Steatohepatitis alters lymphocytes cytotoxicity and localization, accelerating colorectal liver metastases.

Expanding the liver exposome: Should hepatologists care about air pollution?

Long-term exposure to ambient PM2.5 and its constituents is associated with MAFLD

This study aimed to explore the role of plasma methylated SEPT9 (mSEPT9) in predicting liver metastasis (LM) in colorectal cancer (CRC) patients. The clinicopathological information of 115 consecutive CRC patients were collected. The differences of clinical characteristics and several biomarkers between CRC patients with LM and those with non-liver metastasis (NM) were analyzed. Multivariate logistic regression analysis was used to identify the risk factors for predicting LM in CRC patients. Receiver operating characteristic curve (ROC) analysis was applied to investigate the sensitivity and specificity of potential biomarkers in indicating the presence of LM in CRC. Compared with the CRC without LM, the levels of plasma mSEPT9 and carcinoembryonic antigen (CEA) were significantly increased in CRC with LM. Multivariate logistic regression analysis showed that plasma mSEPT9 was an independent risk factor for predicting LM in CRC. ROC curves showed that mSEPT9 and CEA could efficiently distinguish LM from NM in CRC. The area under the curve (AUC) of mSEPT9 was 0.850, which was slightly higher than that of CEA (0.842). The optimal cut-off value of mSEPT9 was 35.09 with a sensitivity of 81.82% and a specificity of 73.33%, both similar with that of CEA (sensitivity 87.27% and specificity 75.00%). In addition, the combination of mSEPT9 and CEA had a higher specificity than CEA alone (81.70% Vs 75.00%). Our findings suggest, for the first time, that plasma mSEPT9 might serve as a potential biomarker to predict LM in CRC, which deserves further in-depth study.

The tumor-derived factors involved in the expansion and accumulation of myeloid-derived suppressor cells (MDSCs) in metastatic dissemination of colorectal cancer (CRC) to the liver has not been studied. Immunohistochemistry was used to detect sphingosine-1-phosphate receptor 1 (S1PR1) and signal transducer and activator of transcription-3 (STAT3) in human colorectal tumors. IL-6 and interferon-γ were detected by enzyme-linked immunosorbent assay (ELISA). Tumor growth, invasion, and migration were evaluated by MTT, transwell, and wound healing assays, respectively. Subcutaneous tumor-bearing and CRC liver metastasis (CRLM) nude mouse models were constructed. The percentage of MDSCs was measured using multicolor flow cytometry. Western blot assay was used to evaluate S1PR1 and p-STAT3 expression in MDSCs after separation from the liver and tumor by magnetic antibody. T-cell suppression assay was detected by carboxyfluorescein succinimidyl ester (CFSE). Aberrant co-expressed S1PR1 and p-STAT3 was correlated with metachronous liver metastasis and poor prognosis in CRC. A mutual activation loop between S1PR1 and STAT3 can enhance CRC cell proliferation, migration, and invasion in vitro and in vivo. The expression of p-STAT3 and its downstream proteins can be regulated by S1PR1. p-STAT3 was the dependent signaling pathway of S1PR1 in the promotion of cell growth and liver metastasis in CRC. The level of IL-6 and the associated MDSCs stimulated by the S1PR1–STAT3 correlated with the number of liver metastatic nodes in the CRLM mouse models and patients. Increased CD14+HLA-DR−/low MDSCs from CRLM patients inhibited autologous T-cell proliferation and predict poor prognosis. The S1PR1–STAT3–IL-6–MDSCs axis operates in both tumor cells and MDSCs involved in the promotion of growth and liver metastasis in CRC. MDSCs induced by S1PR1–STAT3 in CRC cells formed the premetastatic niche in the liver can promote organ-specific metastasis.

目的 探讨结直肠癌肝转移患者血清中 CD44和 CD54含量与结直肠癌肝转移发生发展的关系,寻找一个稳定的早期诊断结直肠癌肝转移的生物学指标.方法应用酶联免疫吸附测定方法( ELISA)检测 38例结直肠癌和 21例结直肠癌肝转移患者以及 40例健康成人(正常对照组)的血清 CD44和 CD54含量, 并比较血清中 CD44和 CD54含量在治疗前后的变化.结果结直肠癌肝转移组和结直肠癌组血清中 CD44和 CD54含量明显高于正常对照组,且结直肠癌肝转移组较结直肠癌组含量也明显增高.结直肠癌肝转移组和结直肠癌组治疗后的血清 CD44和 CD54含量比治疗前下降.结论 CD44和 CD54可以作为临床早期诊断结直肠癌肝转移的生物学指标,同时也可以作为监测结直肠癌和结直肠癌肝转移预后的客观指标.

