TRIM47-CDO1 axis dictates hepatocellular carcinoma progression by modulating ferroptotic cell death through the ubiquitin‒proteasome system.

Hepatocellular carcinoma (HCC) is the predominant form of liver cancer, characterized by high morbidity and mortality rates, as well as unfavorable treatment outcomes. Tripartite motif-containing protein 47 (TRIM47) has been implicated in various diseases including tumor progression with the activity of E3 ubiquitin ligase. However, the precise regulatory mechanisms underlying the involvement of TRIM47 in HCC remain largely unexplored. Here, we provide evidence that TRIM47 exhibits heightened expression in tumor tissues, and its expression is in intimate association with clinical staging and patient prognosis. TRIM47 promotes HCC proliferation, migration, and invasion as an oncogene by in vitro gain- and loss-of-function experiments. TRIM47 knockdown results in HCC ferroptosis induction, primarily through CDO1 involvement to regulate GSH synthesis. Subsequent experiments confirm the interaction between TRIM47 and CDO1 dependent on B30.2 domain, wherein TRIM47 facilitates K48-linked ubiquitination, leading to a decrease in CDO1 protein abundance in HCC. Furthermore, CDO1 is able to counteract the promotional effect of TRIM47 on HCC biological functions. Overall, our research provides novel insight into the mechanism of TRIM47 in CDO1-mediated ferroptosis in HCC cells, highlighting its value as a potential target candidate for HCC therapeutic approaches.

Dihydroartemisinin induces ferroptosis of hepatocellular carcinoma via inhibiting ATF4-xCT pathway.

Management of hepatocellular carcinoma (HCC) remains challenging due to population growth, frequent recurrence and drug resistance. Targeting of genes involved with the ferroptosis is a promising alternative treatment strategy for HCC. The present study aimed to investigate the effect of dihydroartemisinin (DHA) against HCC and explore the underlying mechanisms. The effects of DHA on induction of ferroptosis were investigated with the measurement of malondialdehyde concentrations, oxidised C11 BODIPY 581/591 staining, as well as subcutaneous xenograft experiments. Activated transcription factor 4 (ATF4) and solute carrier family 7 member 11 (SLC7A11 or xCT) were overexpressed with lentiviruses to verify the target of DHA. Here, we confirmed the anticancer effect of DHA in inducing ferroptosis is related to ATF4. High expression of ATF4 is related to worse clinicopathological prognosis of HCC. Mechanistically, DHA inhibited the expression of ATF4, thereby promoting lipid peroxidation and ferroptosis of HCC cells. Overexpression of ATF4 rescued DHA-induced ferroptosis. Moreover, ATF4 could directly bound to the SLC7A11 promoter and increase its transcription. In addition, DHA enhances the chemosensitivity of sorafenib on HCC in vivo and in vitro. These findings confirm that DHA induces ferroptosis of HCC via inhibiting ATF4-xCT pathway, thereby providing new drug options for the treatment of HCC.

Analysis of the Cadmium Removal Mechanism of Human Gut Bacteria Enterococcus faecalis Strain ATCC19433 from a Genomic Perspective.

Cadmium (Cd) is one of the most well-known toxic metals capable of entering the human body via the food chain, leading to serious health problems. Human gut microbes play a pivotal role in controlling Cd bioavailability and toxicity within the human gastrointestinal tract, primarily due to their capacity for Cd adsorption and metabolism. In this work, a Cd-resistant bacterial strain, Enterococcus faecalis strain ATCC19433 was isolated from human gut microbiota. Cd binding assays and comprehensive characterization analyses were performed, revealing the ability of strain ATCC19433 to remove Cd from the solution. Cd adsorption primarily occurred on the bacterial cell walls, which was ascribed to the exciting of functional groups on the bacterial surfaces, containing alkyl, amide II, and phosphate groups; meanwhile, Cd could enter cells, probably through transport channels or via diffusion. These results indicated that Cd removal by the strain was predominantly dependent on biosorption and bioaccumulation. Whole-genome sequencing analyses further suggested the probable mechanisms of biosorption and bioaccumulation, including Cd transport by transporter proteins, active efflux of Cd by cadmium efflux pumps, and mitigating oxidative stress-induced cell damage by DNA repair proteases. This study evaluated the Cd removal capability and mechanism of Enterococcus faecalis strain ATCC19433 while annotating the genetic functions related to Cd removal, which may facilitate the development of potential human gut strains for the removal of Cd.

