Inhibition of FoxO1 ameliorates hepatic steatosis and hepatitis in nonalcoholic steatohepatitis mice through regulation of gut microbiota.

OBJECTIVE: We aimed to investigate the role of forkhead box O1 (FoxO1) inhibitor AS1842856 (AS) in nonalcoholic steatohepatitis (NASH) mice and the potential mechanisms. METHODS: Mice were given methionine-choline-sufficient (MCS), or methionine- and choline-deficient (MCD) diet for 5 weeks, along with AS (60 mg/kg) or vehicle gavage treatment (0.2 mL/day). Body and liver weight, serum triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting glucose and insulin levels were measured. Liver macrophage infiltration and ileal ZO-1 protein expression were also detected. Interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α, sterol regulatory element binding protein (SREBP)-1c, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase), α-smooth muscle actin (SMA), recombinant collagen type III α1 (Col3a1), and connective tissue growth factor (Ctgf) expressions were measured. Stool samples were collected for 16S rDNA sequencing. RESULTS: Compared to the MCD group, AS attenuated liver weight, reduced serum TG, ALT, and AST levels, increased HDL-C levels, mitigated hepatic steatosis, decreased macrophage infiltration, and augmented ileal ZO-1 proteins in NASH mice. It also reduced the levels of IL-6, IL-1ß, and TNF-α, alongside with the Srebp-1c mRNA expression. However, no significant effects on Pepck, G6Pase, α-SMA, Col3a1, or Ctgf were observed. Furthermore, AS promoted diversity and altered gut microbiota composition in NASH mice, causing increased beneficial bacteria like Akkermansia muciniphila, Parabacteroides distasonis, and Prevotellamassilia, which were associated with metabolic functions. CONCLUSION: FoxO1 inhibitor AS ameliorated hepatic steatosis, inflammation, and intestinal dysbiosis in NASH mice, making it a potentially promising treatment for NASH.

Damage Effect of Amorphous Carbon Black Nanoparticle Aggregates on Model Phospholipid Membranes: Surface Charge, Exposure Concentration and Time Dependence.

Commercial nano-scale carbon blacks (CB) are being harnessed widely and may impose potentially hazardous effects because of their unique properties, especially if they have been modified to grow reactive functional groups on their surface. Cytotoxicity of CB has been well studied but the membrane damage mechanisms and role of surface modification are still open to debate. Negatively and positively charged giant unilamellar vesicles (GUVs) were prepared using three lipids as model cell membranes to examine the mechanistic damage of CB and MCB (modified by acidic potassium permanganate) aggregates. Optical images showed that both anionic CB and MCB disrupted the positively charged but not the negatively charged GUVs. This disruption deteriorated with the rise and extension of exposure concentration and time. Lipids extraction caused by CBNs (CB and MCB together are called CBNs) was found. MCB caused more severe disruption than CB. MCB was enveloped into vesicles through an endocytosis-like process at 120 mg/L. MCB mediated the gelation of GUVs, perhaps through C-O-P bonding bridges. The lower hydrodynamic diameter and more negative charges may have been responsible for the distinction effect of MCB over CB. The adhesion and bonding of CBNs to the membrane were favored by electrostatic interaction and the practical application of CBNs warrants more attention.

Combined toxicity of functionalized nano-carbon black and cadmium on Eisenia fetida coelomocytes: The role of adsorption.

Little is known about the potential threats of functionalized nano-carbon black (FNCB) combined with cadmium (Cd) to soil invertebrates. In this study, immunocompetent coelomocytes from Eisenia fetida are harnessed, and the joint cytotoxicity types of FNCB and Cd co-exposure are analyzed. The extracellular interaction mechanisms of FNCB and Cd were completely explored using adsorption kinetics and thermodynamics accompanied by isotherm batch experiments and Fourier infrared spectroscopy. The results indicated that functional amorphous carbon nanoparticles up to certain dose may injure cells due to their surface oxygen-containing groups. The MIXTOX model and the combination index suggested that the combined action of FNCB and Cd exhibited antagonism at the low dose/effect-level and synergism at the high dose/effect-level. FNCB decreased the intracellular free Cd2+ content at a low mixture dose, while it increased it at a high mixture dose. The adsorption of Cd on FNCB followed pseudo-second-kinetics and the Langmuir isotherm, hence better indicating a chemisorption, which was also supported by the activation energy (Ea = 36.6 kJ/mol), enthalpy change (ΔH = -98.4 kJ/mol), and functional group changes. Coordination binding should be responsible for the subsequent interaction of toxicity.

Effect of Nano-Carbon Black Surface Modification on Toxicity to Earthworm (Eisenia fetida) Using Filter Paper Contact and Avoidance Test.

Engineered nanomaterials (NMs) may enter the soil through various channels and pose potential harm to soil animals, especially those proactively applied for soil heavy metal remediation. Effects of nano-carbon black (CB) and surface modified carbon black (MCB) on catalase (CAT) activity and malondialdehyde (MDA) content in earthworms exposed on filter paper for 48 h were tested. Avoidance test was used to determine hazard of soil treated with 0.015% and 1.5% CB and MCB. Surface properties of NMs were also characterized. MCB has a significant effect on CAT activity at 70 and 1000 mg/L (1.1 and 15.7 µg/cm2), but has no impact on MDA content in earthworm. Strongly avoidance behavior of worms was also found in soil added 1.5% MCB. Negative charges and oxygen functional groups increased for MCB and its adverse effect on earthworm was higher than CB. The application of MCB in soil remediation warrants more attention.

