Sepsis is a severe, often life-threatening form of organ dysfunction that arises from an inappropriately regulated host response to infectious pathogen exposure. As the largest gland in the body, the liver serves as a regulatory hub for metabolic, immune, and detoxification activity. It is also an early sepsis target organ such that hepatic dysfunction is observed in 34-46% of patients with sepsis. The precise mechanisms that give rise to sepsis-induced liver injury, however, remain incompletely understood. Based on the research conducted to date, dysregulated systemic inflammation, microbial translocation, microcirculatory abnormalities, cell death, metabolic dysfunction, and liver inflammation may all contribute to the liver damage that can arise in the context of septicemia. This review was developed to provide an overview summarizing the potential mechanisms underlying sepsis-induced liver injury, informing the selection of potential targets for therapeutic intervention and providing a framework for the alleviation of patient symptoms and the improvement of prognostic outcomes.

α‑hederin, a monodesmosidic triterpenoid saponin, had previously demonstrated strong anticancer effects. In the current study, the pharmacological mechanism of autophagic cell death induced by α‑hederin was investigated in human colorectal cancer cells. First, through cell counting kit‑8 and colony formation assays, it was demonstrated that α‑hederin could inhibit the proliferation of HCT116 and HCT8 cell. Results of flow cytometry using fluorescein isothiocyanate Annexin V/propidium iodide and Hoechst 33258 staining indicated that α‑hederin could induce apoptosis. Western blotting demonstrated that α‑hederin could activate mitochondrial apoptosis signal pathway. Then, using light chain 3 lentiviral and electron microscope assay, it was demonstrated that α‑hederin could induce autophagy in colorectal cancer cells. In addition, immunohistochemistry results from in vivo experiments also demonstrated that α‑hederin could induce autophagy. AMP‑activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling was demonstrated to be activated by α‑hederin, which could be blocked by reactive oxygen species (ROS) inhibitor NAC. Furthermore, NAC could inhibit apoptosis and autophagy induced by α‑hederin. Finally, 3‑MA (autophagy inhibitor) reduced the inhibition of α‑hederin on cell activity, but it had no significant effect on apoptosis. In conclusion, α‑hederin triggered apoptosis through ROS‑activated mitochondrial signaling pathway and autophagic cell death through ROS dependent AMPK/mTOR signaling pathway activation in colorectal cancer cells.

Drug resistance is an obstacle to chemotherapy in tumor patients. Recent studies have shown that the high stemness of cancer cells may be induced by chemotherapeutic drugs, which is correlated with drug resistance. In the present study, we investigated the effects of bufalin on the stemness of colorectal cancer. We found that cisplatin could induce high stemness through the tumorsphere formation assay in vitro and in vivo in the colorectal cancer cell lines HCT116 and LoVo. In addition, cisplatin-treated tumorsphere cells showed drug‑resistant properties. These results suggested that acquired drug resistance induced by cisplatin in colorectal cancer cells occurred via high stemness. On assessing the effects of bufalin, a traditional Chinese medicine monomer, we found that it could reverse the high stemness and drug resistance induced by cisplatin in colorectal cancer. These findings suggest that bufalin plays an adjuvant role in colorectal cancer chemotherapy and may help reverse acquired drug resistance. These findings may aid in the development of new therapeutic strategies.

Tumour-derived extracellular vesicles (TEVs) have been confirmed to facilitate colorectal cancer (CRC) metastasis by remodelling the tumour microenvironment (TME). Drugs targeted TEVs is considered as a promising therapeutic strategy for cancer treatment. Traditional Chinese medicine (TCM) plays a vital role in improving the prognosis of CRC patients and eventually CRC patients with distant metastasis. Although the anti-tumour effects of active compounds from TCM prescriptions are observed widely, the molecular mechanisms remain unknown. This study aims to investigate the effects of active compounds in our library of TCM on preventing CRC metastasis, and also explore the potential mechanisms from the perspective of TEVs. Materials and methods: The effects of active compounds on the proliferation of CRC cells were determined by CCK-8 assay. TEVs were extracted from MC38 cells by ultracentrifugation and characterized by electron microscopy, Nanosight NS300 and western blotting. The TEV particles were quantified by Nanosight NS300. The potential mechanism by which astragaloside IV (ASIV) reduced TEV secretion was determined by western blotting. RAW264.7 cells were cocultured with the conditioned medium (CM) of MC38 cells treated with or without ASIV, and the activation of tumour-associated macrophages (TAMs) was assessed by immunofluorescence and quantitative polymerase chain reaction (qPCR). The migration of CRC cells was measured by wound healing and Transwell assay. A spleen-to-liver metastasis model of colorectal cancer was used to confirm the efficiency of ASIV in vivo. Liver metastatic tumours of the mice were used for liver weight measures and H&E staining. Immunofluorescence was applied to observe the infiltration of TAMs, the expression of neutral sphingomyelinase 2 (nSMase2) and Rab27a. By screening our TCM monomer library, we found that ASIV, which is mainly extracted from Radix Astragali, reduced the release of TEVs from CRC cells in a time- and concentration-dependent manner. Mechanistically, ASIV inhibited the production and secretion of TEVs by downregulating nSMase2 and Rab27a expression in CRC cells. CM from ASIV-treated CRC cells reshaped the polarization of TAMs by decreasing M2-type polarization, increasing M1-type polarization. Consequently, the repolarization of M2-type to M1-type macrophages led to reduced invasion and migration of CRC cells. Moreover, we confirmed that ASIV inhibited the liver metastasis of CRC, reduced M2-type macrophage infiltration and decreased the expression of nSMase2 and Rab27a in liver metastases. ASIV inhibited CRC metastasis by reducing EVs release and suppressing M2-type TAMs activation. All these findings reveal a new insight into the mechanisms of ASIV in preventing CRC progression and provide a promising approach for anti-tumour therapy.

Overexpression of colorectal cancer oncogene CHRDL2 predicts a poor prognosis Overexpression of colorectal cancer oncogene CHRDL2 predicts a poor prognosis

The development of drug resistance by cancer cells is among the main reasons for cancer treatment failure, greatly limiting the efficacy of chemotherapy, targeted therapy, and immunotherapy. Mitochondria, as the core organelles of cellular energy metabolism, play a key role in the cellular stress response. The dynamic changes in mitochondria, including fusion, fission, and mitophagy, not only regulate cellular energy metabolism and biosynthesis but also affect cell survival and death. Through mitochondrial fusion, fission, and mitophagy, a sufficient number of effective mitochondria are ensured to supply cellular energy, thereby increasing the tolerance of tumor cells to chemotherapeutic drugs and generating drug resistance. Recently, the role of mitochondrial dynamics and mitophagy in cancer drug resistance has gradually gained attention, but their complex structure and function and multiple roles in tumor biology pose challenges for the clinical application of cancer treatment strategies based on it. Therefore, targeting mitochondrial dynamics and mitophagy for cancer drug resistance has attracted increasing attention for various cancer types. In this study, we provide insights into the molecular mechanisms of mitochondrial fusion, fission, and mitophagy and summarize their complex associations with cancer drug resistance through a systematic review of the latest literature.