Intestinal stent implantation using a water injection device with carbon dioxide and transparent cap: A case report.

RATIONALE: Preoperative endoscopic intestinal stent placement can relieve the symptoms of malignant bowel obstruction (MBO) pending investigations, staging, and surgery, but it is a technically challenging procedure. This paper presents a woman with MBO who successfully underwent intestinal stent implantation using a water injection device with carbon dioxide and a transparent cap. PATIENT CONCERNS: We reported a technique for endoscopic intestinal stent placement. A 60-year-old female patient was admitted for abdominal pain and poor bowel movement for 10 days. Computed tomography at a local hospital suggested local stenosis. DIAGNOSES: A transparent cap was placed in front of a gastroscope and was used to cross part of the stenotic segment, with water being injected to fill the intestinal cavity continuously. An angiographic catheter was sent along the yellow zebra guidewire passing through the stenotic segment. After exchanging for a colonoscope, a 12-cm intestinal stent was placed along the guidewire. INTERVENTIONS: The physician used a single-person water injection-assisted colonoscopy technique in combination with a carbon dioxide gas pump to assist with the air insufflation for colonoscope insertion through the lumen and repeatedly injected water solution to ensure a transparent colonoscopic view. OUTCOMES: No intraoperative or postoperative complications were observed. One week after endoscopic intestinal stent placement, the patient underwent radical left hemicolectomy for colon cancer and release of bowel adhesion. The postoperative pathology revealed adenocarcinoma with perineural invasion. The patient recovered well after surgery. LESSONS: Single-person intestinal stent implantation using a water injection device with carbon dioxide and a transparent cap can achieve endoscopic intestinal stent placement for MBO.

Deciphering roles of TRIMs as promising targets in hepatocellular carcinoma: current advances and future directions.

Tripartite motif (TRIM) family is assigned to RING-finger-containing ligases harboring the largest number of proteins in E3 ubiquitin ligating enzymes. E3 ubiquitin ligases target the specific substrate for proteasomal degradation via the ubiquitin-proteasome system (UPS), which seems to be a more effective and direct strategy for tumor therapy. Recent advances have demonstrated that TRIM genes associate with the occurrence and progression of hepatocellular carcinoma (HCC). TRIMs trigger or inhibit multiple biological activities like proliferation, apoptosis, metastasis, ferroptosis and autophagy in HCC dependent on its highly conserved yet diverse structures. Remarkably, autophagy is another proteolytic pathway for intracellular protein degradation and TRIM proteins may help to delineate the interaction between the two proteolytic systems. In depth research on the precise molecular mechanisms of TRIM family will allow for targeting TRIM in HCC treatment. We also highlight several potential directions warranted further development associated with TRIM family to provide bright insight into its translational values in hepatocellular carcinoma.

Promotion of colorectal cancer cell death by ezetimibe via mTOR signaling-dependent mitochondrial dysfunction.

Introduction: Colorectal cancer (CRC) is the fourth most common cancer worldwide, with high morbidity and mortality rates. In recent years, high-fat diet has been shown to increase CRC morbidity, highlighting the possibility of the application of hypolipidemic drugs for CRC treatment. In this study, we preliminarily evaluated the effects and mechnisms of ezetimibe against CRC through the blockage of lipid absorption in small intesine. Methods: In this study, CRC cell proliferation, invasion, apoptosis, and autophagy were evaluated using cellular and molecular assays. Fluorescent microscopy, and a flow cytometric assay were used to assess mitochondrial activity in vitro. A subcutaneous xenograft mouse model was used to evaluate the effects of ezetimibe in vivo. Results: We found that ezetimibe inhibited CRC cell proliferation, and migration, and facilitated autophage-associated apoptosis in HCT116 and Caco2 cells. Ezetimibe-induced mitochondrial dysfunction in CRC cells was found to be correlated with mTOR signaling activity. Discussion: Ezetimibe exhibits effects against CRC through the promotion of cancer cell death via mTOR signaling-dependent mitochondrial dysfunction, highlighting its potential value in CRC therapy.

Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis.

BACKGROUND: Sorafenib resistance is a key impediment to successful treatment of patients with advanced hepatocellular carcinoma (HCC) and recent studies have reported reversal of drug resistance by targeting ferroptosis. The present study aimed to explore the association of fatty acid synthase (FASN) with sorafenib resistance via regulation of ferroptosis and provide a novel treatment strategy to overcome the sorafenib resistance of HCC patients. METHODS: Intracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe2+ were measured as indicators of ferroptosis status. Biological information analyses, immunofluorescence assays, western blot assays, and co-immunoprecipitation analyses were conducted to elucidate the functions of FASN in HCC. Both in vitro and in vivo studies were conducted to examine the antitumor effects of the combination of orlistat and sorafenib and CalcuSyn software was used to calculate the combination index. RESULTS: Solute carrier family 7 member 11 (SLC7A11) was found to play an important role in mediating sorafenib resistance. The up-regulation of FASN antagonize of SLC7A11-mediated ferroptosis and thereby promoted sorafenib resistance. Mechanistically, FASN enhanced sorafenib-induced ferroptosis resistance by binding to hypoxia-inducible factor 1-alpha (HIF1α), promoting HIF1α nuclear translocation, inhibiting ubiquitination and proteasomal degradation of HIF1α, and subsequently enhancing transcription of SLC7A11. Orlistat, an inhibitor of FASN, with sorafenib had significant synergistic antitumor effects and reversed sorafenib resistance both in vitro and in vivo. CONCLUSION: Targeting the FASN/HIF1α/SLC7A11 pathway resensitized HCC cells to sorafenib. The combination of orlistat and sorafenib had superior synergistic antitumor effects in sorafenib-resistant HCC cells.

The Gut Microbiome and Ferroptosis in MAFLD.

Metabolic-associated fatty liver disease (MAFLD) is a new disease definition, and is proposed to replace the previous name, nonalcoholic fatty liver disease (NAFLD). Globally, MAFLD/NAFLD is the most common liver disease, with an incidence rate ranging from 6% to 35% in adult populations. The pathogenesis of MAFLD/NAFLD is closely related to insulin resistance (IR), and the genetic susceptibility to acquired metabolic stress-associated liver injury. Similarly, the gut microbiota in MAFLD/NAFLD is being revaluated by scientists, as the gut and liver influence each other via the gut-liver axis. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Emerging evidence suggests that ferroptosis has a key role in the pathological progression of MAFLD/NAFLD, and inhibition of ferroptosis may become a novel therapeutic strategy for the treatment of NAFLD. This review focuses on the main mechanisms behind the promotion of MAFLD/NAFLD occurrence and development by the intestinal microbiota and ferroptosis. It outlines new strategies to target the intestinal microbiota and ferroptosis to facilitate future MAFLD/NAFLD therapies.

Cordycepin Protects against Hepatic Ischemia/Reperfusion Injury via Inhibiting MAPK/NF-κB Pathway.

Hepatic ischemia/reperfusion injury (HIRI) is a common complication of liver surgery requiring hepatic disconnection, such as hepatectomy and liver transplantation. The aim of this study was to investigate the effects of cordycepin on HIRI and to elucidate the underlying mechanisms. Balb/c mice were randomly divided into six groups: a normal control group, sham group, H-cordycepin group, HIRI group, L-cordycepin (25 mg/kg) + HIRI group, and H-cordycepin (50 mg/kg) + HIRI group. Mice were subjected to I/R, and cordycepin was intragastrically administered for seven consecutive days before surgery. Orbital blood and liver specimens were collected at 6 and 24 h after HIRI. Serum levels of ALT and AST were decreased in the cordycepin pretreatment groups. Notably, cordycepin attenuated the inflammatory response and the production of proapoptosis proteins, while increasing expression of antiapoptosis proteins and decreasing expression of autophagy-linked proteins. Furthermore, cordycepin inhibited activation of the MAPK/NF-κB signaling pathway. Collectively, these results indicate that cordycepin pretreatment ameliorated hepatocyte injury caused by HIRI. As compared with the HIRI group, cordycepin pretreatment mitigated the inflammatory response and inhibited apoptosis and autophagy via regulation of the MAPK/NF-κB signaling pathway.

