Berberine inhibited the formation of metastasis by intervening the secondary homing of colorectal cancer cells in the blood circulation to the lung and liver through HEY2.

BACKGROUND: Metastasis is the leading cause of death in patients with colorectal cancer (CRC). The 5-year survival rate of CRC patients in whom the cancer has spread to distant sites is 13.5%. The most common sites of CRC metastasis are liver and lung. The principal therapies for CRC metastatic disease are surgery, but its benefits are limited. PURPOSE: This study aimed to reveal the regulatory mechanism of berberine on secondary homing of CRC cells to form metastatic focus. This was more valuable than the previous direct study of the migration and metastasis characteristics of CRC cells. METHODS: In this study, we used the functional enrichment analysis of differentially expressed genes after berberine treatment and investigated co-expression modules related with CRC metastasis by WGCNA. PPI and survival analyses of significant modules were also conducted. The biological functions of berberine in CRC lung and liver metastasis were investigated by a series of in vitro and in vivo experiments: MTT, colony formation and mouse tail vein injection. And we scanned through the entire extracellular domain of HEY2 protein for autodocking analysis with berberine. RESULTS: We found the differentially expressed genes (DEGs) after berberine treatment were related with cancer progression and metastasis related pathways. Through WGCNA analysis, four cancer progression and metastasis related modules were detected. After PPI and survival analysis, we identified and validated HEY2 as a hub gene, high expression and poor survival at the metastatic stage. Functionally, berberine inhibited the survival, invasion and migration of CRC cells in vitro and in vivo. Mechanistically, berberine treatment down-regulated the expression of HEY2, metastasis related protein E-cadherin, ß-catenin and Cyclin D1 during Mesenchymal epithelial transformation (MET). Berberine and HEY2 showed a significant interaction, and berberine binded to HEY2 protein at the residue HIS-99 interface with a hydrogen-bond distance of 1.9A. CONCLUSIONS: We revealed that berberine could significantly inhibit the expression of hub gene HEY2 and metastasis related proteins E-cadherin and ß-catenin and Cyclin D1 during MET in CRC lung and liver metastases. In total, HEY2 was a promising candidate biomarker for prognosis and molecular characteristics in CRC metastasis.

The Experimental Exploration of TCM Theory "Treating the Same Disease with Different Approaches" on an Ulcerative Colitis Model.

There is a relationship between lung injury and ulcerative colitis. Currently, traditional Chinese medicine (Huangqi Jiegeng (HQJGD) and Huangqi Huanglian decoctions (HQHLD)) is commonly used for UC-related lung injury; however, the mechanisms of these drugs remain unclear. In this study, UC models were established with the mucous membrane of colon allergize combined with TNBS-alcohol enteroclysis for 4 weeks. The pathological changes in the lung, intestine, liver, and kidney were observed; cytokines, chemokines, and adhesion molecules in lung tissue were detected in order to explore the immunological mechanism of UC-related lung injury and the intervention mechanism of traditional Chinese medicine in treating the lung and intestine in the immune-TNBS-ethanol rat model. Histology examinations demonstrated evident pathological changes in the lungs and intestines of the model groups. Furthermore, all groups treated with TCMs demonstrated reduced expressions of toll-like receptor 4, nuclear factor kappa-B, and macrophage migration inhibitory factor. Additionally, radioimmunoassay and immunohistochemistry showed tumor necrosis factor-α, interleukin-6, and 8 expression downregulation. The results showed that HQJGD and HQHLD could alleviate pulmonary inflammation in UC-related lung injury by obviously improving the pathology and fibrosis of the lung, inhibiting the positive feedback loop of MIF/NF-κB, and reducing lymphocyte homing to bronchial mucosa. This model revealed the immune mechanism of UC-related lung injury and the intervention mechanism of the Chinese medicine, which provided the rationale for treating ulcerative colitis clinically, so as to demonstrate the theory of "the lung and the large intestine being interior-exteriorly related" and "treating the same disease with different approaches."

Glycyrrhiza uralensis promote the metabolism of toxic components of Aconitum carmichaeli by CYP3A and alleviate the development of chronic heart failure.

Aconitum, as "the first drug of choice for invigorating Yang and saving lives", has been widely used for the treatment of heart failure. However, toxic components of Aconitum can easily lead to serious arrhythmia, even death (Y. CT., 2009; Zhang XM., 2018). In this study, a High Performance Liquid Chromatography (HPLC) method for the determination of aconitine (AC), mesaconitine (MA) and hypaconitine (HA) was established; The effect of Glycyrrhiza on CYP3A1 / 2 mRNA expression was detected by RT-PCR; SD rats were given Aconitum and compatibility of Glycyrrhizae and Aconitum by gavage respectively, the blood concentration of toxic components were determined by LC-MS / MS; The CHF rat model was established by intraperitoneal injection of adriamycin (2.5 mg / kg), and were randomly divided into model, Aconitum, the compatibility of Glycyrrhizae and Aconitum and Captopril group, 5 mice/group. After 4 weeks of gavage, the corresponding indexes were detected by ELISA and HPLC. The results showed that Ketoconazole significantly inhibited the metabolites of AC, MA and HA; Glycyrrhiza induced CYP3A gene expression; The level of ALD in the compatibility of Glycyrrhizae and Aconitum group was significantly lower than that in Aconitum group. After intervention with the compatibility of Glycyrrhizae and Aconitum, ATP increased, ADP decreased significantly. In conclusion, we found Glycyrrhiza promoted the metabolism of toxic components of Aconitum by up regulating the expression of CYP3A, and reduced the content of BNP, Ang II and ALD, improved the energy metabolism disorder of myocardium, alleviated the development of CHF.

