Exploring the therapeutic mechanisms of Coptidis Rhizoma in gastric precancerous lesions: a network pharmacology approach.

BACKGROUND: Gastric precancerous lesions are a critical stage in the development of gastric cancer or gastric adenocarcinoma, and their outcome plays an important role in the malignant progression of gastric cancer. Coptidis Rhizoma has a good effect on Gastric precancerous lesions. However, the specific mechanisms of its action remain incompletely elucidated. METHODS: Network pharmacology and molecular docking techniques were used to explore the active ingredients and molecular mechanism of Coptidis Rhizoma in treating gastric precancerous lesions. The active compounds of Coptidis Rhizoma and their potential gastric precancerous lesions related targets were obtained from TCMSP, GeneCards, and OMIM databases. An interaction network based on protein-protein interactions (PPIs) was constructed to visualize the interactions between hub genes. Analysis of GO enrichment and KEGG pathway were conducted using the DAVID database. An investigation of interactions between active compounds and potential targets was carried out by molecular docking. Finally, animal experiments were conducted to verify the effect and mechanism of Coptidis Rhizoma in treating precancerous lesions of gastric cancer. RESULTS: A total of 11 active compounds and 95 anti-gastric precancerous lesions targets of Coptidis Rhizoma were screened for analysis. GO enrichment analysis showed that the mechanism of Coptidis Rhizoma acting on gastric precancerous lesions involves gene expression regulation and apoptosis regulation. KEGG pathway enrichment analysis showed that Coptidis Rhizoma against gastric precancerous lesions involving the AKT /HIF-1α/VEGF signalling pathway. Molecular docking simulations indicated potential interactions between these compounds and core targets involved in anti-gastric precancerous lesions activity. In addition, it was confirmed in vivo that Berberine and Coptidis Rhizoma may reverse atrophy and potential intestinal metaplasia by inhibiting the expression of p-AKT, HIFA, and VEGF. CONCLUSION: Bioactive compounds in Coptidis Rhizoma have the potential to prevent atrophy and intestinal metaplasia. These compounds function by regulating the proteins implicated in AKT /HIF-1α/VEGF signalling pathways that are crucial in gastric epithelial cell differentiation, proliferation and maturation.

Different effects of TCBPA exposure on liver cancer cells and liver cells: two sides of the coin.

Tetrachlorobisphenol A (TCBPA), widely used as a substitute for tetrabromobisphenol A (TBBPA), has been detected in various environmental media. Therefore, a detailed evaluation of the toxicological properties of TCBPA is necessary. In this study, we used hepatoma and normal liver cell models in vitro to investigate the effects of TCBPA. Our findings indicate that TCBPA promotes the proliferation of liver cancer cells, as evidenced by MTT and EdU assays, and enhances the expression levels of molecules related to hepatoma proliferation. Further investigation into the molecular mechanism revealed that TCBPA-induced hepatoma proliferation is regulated by an NLRP3-mediated inflammatory process. Additionally, TCBPA was found to promote the epithelial-mesenchymal transition (EMT) process in liver cancer cells. Conversely, TCBPA inhibited the proliferation of normal liver cells. Mechanistic studies showed that TCBPA induced cell pyroptosis in normal liver cells by evaluating a series of related markers, including NLRP3, IL-1ß, ASC, GASDMD, and Caspase 1. In vivo models further showed that TCBPA causes liver tissue damage. In summary, this study demonstrates that TCBPA has a dual effect: promoting the occurrence and development of liver tumor cells in vitro, while inhibiting the proliferation of normal liver cells, like two sides of a coin. These opposite cellular outcomes are regulated by NLRP3-mediated inflammatory processes, providing valuable insights for evaluating the potential health impacts of TCBPA.

Mechanism of M2 type macrophage-derived extracellular vesicles regulating PD-L1 expression via the MISP/IQGAP1 axis in hepatocellular carcinoma immunotherapy resistance.

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevailing cancer affecting human health. M2 macrophages are essential in mediating immune responses in tumors. This study investigated the action of M2 macrophages in immune escape of HCC. METHODS: Mitotic spindle positioning (MISP), IQ motif containing GTPase activating protein 1 (IQGAP1) and programmed cell death-1 (PD-L1) levels in primary HCC/tumor-adjacent tissues were determined by Western blot, followed by correlation analysis. M2 macrophage and CD3+CD8+T cell percentages were estimated by flow cytometry. Hep3B and HepG2 cells were treated with M2 macrophage conditioned medium (M2-CM) and M2 macrophage-derived extracellular vesicles (M2-EVs) and/or co-cultured with CD8+T cells, followed by assessment of cell viability and apoptosis. TNF-α and INF-γ levels were measured by ELISA. MISP and IQGAP1 overexpression plasmids were transfected into HCC cells to explore their role in immune escape. The interactions among MISP, IQGAP1, STAT3, and PD-L1 were analyzed by co-immunoprecipitation. The mechanism of M2-EVs in HCC immune escape was verified in nude mice. RESULTS: MISP/IQGAP1/PD-L1 were upregulated in HCC tissues. MISP negatively-correlated with IQGAP1/PD-L1 and IQGAP1 positively-correlated with PD-L1. M2 macrophages were reduced but CD8+T cells were increased in HCC tissues with high MISP expression. M2-CM or M2-EVs inhibited the killing ability of CD8+T cells, increased HCC cell viability, impeded HCC cell apoptosis, induced CD8+T cell apoptosis, downregulated TNF-α and INF-γ, and upregulated PD-L1. M2-EVs facilitated HCC cell immune escape by potentiating IQGAP1 nuclear translocation and activating STAT3 phosphorylation through MISP downregulation. In vivo experiments further verified the action of M2-EVs through MISP. CONCLUSION: M2-EVs promote HCC cell immune escape by upregulating PD-L1 through the MISP/IQGAP1/STAT3 axis.