High Expression of EIF4G2 Mediated by the TUG1/Hsa-miR-26a-5p Axis Is Associated with Poor Prognosis and Immune Infiltration of Gastric Cancer.

Objective: Eukaryotic translation initiation factor 4 gamma 2 (EIF4G2) is involved in the occurrence and development of various tumors. However, the effect of EIF4G2 in gastric cancer (GC) has not been fully explored. The purpose of this study was to explore the function and mechanism of EIF4G2 in GC. Methods: The Tumor Immune Estimation Resource 2.0 database was used to analyze EIF4G2 expression in various cancers and the relationship between EIF4G2 expression and tumor-infiltrating immune cells. Gene Expression Profiling Interactive Analysis was utilized to assess the EIF4G2 expression level and its effect on survival in GC. UALCAN was conducted to analyze EIF4G2 expression in various subgroups of GC. The Kaplan-Meier plotter was employed for survival analysis. Receiver operator characteristic (ROC) curve analysis was applied to evaluate the diagnostic role of EIF4G2 in GC. LinkedOmics was used to identify the co-expressed genes and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. The Tumor-Immune System Interaction database was employed to analyze the correlation between EIF4G2 expression and tumor-infiltrating lymphocytes. The starBase web platform was used to predict the upstream microRNAs and long noncoding RNAs. Results: EIF4G2 expression was upregulated in GC tissues compared to normal controls. High expression of EIF4G2 indicated poor prognosis in GC. ROC analysis revealed that EIF4G2 had good diagnostic ability to distinguish GC from normal tissues. Immune infiltration analysis indicated that EIF4G2 expression may be involved in the modulation of tumor immune infiltration in GC. Finally, we determined that the Taurine Upregulated 1 (TUG1)/hsa-miR-26a-5p/EIF4G2 axis was the most likely regulatory pathway involved in GC development. Conclusions: EIF4G2 was upregulated in GC and elevated expression of EIF4G2 indicated unfavorable prognosis. Moreover, EIF4G2 expression may be involved in the regulation of tumor immune cell infiltration. The TUG1/hsa-miR-26a-5p axis is a likely upstream regulatory mechanism of EIF4G2 in GC. EIF4G2 may thus serve as a prognosis biomarker and present a new therapeutic target.

Luteolin Pretreatment Attenuates Hepatic Ischemia-Reperfusion Injury in Mice by Inhibiting Inflammation, Autophagy, and Apoptosis via the ERK/PPARα Pathway.

Hepatic ischemia-reperfusion (IR) injury is a clinically significant process that frequently occurs in liver transplantation, partial hepatectomy, and hemorrhagic shock. The aim of this study was to explore the effectiveness of luteolin in hepatic IR injury and the underlying mechanism. BALB/c mice were randomly divided into six groups, including normal controls (NC), luteolin (50 mg/kg), sham procedure, IR+25 mg/kg luteolin, and IR+50 mg/kg luteolin group. Serum and tissue samples were collected at 6 and 24 h after reperfusion to assay liver enzymes, inflammatory factors, expression of proteins associated with apoptosis and autophagy, and factors associated with the extracellular signal-regulated kinase/peroxisome proliferator-activated receptor alpha (ERK/PPARα) pathway. Luteolin preconditioning decreased hepatocyte injury caused by ischemia-reperfusion, downregulated inflammatory factors, and inhibited apoptosis and autophagy. Luteolin also inhibited ERK phosphorylation and activated PPARα.

Sodium butyrate inhibits aerobic glycolysis of hepatocellular carcinoma cells via the c-myc/hexokinase 2 pathway.

