FARSB Facilitates Hepatocellular Carcinoma Progression by Activating the mTORC1 Signaling Pathway.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality. Human phenylalanine tRNA synthetase (PheRS) comprises two α catalytic subunits encoded by the FARSA gene and two ß regulatory subunits encoded by the FARSB gene. FARSB is a potential oncogene, but no experimental data show the relationship between FARSB and HCC progression. We found that the high expression of FARSB in liver cancer is closely related to patients' low survival and poor prognosis. In liver cancer cells, the mRNA and protein expression levels of FARSB are increased and promote cell proliferation and migration. Mechanistically, FARSB activates the mTOR complex 1 (mTORC1) signaling pathway by binding to the component Raptor of the mTORC1 complex to play a role in promoting cancer. In addition, we found that FARSB can inhibit erastin-induced ferroptosis by regulating the mTOR signaling pathway, which may be another mechanism by which FARSB promotes HCC progression. In summary, FARSB promotes HCC progression and is associated with the poor prognosis of patients. FARSB is expected to be a biomarker for early screening and treatment of HCC.

Nuclear respiratory factor 1 drives hepatocellular carcinoma progression by activating LPCAT1-ERK1/2-CREB axis.

BACKGROUND: Nuclear respiratory factor 1 (NRF1) is a transcription factor that participates in several kinds of tumor, but its role in hepatocellular carcinoma (HCC) remains elusive. This study aims to explore the role of NRF1 in HCC progression and investigate the underlying mechanisms. RESULTS: NRF1 was overexpressed and hyperactive in HCC tissue and cell lines and high expression of NRF1 indicated unfavorable prognosis of HCC patients. NRF1 promoted proliferation, migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, NRF1 activated ERK1/2-CREB signaling pathway by transactivating lysophosphatidylcholine acyltransferase 1 (LPCAT1), thus promoting cell cycle progression and epithelial mesenchymal transition (EMT) of HCC cells. Meanwhile, LPCAT1 upregulated the expression of NRF1 by activating ERK1/2-CREB signaling pathway, forming a positive feedback loop. CONCLUSIONS: NRF1 is overexpressed in HCC and promotes HCC progression by activating LPCAT1-ERK1/2-CREB axis. NRF1 is a promising therapeutic target for HCC patients.

Influence Mechanism of Osteopontin on Renal Injury in Patients with hereditary hypercalcemia by Enzyme-linked immunosorbent assay.

This study was to investigate the role and mechanism of osteopontin(OPN) in renal injury in patients with inherited hypercalciuria-bearing urinary calculi. The genetic hypercalcemia urolithiasis (GHS) rat model was established, and GHS rats were set as the experimental group (12 cases) and normal SD rats as the control group (12 cases). OPN and calcification levels in the kidney tissues of the two groups were compared by ELISA. According to calcium intervention or not, GHS rats were rolled into an intervention group (the intervention group was divided into 0.2g/L group, 0.4g/L group, and 0.7g/L group regarding the calcium injection dose, each group with 2 cases) and a normal group, each group with 6 cases. The levels of OPN and kidney injury in the two groups after 5h, 20h, and 40h were compared. Seventy patients with idiopathic hypercalciuria (IH) were rolled into a control group (injected with normal saline) and an observation group (injected with saline and OPN). The levels of OPN and calcification in kidney tissue of GHS rats in the experimental group were higher than those in the control group (P<0.05). The OPN level of GHS rats in the 0.2g/L group, 0.4g/L group, and 0.7g/L group was higher than that in the intervention group, and the OPN level at 5h, 10h, and 20h showed an upward trend (P<0.05). The incidence of renal injury in the intervention group (100%) was higher than that in the non-intervention group (16.67%) (P<0.05). Clinical verification results showed that urinary calcium excretion of IH patients in the observation group significantly decreased at 6 and 12 days, with statistical significance (P<0.05). The high probability of overactivation of OPN was one of the pathogeneses of hypercalciuria and calcium-bearing urolithiasis. The results suggested that OPN was closely related to the formation of urinary calculi and may cause certain damage to the kidney, which may be a key step in the prevention and treatment of urinary calculi.

Alpha-ketoglutarate alleviates cadmium-induced inflammation by inhibiting the HIF1A-TNFAIP3 pathway in hepatocytes.

