phenotyping in vitro and in vivo by flow cytometry,immunofluorescence staining,pathological staining,PCR technique,and Western blot,and we validated the effects of the drugs on macrophage polarization using an in vitro induction model with primary macrophages.Transcriptome sequencing was also used to investigate the regulatory effects of the combination on the glucose metabolic network in macrophages,and the HIF-?/NF-?B and AMPK signaling pathways,which are closely related to glucose metabolism,were selected to carry out gene and protein validation,and to initially investigate the molecular mechanisms underlying its efficacy.Results 1.The 'stasis toxin theory' was generated as an extension and development of the theory of the pathogenesis of 'stasis' and 'toxic' in traditional Chinese medical(TCM).The generation of this theory is the deep understanding of tumors in TCM,the advancement and development of theory itself,the sufficient intermixing of modern medical theory are also the reasons for promoting its formation.2.The therapeutic principles of activating blood circulation to dissipate blood stasis,dissipating blood stasis with potent drugs,clearing away heat and toxic materials,and treating the malignant disease with poisonous agents are the core therapeutic regimens for the homologous treatment of stasis and toxic.According to the severity and severity of the disease of patients with clinical tumors,different drug combinations can be selected.Taken together,activating blood circulation to dissipate blood stasis and treating the malignant disease with poisonous agents are more appropriate treatment options at all stages.3.Salvia miltiorrhiza combined with arsenic trioxide is a very reasonable form of drug combination based on the 'stasis toxin theory'.This form has a good anti-tumor effects and less damage to the human body,while it also can avoid increasing the risk of tumor metastasis.4.Cryptotanshinone from Salvia miltiorrhiza,a preferable regimen for combined arsenic trioxide treatment of liver cancer guided by the the 'stasis toxin theory',can effectively inhibit liver cancer progression in vitro and in vivo,with an optimal ratio of about 10:1.5.The mechanism of cryptotanshinone combined with arsenic trioxide in the treatment of liver cancer is associated with promoting the activation of macrophages and the phagocytosis of macrophages.In addition,prompting their activation toward M1 type macrophages,and inhibiting their activation toward M2 type macrophages are also the mechanism of action for this drug combination.6.Cryptotanshinone combined with arsenic trioxide achieves the regulation of glucose metabolism in macrophages and tumor cells by activating the AMPK signaling pathway and inhibiting the HIF-?/NF-?B signaling pathway.The combination of the two promotes the glycolysis of macrophages and inhibits the glycolysis of tumor cells,promoting the redistribution of glucose to achieve the purpose of reversing macrophage polarization and inhibiting the proliferation of liver cancer cells.Conclusion The 'stasis toxin theory' is one of the core aetiological mechanisms of tumors.Activating blood circulation to dissipate blood stasis combining with treating the malignant disease with poisonous agents is one of the scientific cures for the treatment of stasis and toxins.Salvia miltiorrhiza combined with arsenic trioxide is an effective compatibility combination in liver cancer therapy.The rational drug ratio under the guidance of 'stasis toxin theory',which can effectively treat liver cancer,deserves further clinical and deep research. |
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