The liver is the commonest site of distant metastasis of colorectal cancer and nearly half of the patients with colorectal cancer ultimately develop liver involved during the course of their diseases. Surgery is the only therapy that offers the possibility of cure for patients with hepatic metastatic diseases. Five-year survival rates after resection of all detectable liver metastases can be up to 40 %. Unfortunately, only 25 % of patients with colorectal liver metastases are candidates for liver resection, while the others are not amenable to surgical resection. Regional therapies such as radiofrequency ablation and cryotherapy may be offered to patients with isolated unresectable metastases but no extrahepatic diseases. Hepatic artery catheter chemotherapy and chemoembolization and portal vein embolization are often used for the patients with extensive liver metastases but without extrahepatic diseases, which are not suitable for regional ablation. For the patients with metastatic colorectal cancer beyond the liver, systemic chemotherapy is a more appropriate choice. Immunotherapy is also a good option when other therapies are used in combination to enhance the efficacy. Selective internal radiation therapy is a new radiation method which can be used in patients given other routine therapies without effects.
BackgroundHepatic ischemia-reperfusion injury (I/Ri) is a serious complication occurring during liver surgery that may lead to liver failure. Hepatic I/Ri induces formation of reactive oxygen species, hepatocyte apoptosis, and release of pro-inflammatory cytokines, which together causes liver damage and organ dysfunction. A potential strategy to alleviate hepatic I/Ri is to exploit the potent anti-inflammatory and cytoprotective effects of carbon monoxide (CO) by application of so-called CO-releasing molecules (CORMs). Here, we assessed whether CO released from CORM-2 protects against hepatic I/Ri in a rat model.MethodsForty male Wistar rats were randomly assigned into four groups (n = 10). Sham group underwent a sham operation and received saline. I/R group underwent hepatic I/R procedure by partial clamping of portal structures to the left and median lobes with a microvascular clip for 60 minutes, yielding ~70% hepatic ischemia and subsequently received saline. CORM-2 group underwent the same procedure and received 8 mg/kg of CORM-2 at time of reperfusion. iCORM-2 group underwent the same procedure and received iCORM-2 (8 mg/kg), which does not release CO. Therapeutic effects of CORM-2 on hepatic I/Ri was assessed by measuring serum damage markers AST and ALT, liver histology score, TUNEL-scoring of apoptotic cells, NFkB-activity in nuclear liver extracts, serum levels of pro-inflammatory cytokines TNF-α and IL-6, and hepatic neutrophil infiltration.ResultsA single systemic infusion with CORM-2 protected the liver from I/Ri as evidenced by a reduction in serum AST/ALT levels and an improved liver histology score. Treatment with CORM-2 also up-regulated expression of the anti-apoptotic protein Bcl-2, down-regulated caspase-3 activation, and significantly reduced the levels of apoptosis after I/Ri. Furthermore, treatment with CORM-2 significantly inhibited the activity of the pro-inflammatory transcription factor NF-κB as measured in nuclear extracts of liver homogenates. Moreover, CORM-2 treatment resulted in reduced serum levels of pro-inflammatory cytokines TNF-α and IL-6 and down-regulation of the adhesion molecule ICAM-1 in the endothelial cells of liver. In line with these findings, CORM-2 treatment reduced the accumulation of neutrophils in the liver upon I/Ri. Similar treatment with an inactive variant of CORM-2 (iCORM-2) did not have any beneficial effect on the extent of liver I/Ri.ConclusionsCORM-2 treatment at the time of reperfusion had several distinct beneficial effects on severity of hepatic I/Ri that may be of therapeutic value for the prevention of tissue damage as a result of I/Ri during hepatic surgery.
Background: The gut microbiota participates in the metabolism of substances and energy, promotes the development and maturation of the immune system, forms the mucosal barrier, and protects the host from pathogen attacks. Although the pathogenesis of cholesterol gallstones is still not clear, studies have suggested that gut microbiota dysbiosis plays an important role in their formation. Methods: Microbial DNA from faeces of normal control patients and those of patients with calculi was subjected to 16S rRNA gene sequencing to detect gene expression changes in intestinal microbes. ELISA kits were used to measure free bile acids, secondary bile acids and coprostanol according to the manufacturer's instructions. The relationship between flora and their metabolites was then analysed. Results: In the gallstone group, the diversity of intestinal bacteria and the abundances of certain phylogroups were significantly decreased (p < 0.05), especially Firmicutes (p < 0.05), the largest phylum represented by the gut microbiota. This study found an increase in free bile acids (p < 0.001) and secondary bile acids (p < 0.01) in the enterohepatic circulation. Bile salt hydrolase activity was not related to the abundances of BSH-active bacteria. 7adehydroxylating gut bacteria were significantly increased (p < 0.01), whereas cholesterol-lowering bacteria were significantly reduced (p < 0.05). The Ruminococcus gnavus group could be used as a biomarker to distinguish the gallstone group from the control group. Conclusion: We conclude that intestinal flora imbalance affects bile acid and cholesterol metabolism and is associated with gallstone formation.
Arsenic trioxide altered miRNA expression profile in HepG-2 cells. Among the altered miRNA, miR-29a seemed to take a role in the mechanism of arsenic trioxide in liver cancer therapy. The synergy effect between miR-29a and arsenic trioxide may offer this drug a new chance in cancer therapy by decreasing its dose and toxic side-effects.
Macrophage activation plays an important role in the inflammatory response in acute pancreatitis. In the present study, the activation of AR42J pancreatic acinar cells was induced by taurolithocholate treatment. The results showed that the culture medium from the activated AR42J cells significantly enhanced NFκB activation in the macrophages compared to that without taurolithocholate treatment. Additionally, the precipitates obtained from ultracentrifugation of the culture media that were rich in exosomes were markedly more potent in activating macrophages compared with the supernatant fraction lacking exosomes. The results indicated that the mediators carried by the exosomes played important roles in macrophage activation. Exosomal miRNAs were extracted and examined using microarrays. A total of 115 differentially expressed miRNAs were identified, and 30 showed upregulated expression, while 85 displayed downregulated expression. Target genes of the differentially expressed miRNAs were predicted using TargetScan, MiRanda, and PicTar software programs. The putative target genes were subjected to KEGG functional analysis. The functions of the target genes were primarily enriched in MAPK pathways. Specifically, the target genes regulated macrophage activation through the TRAF6-TAB2-TAK1-NIK/IKK-NFκB pathway. As the mediators of signal transduction, miRNAs and their predicted target mRNAs regulate every step in the MAPK pathway.
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