The threat to public health posed by rapidly increasing levels of cadmium (Cd) in the environment is receiving worldwide attention. Although, Cd is known to be absorbed into the body and causes non-negligible damage to the liver, the detailed mechanisms underlying its hepatoxicity are incompletely understood. In the present study, investigated the effect of TNFAIP3 and α-ketoglutarate (AKG) on Cd-induced liver inflammation and hepatocyte death. Male C57BL/6 mice were exposed to cadmium chloride (1.0 mg/kg) while being fed a diet with 2 % AKG for two weeks. We found that Cd induced hepatocyte injury and inflammatory infiltration. In addition, TNFAIP3 expression was inhibited in the liver tissues and cells of CdCl2-treated mice. Mouse hepatocyte-specific TNFAIP3 overexpression by tail vein injection of an adeno-associated virus (AAV) vector effectively alleviated Cd-induced hepatic necrosis and inflammation, which was mediated by the NF-κB signaling pathway. Notably, this inhibitory effect of TNFAIP3 on Cd-induced liver injury was dependent on AKG. Exogenous addition of AKG prevented Cd exposure-induced increases in serum ALT, AST and LDH levels, production of pro-inflammatory cytokines, activation of the NF-κB signaling pathway, and even significantly reduced Cd-induced oxidative stress and hepatocyte death. Mechanistically, AKG exerted its anti-inflammatory effect by promoting the hydroxylation and degradation of HIF1A to reduce its Cd-induced overexpression in vivo and in vitro, avoiding the inhibition of the TNFAIP3 promoter by HIF1A. Moreover, the protective effect of AKG was significantly weaker in Cd-treated primary hepatocytes transfected with HIF1A pcDNA. Overall, our results reveal a novel mechanism of Cd-induced hepatotoxicity.

PEDOT:PSS hydrogels with high conductivity and biocompatibility for in situ cell sensing.

Conducting polymer hydrogels, especially poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) hydrogels, show great promise in soft bioelectronics due to their high conductivity and the ability of electrical coupling with tissues for sensing and stimulation. However, it is challenging to solve the problem of poor biocompatibility of PEDOT:PSS hydrogels due to the existing harsh preparation methods with the use of toxic and harmful reagents. Herein, we report the synthesis of PEDOT:PSS hydrogels with positively charged conductive polymers as a cross-linker and the application of PEDOT:PSS hydrogels as in situ electrochemical sensors for living cells. The conductivities of PEDOT:PSS hydrogels prepared using this method without any toxic or harmful reagents can reach up to 3265 S m-1. The facile synthesis approach with a simple mixture of PEDOT:PSS aqueous solution and the monomers of conductive polymers at room temperature also enables the printability of PEDOT:PSS hydrogels to fabricate patterned electrodes. Moreover, all the proposed PEDOT:PSS hydrogels demonstrated good biocompatibility. The in situ electrochemical detection of dopamine secreted from PC12 cells cultured within PEDOT:PSS hydrogels suggests that our PEDOT:PSS hydrogels with high conductivity and biocompatibility offer great potential for the integration of biosensors within 3D cell culture.

Biodistribution and biocompatibility of glycyrrhetinic acid and galactose-modified chitosan nanoparticles as a novel targeting vehicle for hepatocellular carcinoma.

Aim: The dual-ligand glycyrrhetinic acid and galactose-modified chitosan nanoparticles were designed to further improve the targeting capability to hepatocellular carcinoma (HCC). Materials & methods: The dual-ligand glycyrrhetinic acid and galactose-modified chitosan nanoparticles were fabricated by using ionic gelation method and their characteristics have been measured. Furthermore, the biodistribution and biocompatibility of this targeting vehicle were investigated in vitro and in vivo, respectively. Results: The targeting vehicle was specifically internalized into hepatoma cells in vitro and accumulated into tumor tissue in vivo with high efficacy. Moreover, the vehicle did not induce inflammation reaction and affect morphologies and organ functions. Conclusion: The targeting accumulation in HCC tissue and great biocompatibility of the dual-ligand modified chitosan nanoparticles highlight the potential of delivering anticancer agents into HCC cells.

Detection of early-stage extrahepatic cholangiocarcinoma in patients with biliary strictures by soluble B7-H4 in the bile.