Aerobic glycolysis is a well-known hallmark of hepatocellular carcinoma (HCC). Hence, targeting the key enzymes of this pathway is considered a novel approach to HCC treatment. The effects of sodium butyrate (NaBu), a sodium salt of the short-chain fatty acid butyrate, on aerobic glycolysis in HCC cells and the underlying mechanism are unknown. In the present study, data obtained from cell lines with mouse xenograft model revealed that NaBu inhibited aerobic glycolysis in the HCC cells in vivo and in vitro. NaBu induced apoptosis while inhibiting the proliferation of the HCC cells in vivo and in vitro. Furthermore, the compound inhibited the release of lactate and glucose consumption in the HCC cells in vitro and inhibited the production of lactate in vivo. The modulatory effects of NaBu on glycolysis, proliferation and apoptosis were related to its modulation of hexokinase 2 (HK2). NaBu downregulated HK2 expression via c-myc signalling. The upregulation of glycolysis in the HCC cells induced by sorafenib was impeded by NaBu, thereby enhancing the anti-HCC effect of sorafenib in vitro and in vivo. Thus, NaBu inhibits the expression of HK2 to downregulate aerobic glycolysis and the proliferation of HCC cells and induces their apoptosis via the c-myc pathway.

Cellular based immunotherapy for primary liver cancer.

Primary liver cancer (PLC) is a common malignancy with high morbidity and mortality. Poor prognosis and easy recurrence on PLC patients calls for optimizations of the current conventional treatments and the exploration of novel therapeutic strategies. For most malignancies, including PLC, immune cells play crucial roles in regulating tumor microenvironments and specifically recognizing tumor cells. Therefore, cellular based immunotherapy has its instinctive advantages in PLC therapy as a novel therapeutic strategy. From the active and passive immune perspectives, we introduced the cellular based immunotherapies for PLC in this review, covering both the lymphoid and myeloid cells. Then we briefly review the combined cellular immunotherapeutic approaches and the existing obstacles for PLC treatment.

Evaluation of Cadmium Transfer from Soil to the Human Body Through Maize Consumption in a Cadmium Anomaly Area of Southwestern China.

Evaluating the bioavailability, bioaccessibility, and transferability of cadmium (Cd) in soil-grain-human systems is essential in areas with a Cd anomaly in the karst region of southwestern China. In the present study, the main controlling factors and prediction models for Cd transfer in a soil-grain-human system were investigated in a typical area where natural processes and anthropogenic activities interact in the karst region of southwestern China. The environmental availability of Cd (diethylenetriaminepentaacetic acid- and CaCl2 -extractable Cd [ CdCaCl2 ]) in the soil varies significantly because of the diversity of soil properties. However, Cd concentrations in the maize grain were significantly related only to the CdCaCl2 concentrations in the soil (r = 0.595, p < 0.01), indicating that soil CdCaCl2 is a good indicator for evaluating Cd uptake by maize grain. Of all the measured soil properties, the soil cation exchange capacity (CEC) and the soil calcium (Casoil ) were the most important factors influencing Cd accumulation in the soil-maize grain system. A transfer model combining CdCaCl2 , soil CEC, and Casoil was sufficiently reliable for predicting Cd accumulation in the maize grain (R2 = 0.505). Although there is room for improvement regarding the prediction performance of the chain model combining soil CdCaCl2 with Casoil to predict the bioaccessible Cd concentration in maize grain (R2 = 0.344 for the gastric phase and R2 = 0.356 for the gastrointestinal phase), our findings provide a useful reference to further explore a model that can be used for a relatively rapid and reliable estimation of dietary Cd exposure for specific regions prior to crop harvest. Environ Toxicol Chem 2021;40:2923-2934. © 2021 SETAC.

The Agonists of Peroxisome Proliferator-Activated Receptor-γ for Liver Fibrosis.

Liver fibrosis is a common link in the transformation of acute and chronic liver diseases to cirrhosis. It is of great clinical significance to study the factors associated with the induction of liver fibrosis and elucidate the method of reversal. Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear transcription factors that can be activated by peroxisome proliferators. PPARs play an important role in fibrosis of various organs, especially the liver, by regulating downstream targeted pathways, such as TGF-ß, MAPKs, and NF-κB p65. In recent years, the development and screening of PPAR-γ ligands have become a focus of research. The PPAR-γ ligands include synthetic hypolipidemic and antidiabetic drugs. In addition, microRNAs, lncRNAs, circRNAs and nano new drugs have attracted research interest. In this paper, the research progress of PPAR-γ in the pathogenesis and treatment of liver fibrosis was discussed based on the relevant literature in recent years.

