Integrative analysis reveals that SLC38A1 promotes hepatocellular carcinoma development via PI3K/AKT/mTOR signaling via glutamine mediated energy metabolism.

Although hepatocellular carcinoma (HCC) is rather frequent, little is known about the molecular pathways underlying its development, progression, and prognosis. In the current study, we comprehensively analyzed the deferentially expressed metabolism-related genes (MRGs) in HCC based on TCGA datasets attempting to discover the potentially prognostic genes in HCC. The up-regulated MRGs were further subjected to analyze their prognostic values and protein expressions. Twenty-seven genes were identified because their high expressions were significant in OS, PFS, DFS, DSS, and HCC tumor samples. They were then used for GO, KEGG, methylation, genetics changes, immune infiltration analyses. Moreover, we established a prognostic model in HCC using univariate assays and LASSO regression based on these MRGs. Additionally, we also found that SLC38A1, an amino acid metabolism closely related transporter, was a potential prognostic gene in HCC, and its function in HCC was further studied using experiments. We found that the knockdown of SLC38A1 notably suppressed the growth and migration of HCC cells. Further studies revealed that SLC38A1 modulated the development of HCC cells by regulating PI3K/AKT/mTOR signaling via glutamine mediated energy metabolism. In conclusion, this study identified the potentially prognostic MRGs in HCC and uncovered that SLC38A1 regulated HCC development and progression by regulating PI3K/AKT/mTOR signaling via glutamine mediated energy metabolism, which might provide a novel marker and potential therapeutic target in HCC.

High-intensity focused ultrasound versus transarterial chemoembolization for hepatocellular carcinoma: a meta-analysis.

PURPOSE: The application of high-intensity focused ultrasound (HIFU) in hepatocellular carcinoma (HCC) was promising. However, whether the effect of HIFU is comparable with that of transarterial chemoembolization (TACE) has not been determined. MATERIALS AND METHODS: PubMed, Embase, Cochrane Library, Web of Science, WanFang Data, CqVip, CNKI, and CBM databases were searched for randomized controlled trials (RCTs), cohort studies, and case-control studies. The methodological quality of each study was evaluated. When there is no statistical heterogeneity, the fixed effect model would be used to merge data. Otherwise, the random effect model would be utilized. Sensitivity analyses were conducted by excluding one study each time. Subgroup analyses were conducted based on age, sex, tumor number, relative number of the patients with Child-Pugh C grade in each group, the percentage of patients with Child-Pugh C grade in the whole study, and tumor load. Publication bias was evaluated by Egger's test and Begg's test. RESULTS: Six cohort studies including 188 patients from HIFU group and 224 patients from TACE group were obtained for further analysis. The meta-analysis suggested HIFU and TACE showed no differences in postoperative 1-year overall survival (OS) rate, tumor response (including complete response, partial response, stable disease, and progressive disease), and postoperative complications. Moreover, compared with TACE, HIFU showed higher postoperative 6-month and 2-year OS rates. Subgroup analyses, meta regression analysis and sensitivity analyses indicated the findings above were reliable. Additionally, no potential publication bias was detected. CONCLUSION: For HCC, when compared with TACE, HIFU might show comparable safety but better effect. Considering the limitations of current studies, more well-designed studies are needed to validate our conclusion.

Effectiveness and safety of focused ultrasound ablation surgery compared with radiofrequency ablation in primary hepatocellular carcinoma treatment: a meta-analysis.