Surgical site wound infection and pain after laparoscopic repeat hepatectomy for recurrent hepatocellular carcinoma.

This study aimed to compare the effects of laparoscopic repeat liver resection (LRLR) and open repeat liver resection (ORLR) on surgical site wound infection and pain in recurrent hepatocellular carcinoma. PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Data were systematically searched for studies comparing LRLR with ORLR for the treatment of recurrent hepatocellular carcinoma, with a search timeframe from their inception to December 2022. Two investigators independently screened the literature, extracted information, and evaluated the quality of the studies according to the inclusion and exclusion criteria. This study was performed using RevMan 5.4 software. A total of 20 publications with 4380 patients were included, with 1108 and 3289 patients in the LRLR and ORLR groups, respectively. The results showed that LRLR significantly reduced surgical site wound infection rate (1.71% vs. 5.16%, odds ratio [OR]:0.32, 95% confidence interval [CI]: 0.18-0.56, P < .001), superficial wound infection rate (1.29% vs. 4.92%, OR: 0.29, 95% CI: 0.14-0.58, P < .001), bile leakage (3.34% vs. 6.05%, OR: 0.59, 95% CI: 0.39-0.90, P = .01), organ/space wound infection rate (0.4% vs. 5.11%, OR: 0.23, 95% CI: 0.07-0.81, P = .02), and surgical site wound pain (mean difference: -2.00, 95% CI: -2.99 to -1.02, P < .001). Thus, the findings of this study showed that LRLR for recurrent hepatocellular carcinoma significantly reduced wound infection rates and improved postoperative wound pain.

Jinlian Xiaodu Decoction Protects against Bleomycin-Induced Pulmonary Fibrosis in Rats.

Background: Jinlian Xiaodu Decoction (JXD) was reported to have anti-inflammatory and lung protection effects. This study aimed to explore the role and mechanism of JXD on bleomycin (BLM)-induced pulmonary fibrosis (PF). Methods: The UHPLC-Q/TOF-MS system was applied to analyze JXD composition. The PF model was established by BLM intratracheal administration in Wistar rats. Subsequently, BLM-treated rats were intragastrically administered with dexamethasone (DXM, 1 g/kg/d) or JXD (3.5, 7 or 14 g/kg/d). Next, the lung coefficient was calculated; H&E, Masson, and TUNEL staining were used for lung morphological analysis and apoptosis assessment. Bronchoalveolar lavage fluid (BALF) biochemical analysis was conducted to count the inflammatory cell number. The expression of inflammatory factors mRNA in the lung tissue and BALF were measured by qRT-PCR. The content and activity of oxidative stress-related proteins were detected. The expression of PF-related, apoptosis-related, and TGF-ß1 pathway-related protein were assessed by immunohistochemistry or Western blot. Results: Twenty-six compounds were identified from JXD in both negative and positive ion modes. In BLM-induced rats, JXD reduced the lung coefficient and alleviated PF injury. JXD decreased inflammatory cell count and TNF-α, IL-1ß, IL-6, and MCP-1 content. Meanwhile, JXD blunted BLM-induced oxidative stress and a high level of HYP. Furthermore, TUNEL analysis found that JXD inhibited cell apoptosis and increased Bcl-2/Bax ratio in BLM-induced lung. Moreover, JXD relieved the role of BLM on α-SMA, TGF-ß1, collagen I, fibronectin, E-cadherin protein expression, and the phosphorylation of Smad2/3 in PF rat. Conclusion: This study revealed the protective effect and possible element of JXD on BLM-caused PF.

Flurbiprofen suppresses the inflammation, proliferation, invasion and migration of colorectal cancer cells via COX2.

Colorectal cancer is an aggressive disease with a poor prognosis and low survival rate at the advanced stage, therefore new innovative targets are urgently required. Flurbiprofen has been reported to exhibit therapeutic effects in other types of cancer, such as esophageal cancer, breast cancer and colorectal cancer. Therefore, the present study aimed to investigate the function of flurbiprofen in colorectal cancer. SW620 colorectal cancer cells were treated with different concentrations of flurbiprofen to determine the optimum concentration. Subsequently, COX2 expression affected by flurbiprofen was tested using western blotting, reverse transcription-quantitative PCR and immunofluorescence. Enzyme-linked immunosorbent assay was used to determine the levels of tumor necrosis factor-α, interleukin (IL)-6 and IL-1ß. Cell Counting Kit-8, colony formation and flow cytometry assays were used to assess the proliferation and apoptosis of SW620 cells in various groups. Western blotting was performed to investigate the expression of proliferation-, apoptosis- and migration-related proteins after different treatments. Wound healing and Transwell assays were performed to measure the invasion and migration of colorectal cancer cells, respectively. The results demonstrated that flurbiprofen inhibited colorectal cancer cell proliferation. Furthermore, it was identified that flurbiprofen inhibited the expression of COX2. Notably, flurbiprofen suppressed the expression of inflammatory factors by inhibiting COX2. Moreover, flurbiprofen inhibited the proliferation, invasion and migration of colorectal cancer cells by inhibiting COX2. In conclusion, the present study revealed that flurbiprofen inhibited COX2 expression in colorectal cancer, and affected the proliferation, invasion, migration and apoptosis of colorectal cancer cells. These results expand the understanding of the function of COX2 in colorectal cancer and the effect of flurbiprofen on COX2 expression.