Increasing evidence has demonstrated that serum soluble B7-H4 (sB7-H4) is a useful tumour marker for cancer diagnosis and prognosis evaluation. Whether sB7-H4 is expressed in the bile of cholangiocarcinoma (CC) and is related to the progression of CC need to be explored. Bile sB7-H4 was obtained through endoscopic retrograde cholangiopancreatography (ERCP) from 213 patients with biliary strictures and detected was detected by a B7-H4 ELISA kit. Diagnostic value was compared among bile sB7-H4, CA19-9, CA12-5, CEA and ERCP-based cytological/tissue examination. Additionally, the correlations between the bile sB7-H4 concentration and the clinical characteristics of early-stage cholangiocarcinoma (ESCC) were studied. The bile sB7-H4 levels of patients with ESCC were significantly higher than in patients with benign biliary strictures (BBS) (P<0.001). The receiver operating characteristic (ROC) curves of CA19-9, CA12-5 and CEA were 0.713, 0.554 and 0.451, respectively, were significantly lower than the ROC curves of bile sB7-H4 (0.837), the sensitivity of ERCP-based cytological/tissue examination was 57.5% and 68.4%, which was lower than that of bile sB7-H4 (81.7%) at cut-off value. A high level of bile sB7-H4 in patients with ESCC was found to be correlated with vascular invasion (P<0.001), lymph node metastasis (P<0.001) and TNM stage (P=0.018), respectively. The overall survival rate (OS) of ESCC patients in the high sB7-H4 group was significantly lower than the OS of patients in the low sB7-H4 group (P=0.009). Bile sB7-H4 could serve as a valuable biomarker for patients with ESCC and high levels of bile sB7-H4 correlate with poor clinical outcomes.

miR-542-3p Appended Sorafenib/All-trans Retinoic Acid (ATRA)-Loaded Lipid Nanoparticles to Enhance the Anticancer Efficacy in Gastric Cancers.

PURPOSE: In this study, miR-542-3p appended SRF/ATRA-loaded solid lipid nanoparticle was successfully prepared and demonstrated for its therapeutic efficacy against gastric cancers. METHODS: The particles were nanosized and typically spherical in shape. In vitro release study showed that release of ATRA was significantly slower compared to that of SRF from the NPs. RESULTS: MTT assay showed that miR-542-3p have a strong inhibitory effect on the proliferation of MGC-803 cancer cells in a typical dose dependent manner. Nanocarrier encapsulation of SRF + ATRA induced a significantly higher cytotoxic effect compared to either individual drug or cocktail combinations indicating that the cellular uptake of different formulations was rate limiting factor in the therapeutic efficacy. Importantly, miR-542-3p-based miSRNP exhibited an extremely significant toxic effect compared to any other treated group. Importantly, miSRNP induced a significantly higher early (~55%) and late (~15%) apoptotic effect in gastric cancer cells. In vivo anticancer analysis results clearly suggest that nanoparticle encapsulation of combination of SRF and miRNA (with miRNA) will have greater antitumor efficacy in tumor mice. CONCLUSION: Overall, unique combination of miRNA coupled with SRF + ATRA in a lipid nanocarrier could be a promising therapeutic approach in gastric cancer treatment.

A new plasma biomarker enhance the clinical prediction of postoperative acute kidney injury in patients with hepatocellular carcinoma.

BACKGROUND: The ratio of serum γ-glutamyl transferase (GGT) to alanine aminotransferase (ALT) (GGT/ALT) is a marker for evaluating effects to antivirotic treatment and a helpful predictive factor for the prognosis of Child-Pugh A hepatocellular carcinoma (HCC) patients after surgery. The relationship between the incidence of postoperative acute kidney injury (AKI) and preoperative GGT/ALT is studied in hepatectomized hepatitis B- or C- associated HCC patients. METHODS: A total of 253 hepatitis B or C virus-related HCC patients undergoing hepatectomy between September 2012 and August 2016 at our hospital were included in the retrospective study. Serum ALT and GGT value were recorded, and the GGT/ALT was computed. AKI was defined that based on the "Kidney Disease Improving Global Outcomes (KDIGO) criteria". RESULTS: AKI was observed in 22 (8.7%) patients. Mean GGT/ALT of patients with AKI was significantly higher than in those without it (6.0 vs 2.1, P<0.001). Multivariate analysis revealed an increase in GGT/ALT as an independent risk factor for AKI in hepatitis B- or C- associated HCC patients, particularly in patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A staged HCC (odds ratio (OR) 1.400, P<0.001). Multivariate analysis showed that ALT (OR 0.966, P=0.044) was somewhat inversely associated with the incidence of AKI in hepatitis B- or C- associated HCC patients. The best cutoff point of GGT/ALT was 2.92. Multivariate analysis showed that preoperative GGT/ALT ≥2.92 predicted poor prognosis of postoperative AKI in patients with HCC after hepatectomy (odds ratio 17.697, P<0.001). After propensity score matching, preoperative GGT/ALT ≥2.92 remained an independent risk factor for AKI in HCC patients (OR 13.947, P=0.003). CONCLUSIONS: The GGT/ALT of patients with AKI was significantly higher than those without it. Evaluation of GGT/ALT before surgery can be a helpful predictive tool for postoperative AKI in hepatitis B- or C- associated HCC patients undergoing hepatectomy, particularly in patients with BCLC stage 0 or A staged HCC. Hepatitis B- or C- associated HCC patients with low ALT especially within the normal range may have a high risk of AKI. However, the reason remains to be elucidated.