BACKGROUND: The effectiveness and safety of focused ultrasound ablation surgery (FUAS) for primary hepatocellular carcinoma (HCC) treatment has not been fully evaluated. This study analyzed the effectiveness and safety of FUAS compared to radiofrequency ablation (RFA). METHODS: Studies published before November 1, 2020, in the following databases were analyzed: PubMed, Embase, Cochrane Library, Web of Science, Wanfang Data, CqVip, China National Knowledge Infrastructure (CNKI), and Chinese Biomedical (CBM) database. All publications were reviewed independently by two authors. Both randomized controlled trials (RCTs) and cohort studies examining the effectiveness and safety of FUAS and RFA were considered. RCTs and cohort studies' methodological quality were evaluated using the Cochrane collaboration tool and the Newcastle-Ottawa Scale, respectively. RESULTS: A total of 6,597 records were identified, from which 3 cohort studies were selected for quantitative synthesis. All studies had relatively high methodological quality. The meta-analysis indicated that FUAS and RFA had comparable 3-month overall survival (OS) rates [risk ratio (RR): 0.99, 95% confidence interval (CI): 0.86 to 1.14], 6-month OS rates (RR: 1.03, 95% CI: 0.82 to 1.29), and 1-year OS rates (RR: 0.96, 95% CI: 0.84 to 1.11). Also, individual studies reported that the tumor response (reflected by tumor response and tumor ablation rate) and posttreatment complications were comparable between patients treated with FUAS and patients treated with RFA. Due to the limited number of studies reporting tumor response and posttreatment complications, further meta-analyses could not be conducted. DISCUSSION: FUAS and RFA were comparable in terms of effectiveness and safety in the treatment of primary HCC. However, current evidence is limited, and more prospective RCTs are warranted to confirm these findings.

Kupffer Cell-Derived TNF-α Triggers the Apoptosis of Hepatic Stellate Cells through TNF-R1/Caspase 8 due to ER Stress.

PURPOSE: To investigate the roles of ER stress in Kupffer cells (KCs) and KC-derived TNF-α in the apoptosis of hepatic stellate cells (HSCs). METHODS: A rat model of liver fibrosis was established. Liver and blood serum samples were collected. Liver function assays, Masson staining, Sirius Red staining, ELISAs, and TUNEL and immunohistochemical staining were performed. Liver function, liver fibrosis, KC phenotype, inflammatory factors, and number of active HSCs were investigated. KCs were isolated, treated with tunicamycin, and then, cocultured with primary hepatic stellate cells. ELISAs, immunofluorescence staining, flow cytometry, and Western blotting were performed. KC phenotype, inflammatory factors, HSC apoptosis, and TNF-R1/caspase 8 pathway activity were examined. RESULT: s. ER stress in KCs reduced the levels of liver function markers, reduced the degree of liver fibrosis, and increased the number of KCs with the M1 phenotype and the expression of TNF-α. The increase in KC-derived TNF-α reduced the number of active HSCs and increased the activity of TNF-R1/caspase 8. Furthermore, ER stress in KCs promoted the polarization of KCs towards the M1 phenotype and increased the expression of TNF-α. The increase in KC-derived TNF-α triggered the apoptosis of HSCs and the activation of TNF-R1/caspase 8 in vitro, which was consistent with the in vivo results. CONCLUSION: ER stress in KCs promotes the polarization of these cells towards the M1 phenotype and increases the expression of TNF-α. Then, the increase in KC-derived TNF-α triggers the apoptosis of HSCs through TNF-R1/caspase 8.

Retroperitoneal versus open intraperitoneal necrosectomy in step-up therapy for infected necrotizing pancreatitis: A meta-analysis.

BACKGROUND: Step-up therapy is the recommended therapy for infected necrotizing pancreatitis (INP). However, the most appropriate secondary therapy for use after initial drainage has not been fully determined. This meta-analysis was designed to evaluate the efficacy and safety of retroperitoneal versus open intraperitoneal necrosectomy as part of a step-up strategy for INP. MATERIALS AND METHODS: Eight online databases were searched for randomized controlled trials (RCTs) and cohorts comparing retroperitoneal and open intraperitoneal step-up approaches for treating INP. The data was pooled with a random-effects model. RESULTS: A total of 21 controlled studies (one RCT and twenty cohorts) and 2177 patients were included in this study. Our meta-analysis showed that the retroperitoneal group had a lower postoperative complication rate [risk ratio (RR) = 0.575, 95% confidence interval (CI) = 0.459 to 0.719, P < 0.001], lower postoperative mortality (RR = 0.525, 95% CI = 0.430 to 0.642, P < 0.001), higher technical success rate (RR = 1.313, 95% CI = 1.017 to 1.694, P = 0.037), similar surgical reintervention rate (RR = 0.930, 95% CI = 0.783 to 1.106, P = 0.411), shorter operative time [standardized mean difference (SMD) = -2.402, 95% CI = -3.642 to -1.161, P < 0.001], and shorter hospital stay (SMD = -2.034, 95% CI = -3.041 to -1.026, P < 0.001) than the open group. These results were supported by a subgroup analysis. CONCLUSION: For treating INP, the retroperitoneal approach is safer and more effective than the open intraperitoneal approach.

