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Abstract Background Chronic hepatitis B virus (HBV) infection is the major etiology of hepatocellular carcinoma (HCC). However, the mechanism of hepatitis B-related hepatocellular carcinoma (HBV-related HCC) is still unclear. Therefore, understanding the pathogenesis and searching for drugs to treat HBV-related HCC was an effective strategy to treat this disease. Purpose Bioinformatics was used to predict the potential targets of HBV-related HCC. The reverse network pharmacology of key targets was used to analyze the clinical drugs, traditional Chinese medicine (TCM) and small molecules of TCM in the treatment of HBV-related HCC. Methods In this study, three microarray datasets totally containing 330 tumoral samples and 297 normal samples were selected from the GEO database. These microarray datasets were used to screen DEGs. And the expression profile and survival of 6 key genes were analyzed. In addition, Comparative Toxicogenomics Database and Coremine Medical database were used to enrich clinical drugs and TCM of HBV-related HCC by the 6 key targets. Then the obtained TCM were classified based on the Chinese Pharmacopoeia. Among these top 6 key genes, CDK1 and CCNB1 had the most connection nodes and the highest degree and were the most significantly expressed. In general, CDK1 and CCNB1 tend to form a complex, which is conducive to cell mitosis. Hence, this study mainly studied CDK1 and CCNB1. HERB database was used to predict small molecules TCM. The inhibition effect of quercetin, celastrol and cantharidin on HepG2.2.15 cells and Hep3B cells was verified by CCK8 experiment. The effects of quercetin, celastrol and cantharidin on CDK1 and CCNB1 of HepG2.2.15 cells and Hep3B cells were determined by Western Blot. Results In short, 272 DEGs (53 upregulated and 219 downregulated) were identified. Among these DEGs, 6 key genes with high degree were identified, which were AURKA, BIRC5, CCNB1, CDK1, CDKN3 and TYMS. Kaplan–Meier plotter analysis showed that higher expression levels of AURKA, BIRC5, CCNB1, CDK1, CDKN3 and TYMS were associated with poor OS. According to the first 6 key targets, a variety of drugs and TCM were identified. These results showed that clinical drugs included targeted drugs, such as sorafenib, palbociclib and Dasatinib. and chemotherapy drugs, such as cisplatin and doxorubicin. TCM, such as the TCM flavor was mainly warm and bitter, and the main meridians were liver and lung. Small molecules of TCM included flavonoids, terpenoids, alkaloids and glycosides, such as quercetin, celastrol, cantharidin, hesperidin, silymarin, casticin, berberine and ursolic acid, which have great potential in anti-HBV-related HCC. For molecular docking of chemical components, the molecules with higher scores were flavonoids, alkaloids, etc. Three representative types of TCM small molecules were verified respectively, and it was found that quercetin, celastrol and cantharidin inhibited the proliferation of HepG2.2.15 cells and Hep3B cells along concentration gradient. Quercetin, celastrol and cantharidin decreased CDK1 expression in HepG2.2.15 and Hep3B cells, but for CCNB1, only cantharidin decreased CCNB1 expression in the two strains of cells. Conclusion In conclusion, AURKA, BIRC5, CCNB1, CDK1, CDKN3 and TYMS could be potential targets for the diagnosis and prognosis of HBV-related HCC. Clinical drugs include chemotherapeutic and targeted drug, traditional Chinese medicine is mainly bitter and warm TCM. Small molecular of TCM including flavonoids, terpenoids and glycosides and alkaloids, which have great potential in anti-HBV-related HCC. This study provides potential therapeutic targets and novel strategies for the treatment of HBV-related HCC.

Abstract In chronic infections and cancers, T lymphocytes (T cells) are exposed to persistent antigen or inflammatory signals. The condition is often associated with a decline in T-cell function: a state called “exhaustion”. T cell exhaustion is a state of T cell dysfunction characterized by increased expression of a series of inhibitory receptors (IRs), decreased effector function, and decreased cytokine secretion, accompanied by transcriptional and epigenetic changes and metabolic defects. The rise of immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has dramatically changed the clinical treatment paradigm for patients. However, its low response rate, single target and high immunotoxicity limit its clinical application. The multiple immunomodulatory potential of traditional Chinese medicine (TCM) provides a new direction for improving the treatment of T cell exhaustion. Here, we review recent advances that have provided a clearer molecular understanding of T cell exhaustion, revealing the characteristics and causes of T cell exhaustion in persistent infections and cancers. In addition, this paper summarizes recent advances in improving T cell exhaustion in infectious diseases and cancer with the aim of providing a comprehensive and valuable source of information on TCM as an experimental study and their role in collaboration with ICIs therapy.

Abstract Background Interferon-inducible 16 (IFI16)/caspase-1 inflammasome activates and secretes IL-1β. However, it is still unclear whether the IFI16 inflammasome is involved in human laryngeal squamous cell carcinoma. Autophagy directly removed inflammasome components and limited early IL-1β production. RalB is required for the crosstalk between inflammasome and autophagy in macrophages. Dihydroartemisinin (DHA), the main derived ingredient of artemisinin, has a variety of biological activities. The mechanism of DHA in regulating the crosstalk between IFI16 inflammasome and autophagy by inhibiting RalB expression was analyzed in order to provide clues for new therapeutic methods in laryngeal cancer. Methods The expression of IFI16 was analyzed by Oncomine and GEPIA databases and detected by Western blot and immunohistochemistry. The relationship between IFI16 inflammasome and autophagy was investigated by transmission electron microscopy, immunofluorescence assay, etc. in Hep-2, Cal-27 and HeLa cells treated with DHA. The xenograft tumor of hep-2 cell in nude mice were used to assess the effect of DHA on laryngeal cancer. Results It was reported for the first time in this study that IFI16 was overexpressed and positively correlated with caspase-1 in laryngeal carcinoma tissues. DHA significantly inhibited the activation of inflammasome and reduced IL-1β production in the microenvironment of Hep-2 cell xenograft tumor in nude mice. Mechanistically, we found that DHA degraded RalB, inhibited USP33 expression, and triggered autophagy. Meanwhile, enhanced autophagy can reduce the expression of RalB and USP33. Furthermore, DHA promotes autophagy, which suppresses the activation of IFI16/caspase-1 inflammasome and IL-1β production. Conclusions Therefore, our findings demonstrate that DHA may act as a RalB inhibitor to regulate the crosstalk between autophagy and IFI16/caspase-1 inflammasome, which inhibits IL-1β production in tumor microenvironment.