Carvedilol for portal hypertension in cirrhosis: systematic review with meta-analysis.

OBJECTIVE: To assess the clinical and haemodynamic effects of carvedilol for patients with cirrhosis and portal hypertension. DESIGN: A systematic review and meta-analysis. DATA SOURCES: We searched PubMed, Cochrane library databases, EMBASE and the Science Citation Index Expanded through December 2015. Only randomised controlled trials (RCTs) were included. OUTCOME MEASURE: We calculated clinical outcomes (all-cause mortality, bleeding-related mortality, upper gastrointestinal bleeding) as well as haemodynamic outcomes (hepatic venous pressure (HVPG) reduction, haemodynamic response rate, post-treatment arterial blood pressure (mean arterial pressure; MAP) and adverse events). RESULTS: 12 RCTs were included. In 7 trials that looked at haemodynamic outcomes compared carvedilol versus propranolol, showing that carvedilol was associated with a greater reduction (%) of HVPG within 6 months (mean difference -8.49, 95% CI -12.36 to -4.63) without a greater reduction in MAP than propranolol. In 3 trials investigating differences in clinical outcomes between carvedilol versus endoscopic variceal band ligation (EVL), no significant differences in mortality or variceal bleeding were demonstrated. 1 trial compared clinical outcomes between carvedilol versus nadolol plus isosorbide-5-mononitrate (ISMN), and showed that no significant difference in mortality or bleeding had been found. 1 trial comparing carvedilol versus nebivolol showed a greater reduction in HVPG after 14 days follow-up in the carvedilol group. CONCLUSIONS: Carvedilol may be more effective in decreasing HVPG than propranolol or nebivolol and it may be as effective as EVL or nadolol plus ISMN in preventing variceal bleeding. However, the overall quality of evidence is low. Further large-scale randomised studies are required before we can make firm conclusions. TRIAL REGISTRATION NUMBER: CRD42015020542.

Tumour necrosis factor-α promotes liver ischaemia-reperfusion injury through the PGC-1α/Mfn2 pathway.

Tumour necrosis factor (TNF)-α has been considered to induce ischaemia-reperfusion injury (IRI) of liver which is characterized by energy dysmetabolism. Peroxisome proliferator-activated receptor-γ co-activator (PGC)-1α and mitofusion2 (Mfn2) are reported to be involved in the regulation of mitochondrial function. However, whether PGC-1α and Mfn2 form a pathway that mediates liver IRI, and if so, what the underlying involvement is in that pathway remain unclear. In this study, L02 cells administered recombinant human TNF-α had increased TNF-α levels and resulted in down-regulation of PGC-1α and Mfn2 in a rat liver IRI model. This was associated with hepatic mitochondrial swelling, decreased adenosine triphosphate (ATP) production, and increased levels of reactive oxygen species (ROS) and alanine aminotransferase (ALT) activity as well as cell apoptosis. Inhibition of TNF-α by neutralizing antibody reversed PGC-1α and Mfn2 expression, and decreased hepatic injury and cell apoptosis both in cell culture and in animals. Treatment by rosiglitazone sustained PGC-1α and Mfn2 expression both in IR livers, and L02 cells treated with TNF-α as indicated by increased hepatic mitochondrial integrity and ATP production, reduced ROS and ALT activity as well as decreased cell apoptosis. Overexpression of Mfn2 by lentiviral-Mfn2 transfection decreased hepatic injury in IR livers and L02 cells treated with TNF-α. However, there was no up-regulation of PGC-1α. These findings suggest that PGC-1α and Mfn2 constitute a regulatory pathway, and play a critical role in TNF-α-induced hepatic IRI. Inhibition of the TNF-α or PGC-1α/Mfn2 pathways may represent novel therapeutic interventions for hepatic IRI.