Berberine inhibits non-small cell lung cancer cell growth through repressing DNA repair and replication rather than through apoptosis.

At present, there are still many problems in the treatment of lung cancer, such as high cost, side effects and low quality of life. The advantages of traditional Chinese medicine (TCM) in the treatment of lung cancer are reflected. Berberine has been increasingly popular in colorectal cancer treatment, but little is known about its bioactivity against non-small cell lung cancer (NSCLC). Cell proliferation, cell apoptosis, cDNA microarray, gene and protein expression, and NSCLC transplanted tumour growth were performed. Berberine suppressed NSCLC cell proliferation and colony formation in vitro and inhibited NSCLC tumour growth in subcutaneously transplanted tumour lung tumour models, leading to prolonged survival of tumour-bearing mice. However, berberine did not induce the cleavage of Caspase 3 and PARP1, and could not induce apoptosis in all NSCLC cells. Moreover, 646 genes were differentially expressed upon berberine administration, which were involved in seven signal pathways, such as DNA replication. In cDNA microarray, berberine downregulated the expression of RRM1, RRM2, LIG1, POLE2 that involving DNA repair and replication. Our findings demonstrate that berberine inhibits NSCLC cells growth through repressing DNA repair and replication rather than through apoptosis. Berberine could be used as a promising therapeutic candidate for NSCLC patients.

Sudden water pollution accidents and reservoir emergency operations: impact analysis at Danjiangkou Reservoir.

Danjiangkou Reservoir is the source reservoir of the Middle Route of the South-to-North Water Diversion Project (MRP). Any sudden water pollution accident in the reservoir would threaten the water supply of the MRP. We established a 3-D hydrodynamic and water quality model for the Danjiangkou Reservoir, and proposed scientific suggestions on the prevention and emergency management for sudden water pollution accidents based on simulated results. Simulations were performed on 20 hypothetical pollutant discharge locations and 3 assumed amounts, in order to model the effect of pollutant spreading under different reservoir operation types. The results showed that both the location and mass of pollution affected water quality; however, different reservoir operation types had little effect. Five joint regulation scenarios, which altered the hydrodynamic processes of water conveyance for the Danjiangkou and Taocha dams, were considered for controlling pollution dispersion. The results showed that the spread of a pollutant could be effectively controlled through the joint regulation of the two dams and that the collaborative operation of the Danjiangkou and Taocha dams is critical for ensuring the security of water quality along the MRP.

[Studies on chemical constituents from the corm of Cremastra appendiculata].

OBJECTIVE: To study the chemical constituents of the corm of the planted Cremastra appendiculata. METHOD: The compounds were isolated by column chromatography with silica gel and Sephadex LH-20, and their structures were elucidated by means of spectroscopic methods including 2D NMR techniques. RESULT: Six compounds were isolated, and identified as isohircinol (I), flavanthrinin (II), p-hydroxyphenylethyl alcohol (III), 3,4-dihydroxyphenylethyl alcohol (IV), daucosterol (V), beta-sitosterol (VI). CONCLUSION: These compounds were not previously isolated from this plant, and isohircinol (I) was obtained from natural source for the first time.

[Chemical constituents from tuber of Cremastra appendiculata].

OBJECTIVE: To investigate the chemical constituents from the tuber of the planted Cremastra appendiculata. METHOD: The compounds were isolated by column chromatography over silica gel, Sephadex LH-20 and RP-HPLC, and their structures were elucidated on the basis of spectroscopic analysis. RESULT: Eight compounds were isolated, and identified as cirrhopetalanthrin (I), 7-hydroxy-4-methoxyphenanthrene-2-O-beta-D-glucoside (II), 4-(2-hydroxyethyl)-2-methoxyphenyl-1-O-beta-D-glucopyranoside (III), tyrosol 8-O-beta-D-gluco-pyranoside (IV), vanilloloside (V), p-hydroxybenzaldehyde (VI), sucrose (VII), adenosine (VIII). CONCLUSION: These compounds are isolated from this plant for the first time. All compounds were evaluated against human colon cancer (HCT-8), human hepatoma (Bel7402), human stomach cancer(BGC-823), human lung adenocarcinoma (A549), human breast cancer (MCF-7), and human ovarian cancer (A2780) cell lines, and cirrhopetalanthrin (I) showed non-selective moderate cytotoxicity with IC50 values of 8.4-13.3 micromol x L(-1), and other compounds were inactive.