Investigation for role of tissue factor and blood coagulation system in severe acute pancreatitis and associated liver injury.

This study aims to investigate the molecular mechanisms underlying the pathogenesis of severe acute pancreatitis (SAP) and SAP-associated liver injury, we performed an association analysis of the functions of tissue factor (TF) and blood coagulation system in both SAP patients and mouse SAP model. Our results showed that serum TF and tissue factor-microparticle (TF-MP) levels were highly up-regulated in both SAP patients and SAP mouse model, which was accompanied by the dysfunction of blood coagulation system. Besides, TF expression was also highly up-regulated in the Kupffer cells (KCs) of SAP mouse model. After inhibiting KCs in SAP mouse model, the amelioration of blood coagulation system functions was associated with the decrease in serum TF and TF-MPs levels, and the reduction of SAP-associated liver injury was associated with the decrease of TF expression in KCs. In conclusion, the dis-regulated TF expression and associated dysfunction of blood coagulation system are critical factors for the pathogenesis of SAP and SAP-associated liver injury. TF may serve as a potential and effective target for treating SAP and SAP-associated liver injury.

Bone marrow stromal cells attenuate LPS-induced mouse acute liver injury via the prostaglandin E 2-dependent repression of the NLRP3 inflammasome in Kupffer cells.

The nucleotide-binding and oligomerization domain-like receptor 3 (NLRP3) inflammasome participates in the pathogenesis of acute liver injury during sepsis. Bone marrow mesenchymal stem cells (BMSCs) attenuate sepsis through prostaglandin E 2 (PGE2) by increasing the interleukin-10 (IL-10) production of macrophages; moreover, NLRP3 inflammasome assembly is effectively regulated by IL-10 during infection. Whether BMSCs have an effect on the activation of the NLRP3 inflammasome and its underlying mechanism is unclear. Administering of BMSCs to mice or KCs after LPS stimulating have improved liver function and reduced activation of NLRP3 inflammasome in KCs. The beneficial effect of BMSCs was enhanced by over-expression of PGE2 and eliminated by silence of PGE2. Additionally, The IL-10 levels in the serum and supernatant were increased by given BMSCs and further increase by PGE2 over-expressed BMSCs, but decreased markedly by PGE2 silenced BMSCs. Furthermore, extracellular signal-regulated kinase 1 (ERK1) inhibitor reduced IL-10 production in KCs and blocked the inhibitory effect of PGE2 on the activation of the NLRP3 inflammasome. Our data reveal a novel mechanism of BMSC-mediated suppression of the activation of KCs through the secretion of PGE2 by BMSCs, which promotes KCs to secrete IL-10, leading to the inhibition of the NLRP3 inflammasome in KCs.

LXRα represses LPS-induced inflammatory responses by competing with IRF3 for GRIP1 in Kupffer cells.

