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PURPOSE: Cimicifuga dahurica (C. dahurica), which has been used in traditional oriental medicine for a long period, was reported to exert extensive antitumor activity, but the effect and molecular biological mechanism of C. dahurica on multiple myeloma (MM) has not been elaborated. Tumor-associated macrophages (TAMs) exhibit a sustained polarization between tumor killing M1 subtype and tumor supporting M2 subtype. And a lower ratio of M1/M2 is associated with tumor angiogenesis, proliferation and invasion. We explored the inhibitory effect of the aqueous extract of the root of C. dahurica (CRAE) on tumor growth by reprogramming macrophage polarization in the tumor microenvironment. METHODS: Mice bearing SP2/0 multiple myeloma were treated with CRAE. Western blotting (WB), immunohistochemistry (IHC) and immunofluorescence staining were utilized to assess tumor growth and TAM populations. Macrophages were depleted by injection of clodronate liposomes to determine and measure the role of CRAE as an anti-tumor agent by targeting macrophages. To simulate tumor microenvironment, MM cells H929 and TAMs were co-cultured using the transwell co-culture system. By using CRAE as an immunoregulator in M2-like macrophages, we analyzed CRAE-treated macrophage-associated surface markers and cytokines by flow cytometry and WB. RESULTS: The results indicated that CRAE treatment could reduce tumor burden of MM mice and a high degree of M1-like macrophages infiltration was detected in tumor tissues. In vitro co-culture system, CRAE significantly promoted the polarization of M2 to M1 phenotype, which led to the increase in apoptosis of myeloma cells. It was found that the M1 polarization induced by CRAE depended on the TLR4-MyD88-TAK1-NF-κB signal transduction. CONCLUSION: This study elucidated the anticancer mechanism of the aqueous extract of C. dahurica (CRAE) through reprogramming macrophage polarization and highlighted that CRAE could act as a potential novel option for cancer immunotherapy.
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PURPOSE: Proteinuria is an independent risk factor of chronic kidney disease (CKD). Albumin-induced tubulointerstitial inflammation and epithelial-mesenchymal transition (EMT) via the activation of NLRP3 inflammasome is a potential therapeutic target for CKD. Suyin Detoxification Granule (SDG) improves proteinuria and postpones renal failure. However, the underlying mechanism is still unknown. METHODS: Firstly, the rat model of renal failure was established using intragastric administration of adenine. Renal function, proteinuria, inflammatory indicators in serum, and renal pathology were assessed, and renal immunohistochemical staining of NLRP3 inflammasomes was performed after intervention with low and high concentrations of SDG. Secondly, the model of renal tubular epithelial HK-2 cells was established using albumin in vitro, and the cell viability, EMT phenotype, and the expression of proteins in the NLRP3 inflammasome signaling pathway were measured after the freeze-dried powder of Suyin Detoxification Prescription (SDP) and CY-09, which is a selective and direct NLRP3 inhibitor, were co-incubated with albumin. ATP, SOD, mitochondrial membrane potential, and ROS were further measured in vitro, and changes in the mitochondrial function after SDP intervention were observed. The mitochondrial antiviral signaling protein (MAVS) was knocked down using siRNA, and the interaction between MAVS and NLRP3 was verified using Western blotting, polymerase chain reaction (PCR), and immunofluorescence. RESULTS: SDG improved renal function and proteinuria, alleviated renal fibrosis, and reduced serum inflammation and the expression of the components of the NLRP3 inflammasome in the kidney. In vitro, SDP and CY-09 enhanced cell viability after injury with albumin and inhibited pyroptosis induced by the NLRP3 inflammatory signaling pathway and expression of proteins involved in EMT. It was further found that SDP alleviated the mitochondrial dysfunction caused by albumin. The knockdown of MAVS reduced the expression of NLRP3 pathway proteins and their mRNA levels and also weakened the co-localization of NLRP3, thus, reducing cell pyroptosis. CONCLUSION: SDP protected renal tubular epithelial cells from cell pyroptosis and EMT by regulating the albumin-induced mitochondrial dysfunction/ MAVS/ NLRP3-ASC-caspase-1 inflammasome signaling pathway.
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To evaluate the effectiveness and safety of Huachansu in the treatment of cancer-related pain,four Chinese databases( CNKI,VIP,Wan Fang,Sino Med) and three English databases( Cochrane Library,Medline,PubMed) were systematically and comprehensively retrieved since the establishment of each database to October 2018. Randomized controlled trials( RCTs) for the treatment of cancer-related pain with Huachansu were screened out according to pre-established inclusion criteria and exclusion criteria. Rev Man5. 3 software was used for Meta-analysis. A total of 241 articles were retrieved,and finally 10 studies were included. The total sample size was 1 293,including 648 in the experimental group and 645 in the control group. The overall quality of the included studies was generally low. The results of Meta-analysis showed that Huachansu combined with Western medicine acesodynes was superior to the single use of Western medicine acesodynes in the treatment of short-term pain relief,improvement of quality of life and reduction of constipation,nausea and vomiting,dizziness,drowsiness,anorexia and other adverse reactions. And it also has the advantage of a shorter onset time and longer duration time of analgesia,but cannot reduce the incidence of dysuria. Based on the findings,Huachansu had a certain effect in the treatment of cancer-related pain,and a significant positive effect on the improvement of quality of life and the reduction of adverse reactions. No serious adverse reactions occurred. However,due to the small number of studies included,the low quality of the included studies,published biases and other restrictions,the evidence in this study has a low quality,and the conclusion shall be adopted with caution. The effectiveness and safety of Huachansu in the treatment of cancer-related pain remained to be further confirmed in the future with a well-designed,rigorous,and standardized report,with a large sample size,multiple centers,and sufficient follow-up time for randomized controlled trials.