Hepatic ischemia reperfusion (I/R) injury (HIRI) HIRI is a complex, multifactorial pathophysiological process and in liver surgery has been known to significantly affect disease prognosis, surgical success rates, and patient survival. Ginsenoside Rgl (Rgl) monomer is one of the main active ingredients of ginseng. Previous studies have demonstrated that Rgl exerts various pharmacological effects through several mechanisms including suppression of apoptosis-related proteins levels, downregulation of inflammatory mediators and as well as antioxidant, which effectively exerts an organ protective effect I/R-induced damage. However, the exact mechanisms of Rg1 on HIRI remain to be elucidated. In the present study, we investigated the protective effect of Rg1 on hepatic ischemia-reperfusion (I/R) injury (HIRI) and explored its underlying molecular mechanism. A rat warm I/R injury model in vivo and an oxygen-glucose deprivation/reperfusion (OGD/R)-treated BRL-3A cell model in vitro were established after pretreating with Rg1(20 mg/kg). The results showed that Rg1 reduced the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). TUNEL staining showed that pretreated with Rg1 inhibited the apoptosis rate compared with the I/R group. Moreover, pretreated with Rg1 significantly reduced the expression of Cyt-C, Caspase-9 and Caspase-3 to inhibit the cell apoptosis. Flow cytometry analysis showed the MMP in the I/R group was significantly increased, whereas pretreated with Rg1 effectively stabilized the MMP compared with the I/R group. in vitro, the proliferation of BRL-3A cells was significantly decreased by the OGD/R treatment, while Rg1 effectively reversed this phenomenon. In addition, western blotting showed that the increase of Cyt-C, Caspase-9 and Caspase-3 was inhibited by H2O2. These observations suggest that Rg1 exerts the protective effect by inhibiting the CypD protein-mediated mitochondrial apoptotic pathway.

AIM: To investigate the efficacy and molecular mechanisms of induced heme oxygenase (HO)-1 in protecting liver from warm ischemia/reperfusion (I/R) injury. METHODS: Partial warm ischemia was produced in the left and middle hepatic lobes of SD rats for 75 min, followed by 6 h of reperfusion. Rats were treated with saline, cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP) at 24 h prior to the ischemia insult. Blood and samples of ischemic lobes subjected to ischemia were collected at 6 h after reperfusion. Serum transaminases level, plasma lactate dehydrogenase and myeloperoxidase activity in liver were measured. Liver histological injury and inflammatory cell infiltration were evaluated by tissue section and liver immunohistochemical analysis. We used quantitative reverse transcription polymerase chain reaction to analyze liver expression of inflammatory cytokines and chemokines. The cell lysates were subjected to immunoprecipitation with anti-Toll-IL-1R-containing adaptor inducing interferon-β (TRIF) and anti-myeloid differentiation factor 88 (MyD88), and then the immunoprecipitates were analyzed by SDS-PAGE and immunoblotted with the indicated antibodies. RESULTS: HO-1 protected livers from I/R injury, as evidenced by diminished liver enzymes and well-preserved tissue architecture. In comparison with ZnPP livers 6 h after surgery, CoPP treatment livers showed a significant increase inflammatory cell infiltration of lymphocytes, plasma cells, neutrophils and macrophages. The Toll-like receptor (TLR)-4 and TANK binding kinase 1 protein levels of rats treated with CoPP significantly reduced in TRIF-immunoprecipitated complex, as compared with ZnPP treatment. In addition, pretreatment with CoPP reduced the expression levels of TLR2, TLR4, IL-1R-associated kinase (IRAK)-1 and tumor necrosis factor receptor-associated factor 6 in MyD88-immunoprecipitated complex. The inflammatory cytokines and chemokines mRNA expression rapidly decreased in CoPP-pretreated liver, compared with the ZnPP-treated group. However, the expression of negative regulators Toll-interacting protein, suppressor of cytokine signaling-1, IRAK-M and Src homology 2 domain-containing inositol-5-phosphatase-1 in CoPP treatment rats were markedly up-regulated as compared with ZnPP-treated rats. CONCLUSION: HO-1 protects liver against I/R injury by inhibiting TLR2/TLR4-triggered MyD88- and TRIF-dependent signaling pathways and increasing expression of negative regulators of TLR signaling in rats.

Background: Upregulation of Stathmin 1 (STMN1), a cytoplasmic phosphoprotein that controls the dynamics of cellular microtubules, is linked to malignant behavior and poor prognosis in a range of malignancies. However, little research has been done on STMN1’s potential role in HCC as a single factor in DNA methylation, m⁶A, or immunological modulation. Results: STMN1 is overexpressed in hepatocellular carcinoma, where it is related to clinicopathological parameters and affects the prognosis of HCC patients. STMN1 overexpression plays an important role in the diagnosis and prognosis of hepatocellular carcinoma. Meanwhile, methylation of 7 CpG sites of STMN1 in HCC was correlated with prognosis, and STMN1 expression was closely related to m⁶A modification. In addition, STMN1 expression is associated with immune cell infiltration, immune molecules, and immune checkpoints in HCC. Conclusion: STMN1 has a significant role in hepatocellular carcinoma diagnosis and prediction. STMN1 is implicated not just in the onset and course but also in the immunological modulation of the disease. DNA methylation and m⁶A are both linked to STMN1. Therefore, STMN1 could be used as a diagnostic and prognostic biomarker for HCC, as well as a target for immunotherapy.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death in people, and a common primary liver cancer. Lacking early diagnosis and a high recurrence rate after surgical resection, systemic treatment is still an important treatment method for advanced HCC. Different drugs have distinct curative effects, side effects and drug resistance due to different properties. At present, conventional molecular drugs for HCC have displayed some limitations, such as adverse drug reactions, insensitivity to some medicines, and drug resistance. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), have been well documented to be involved in the occurrence and progression of cancer. Novel biomarkers and therapeutic targets, as well as research into the molecular basis of drug resistance, are urgently needed for the management of HCC. We review current research on ncRNAs and consolidate the known roles regulating drug resistance in HCC and examine the potential clinical applications of ncRNAs in overcoming drug resistance barriers in HCC based on targeted therapy, cell cycle non-specific chemotherapy and cell cycle specific chemotherapy.