Liver X receptors (LXRs) in the nucleus play important roles in lipid metabolism and inflammation. The mechanism of LXR regulation of the LPS-induced Toll-like receptor 4 (TLR4) inflammatory signaling pathway remains to be elucidated. C57/BL6 mice were randomly divided into four groups: control, T0901317 (a LXRs agonist), LPS and T0901317+LPS. Additionally, Kupffer cells isolated from male C57/BL6 mice were divided into the same four groups. A decreased amount of inflammatory cells infiltrated the portal areas and the hepatic sinusoids in the livers of mice in the T0901317+LPS group than in those of mice in the LPS group. In the T0901317+LPS group, the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and tumor necrosis factor alpha (TNF-α) were lower, while the serum level of interleukin-10 (IL-10) was higher. In vitro, Kupffer cells pretreated with T0901317 for 24h presented reduced TNF-α, interferon-beta (IFN-ß) and interleukin-1 beta (IL-1ß) levels, while the IL-10 level increased; however, the mRNA and protein expression levels of interferon regulatory factor 3 (IRF3) and glucocorticoid receptor-interacting protein 1 (GRIP1) were not significantly reduced. The co-IP data illustrated that LXRα bound to GRIP1 specifically in the T0901317+LPS group, while less IRF3 was bound to GRIP1 in the T0901317+LPS group than in the LPS group. Furthermore, the DNA-binding activity of NF-κB was decreased by pretreating Kupffer cells with T0901317 for 24h. These results suggest that activated LXRα competes with IRF3 for GRIP1 binding, thus repressing IRF3 and NF-κB transcriptional activity and inhibiting the inflammatory response initiated by LPS in Kupffer cells.

[Effect of the liver X receptor agonist on LPS-induced inflammatory response associated factor IRAK-4 and NF-kappaB].

AIM: To investigate the effect of the activated LXR on the expression of IRAK-4 and NF-kappaB in the inflammatory response which was induced by LPS in Kupffer cells. METHODS: The Kuppfer cells were isolated from male Kunming mice by collagen perfusion in situ. These cells were divided into four groups: normal control group, LPS treatment group, LXR agonist T0901317 treatment group, LPS and T0901317 combined treatment group. The expression of LXR, IRAK-4 and NF-kappaB gene and their protein levels were detected by real time-PCR and Western blot, and the activity of NF-kappaB was observed by EMSA. RESULTS: The levels of LXR mRNA and protein reached the highest in T0901317 group but the lowest in LPS group. The levels of IRAK4 and NF-kappaB mRNA and protein in the combined-treatment group were evidently lower than those in LPS group. The activity of NF-kappaB reached the highest in LPS group but it was lower in the combined-treatment group and T0901317 group. CONCLUSION: LXR agonists can effectively up-regulate the level of LXR gene and protein and down-regulate the levels of IRAK4 and NF-kappaB mRNA and protein expression. They can also inhibit activity of NF-kappaB.

[Influence of continuous high-volume hemofiltration on IRAK-4 protein expression in severe acute pancreatitis].

OBJECTIVE: To investigate the influence of continuous high-volume hemofiltration (CHVHF) on interleukin 1 receptor-associated kinase-4 (IRAK-4) and tumor necrosis factor-alpha (TNF-alpha) levels in patients with severe acute pancreatitis (SAP). METHODS: Forty-one patients with SAP were randomly divided into two groups to receive treatment with CHVHF plus conventional therapy (21 patients) and conventional therapy only (20 patients). Venous blood samples were taken before and 12, 24, and 72 h after the treatment for evaluation of APACHE II scores. The mRNA and protein levels of IRAK-4 in the monocytes were determined by real-time PCR and Western blotting, respectively, and serum TNF-alpha levels was detected using enzyme-linked immunosorbent assay (ELISA). RESULTS: Among the 21 patients receiving CHVHF, 18 survived and 3 died, and in the conventional therapy group, death occurred in 5 cases. In the surviving patients of CHVHF group, the APACHE II scores, IRAK-4 mRNA and protein levels and TNF-alpha levels were all significantly lowered after the treatment, and these indices were also significantly lower than those in the conventional group after treatment (P<0.05). CONCLUSION: CHVHF is effective in reducing monocyte IRAK-4 levels and serum TNF-alpha level in SPA patients, and thus alleviates the symptoms and improves the prognosis of SAP, possibly by reducing the level of the activators that induce monocyte activation via the Toll-like receptor.