Aberrant expression of musashi2 (MSI‐2) has been detected in several malignancies. However, its role in the progression of colorectal cancer (CRC) remains unknown. Our study was designed to investigate the expression and prognostic significance of MSI‐2 protein in patients with colorectal cancer. The expression of MSI‐2 was detected in 164 patients’ colorectal cancer and control specimens by the tissue microarray technique and immunohistochemical staining. The correlations between MSI‐2 expression and clinicopathological variables including overall survival were analyzed. The prognostic value of liver metastasis is evaluated by logistic regression and receiver operating characteristic (ROC) analysis. MSI‐2 was highly expressed in 32.9% (54/164) of the colorectal cancer. Overexpression of MSI‐2 was associated with depth of invasion, lymph node metastasis, distant metastasis, liver metastasis, Tumor Node Metastasis (TNM) clinical stage, and Carcinoembryonicantigen (CEA) level (P = 0.040, 0.014, <0.001, <0.001, 0.003, and 0.002, respectively). In the Cox multivariate test, MSI‐2 overexpression, lymph node metastasis, and distant metastasis were found to be the independent prognostic factors (P = 0.027, 0.010, and 0.001, respectively). Further logistic regression suggested that TNM stage and MSI‐2 high expression were related to liver metastasis in colorectal cancer patients. Conclusively, our study indicates that MSI‐2 overexpression is associated with an unfavorable prognosis and may be a potential biomarker for liver metastasis in colorectal cancer patients.

To explore the associations between cuprotosis-related genes (CRGs) across different stages of liver disease in metabolic dysfunction-associated fatty liver disease (MAFLD), including hepatocellular carcinoma (HCC). We analysed several bulk RNA sequencing datasets from patients with MAFLD (n = 331) and MAFLD-related HCC (n = 271) and two MAFLD single-cell RNA sequencing datasets. To investigate the associations between CRGs and MAFLD, we performed differential correlation, logistic regression and functional enrichment analyses. We also validated the findings in an independent Wenzhou PERSONS cohort of MAFLD patients (n = 656) used for a genome-wide association study (GWAS). GLS, GCSH and ATP7B genes showed significant differences across the MAFLD spectrum and were significantly associated with liver fibrosis stages. GLS was closely associated with fibrosis stages in patients with MAFLD and those with MAFLD-related HCC. GLS is predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction-associated fatty liver to metabolic-associated steatohepatitis, GLS expression in T cells decreased. GWAS revealed that multiple single nucleotide polymorphisms in GLS were associated with clinical indicators of MAFLD. GLS may contribute to liver inflammation and fibrosis in MAFLD mainly through cuprotosis and T-cell activation, promoting the progression of MAFLD to HCC. These findings suggest that cuprotosis may play a role in MAFLD progression, potentially providing new insights into MAFLD pathogenesis.

Metabolic dysfunction associated fatty liver disease (MAFLD) is a leading cause of irreversible liver fibrosis and finally liver cancer. Imperatorin was reported to be effective for liver injury and fibrosis, but its effects and mechanisms on MAFLD remain unidentified. The high fat diet (HFD)-induced MAFLD model in the mice and palmitic acid-induced primary mouse hepatocytes were introduced to investigate the effects of imperatorin on lipid metabolism and inflammation. Molecular docking technique, cellular thermal shift assay and surface plasmon resonance (SPR) were performed to confirm the targeting of imperatorin on suppressor of variegation 3-9 homologue 1 (Suv39h1). RNA-sequencing was used to screen the downstream genes affected by Suv39h1 overexpression. The functional relationship between Suv39h1 and its downstream genes of fatty acid-binding proteins (Fabps) was elucidated by CHIP, DNA Pull Down and dual-luciferase reporter assays. Point mutation and knockdown of Set domain of Suv39h1 in palmitic acid-stimulated AML12 cells and HFD mice were adopted to confirm the function of Set domain in MAFLD. Imperatorin could delay MAFLD by affecting lipid metabolism, inflammation and insulin resistance. Knockdown of Suv39h1, the target of imperatorin, weakened the therapeutic effects of imperatorin on MAFLD. Knockdown of Fabps and choline/ethanolamine phosphotransferase 1 (Cept1), the downstream of Suv39h1, could alleviate the disorder of lipid metabolism. Histone methylation modification of Fabppromoters was mediated by Suv39h1. Knockdown of Set domain of Suv39h1 could increase the protein expression of Fabps and aggravate the progression of MAFLD. Imperatorin ameliorates MAFLD through modulating Suv39h1/Fabps/Cept1 signalling pathway.

Gut microbiota-based metabolism contributes to the protection of pseudolaric acid B against MAFLD.

Baicalin ameliorates high-fat diet induced MAFLD by inhibiting ERK/PPARγ/CD36 pathway.

Multi-target regulation by artemether in MAFLD through EGFR/HSP90 pathways.

Steatosis drives monocyte-derived macrophage accumulation in human metabolic dysfunction-associated fatty liver disease

n - 3 polyunsaturated fatty acids mediate hyodeoxycholic acid-FXR signaling to ameliorate metabolic dysfunction-associated fatty liver disease.

Asperuloside activates hepatic NRF2 signaling to stimulate mitochondrial metabolism and restore lipid homeostasis in high fat diet-induced MAFLD

Methylation of circulating free DNA (CfDNA) has emerged as an efficient marker of tumor screening and prognostics. However, no efficient methylation marker has been developed for monitoring liver metastasis (LM) in colorectal cancer (CRC). Utilizing methylome profiling and bisulfite sequencing polymerase chain reaction of paired primary and LM sites, significantly increased methylation of TCHH was identified in the process of LM in CRC in the present study. Methylight analysis of TCHH methylation in CfDNA displayed a promisingly discriminative power between CRC with and without LM. Besides, significant coefficient of TCHH methylation and LM tumor volume was also validated. Together, these results indicated the potential of TCHH methylation in CfDNA as a monitoring marker of LM in CRC.