Current status of ctDNA in precision oncology for hepatocellular carcinoma.

The conventional method used to obtain a tumor biopsy for hepatocellular carcinoma (HCC) is invasive and does not evaluate dynamic cancer progression or assess tumor heterogeneity. It is thus imperative to create a novel non-invasive diagnostic technique for improvement in cancer screening, diagnosis, treatment selection, response assessment, and predicting prognosis for HCC. Circulating tumor DNA (ctDNA) is a non-invasive liquid biopsy method that reveals cancer-specific genetic and epigenetic aberrations. Owing to the development of technology in next-generation sequencing and PCR-based assays, the detection and quantification of ctDNA have greatly improved. In this publication, we provide an overview of current technologies used to detect ctDNA, the ctDNA markers utilized, and recent advances regarding the multiple clinical applications in the field of precision medicine for HCC.

Fenofibrate Ameliorates Hepatic Ischemia/Reperfusion Injury in Mice: Involvements of Apoptosis, Autophagy, and PPAR-α Activation.

Hepatic ischemia and reperfusion injury is characterized by hepatocyte apoptosis, impaired autophagy, and oxidative stress. Fenofibrate, a commonly used antilipidemic drug, has been verified to exert hepatic protective effects in other cells and animal models. The purpose of this study was to identify the function of fenofibrate on mouse hepatic IR injury and discuss the possible mechanisms. A segmental (70%) hepatic warm ischemia model was established in Balb/c mice. Serum and liver tissue samples were collected for detecting pathological changes at 2, 8, and 24 h after reperfusion, while fenofibrate (50 mg/kg, 100 mg/kg) was injected intraperitoneally 1 hour prior to surgery. Compared to the IR group, pretreatment of FF could reduce the inflammatory response and inhibit apoptosis and autophagy. Furthermore, fenofibrate can activate PPAR-α, which is associated with the phosphorylation of AMPK.

PPARγ/NF-κB and TGF-ß1/Smad pathway are involved in the anti-fibrotic effects of levo-tetrahydropalmatine on liver fibrosis.

Liver fibrosis is a necessary stage in the development of chronic liver diseases to liver cirrhosis. This study aims to investigate the anti-fibrotic effects of levo-tetrahydropalmatine (L-THP) on hepatic fibrosis in mice and cell models and its underlying mechanisms. Two mouse hepatic fibrosis models were generated in male C57 mice by intraperitoneal injection of carbon tetrachloride (CCl4) for 2 months and bile duct ligation (BDL) for 14 days. Levo-tetrahydropalmatine was administered orally at doses of 20 and 40 mg/kg. An activated LX2 cell model induced by TGF-ß1 was also generated. The results showed that levo-tetrahydropalmatine alleviated liver fibrosis by inhibiting the formation of extracellular matrix (ECM) and regulating the balance between TIMP1 and MMP2 in the two mice liver fibrosis models and cell model. Levo-tetrahydropalmatine inhibited activation and autophagy of hepatic stellate cells (HSCs) by modulating PPARγ/NF-κB and TGF-ß1/Smad pathway in vivo and in vitro. In conclusion, levo-tetrahydropalmatine attenuated liver fibrosis by inhibiting ECM deposition and HSCs autophagy via modulation of PPARγ/NF-κB and TGF-ß1/Smad pathway.

Crosstalk between PPARs and gut microbiota in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disorder in both China and worldwide. It ranges from simple steatosis and progresses over time to nonalcoholic steatohepatitis (NASH), advanced liver fibrosis, cirrhosis, or hepatocellular carcinoma(HCC). Furthermore, NAFLD and its complications impose a huge health burden to society. The microbiota is widely connected and plays an active role in human physiology and pathology, and it is a hidden 'organ' in determining the state of the host, in terms of homeostasis, or disease. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptorsuperfamily and can regulate multiple pathways involved in metabolism, and serve as effective targets forthe treatment of many types of metabolic syndromes, including NAFLD. The purpose of this review is to integrate related articles on gut microbiota, PPARs and NAFLD, and present a balanced overview on how the microbiota can possibly influence the development of NAFLD through PPARs.