Percutaneous microwave ablation combined with simultaneous transarterial chemoembolization for the treatment of advanced intrahepatic cholangiocarcinoma.

AIM: To retrospectively evaluate the safety and efficacy of ultrasound-guided percutaneous microwave ablation (MWA) combined with simultaneous transarterial chemoembolization (TACE) in the treatment of patients with advanced intrahepatic cholangiocarcinoma (ICC). METHODS: All patients treated with ultrasound-guided percutaneous MWA combined with simultaneous TACE for advanced ICC at our institution were included. Posttreatment contrast-enhanced computed tomography and/or magnetic resonance imaging were retrieved and reviewed for tumor response to the treatment. Routine laboratory studies, including hematology and liver function tests were collected and analyzed. Procedure-related complications were reviewed and survival rates were analyzed. RESULTS: From January 2011 to December 2014, a total of 26 advanced ICC patients were treated at our single institute with ultrasound-guided percutaneous MWA combined with simultaneous TACE. There were 15 males and eleven females with an average age of 57.9±10.4 years (range, 43-75 years). Of 26 patients, 20 (76.9%) patients were newly diagnosed advanced ICC without any treatment, and six (23.1%) were recurrent and treated with surgical resection of the original tumor. The complete ablation rate was 92.3% (36/39 lesions) for advanced ICC. There were no major complications observed. There was no death directly from the treatment. Median progression-free survival and overall survival were 6.2 and 19.5 months, respectively. The 6-, 12-, and 24-month survival rates were 88.5%, 69.2%, and 61.5%, respectively. CONCLUSION: The study suggests that ultrasound-guided percutaneous MWA combined with simultaneous TACE therapy can be performed safely in all patients with advanced ICC. The complete ablation rate was high and there was no major complication. The overall 24-month survival was 61.5%.

Transcatheter arterial chemoembolization with gemcitabine and oxaliplatin for the treatment of advanced biliary tract cancer.

BACKGROUND: The aim of this study was to determine the therapeutic efficacy and safety of transarterial chemoembolization (TACE) with gemcitabine and oxaliplatin in patients with advanced biliary tract cancer (BTC). METHODS: We retrospectively analyzed the outcomes for 65 patients with advanced BTC treated by TACE with gemcitabine 1,000 mg/m(2) and oxaliplatin 100 mg/m(2). Follow-up laboratory tests and computed tomography or magnetic resonance imaging were performed routinely to evaluate the response of the tumor to treatment. All patients were assessed for adverse effects. RESULTS: Of the 65 patients, 19 (29.2%) achieved a partial response, 36 (55.4%) showed stable disease, and ten (15.4%) showed progressive disease. The overall response rate was 29.2%. At the end of this study, five patients were still alive. The median overall survival was 12.0 months (95% confidence interval 8.5-15.5). There were no serious complications after TACE. CONCLUSION: The disease control rate and overall survival in this retrospective study were consistent with those in previous reports. TACE with gemcitabine and oxaliplatin was well tolerated and highly effective in patients with advanced BTC.

Effects of surface-modified nano-scale carbon black on Cu and Zn fractionations in contaminated soil.

Cu contamination soil (547 mg kg(-1)) was mixed separately with the surface-modified nano-scale carbon black (MCB) and placed in the ratios (w/w) of 0, 1%, 3%, and 5% in pots, together with 0.33 g KH2PO4 and 0.35 g urea/pot. Each pot contained 20 ryegrass seedlings (Lolium multiflorum). Greenhouse cultivation experiments were conducted to examine the effect of the MCB on Cu and Zn fractionations in soil, accumulation in shoot and growth of ryegrass. The results showed that the biomass of ryegrass shoot and root increased with the increasing of MCB adding amount (p < 0.05). The Cu and Zn accumulation in ryegrass shoot and the concentrations of DTPA extractable Cu and Zn in soil were significantly decreased with the increasing of MCB adding amount (p < 0.05). The metal contents of exchangeable and bound to carbonates (EC-Cu or EC-Zn) in the treatments with MCB were generally lower than those without MCB, and decreased with the increasing of MCB adding amount (p < 0.05). There was a positive linear correlation between the Cu and Zn accumulation in ryegrass shoot and the EC-Cu and EC-Zn in soil. The present results indicated the MCB could be applied for the remediation the soils polluted by Cu and Zn.

Transarterial infusion with gemcitabine and oxaliplatin for the treatment of unresectable pancreatic cancer.

The aim of this study was to evaluate the therapeutic efficacy and the safety of transarterial infusion (TAI) with gemcitabine and oxaliplatin in patients with unresectable pancreatic cancer (PC). After celiac arteriogram and super-mesenteric arteriography, 1000 mg/m gemcitabine and 100 mg/m oxaliplatin were infused through 4- or 5-Fr catheters in arteries supplying blood to the tumor. In cases in which the blood-supplying artery could be selectively catheterized, the infusion was performed through a 3-Fr catheter placed in the tumor-supplying artery. Therapeutic courses were repeated every 4 weeks. The tumor response, the overall survival, and adverse effects were monitored. Thirty-two patients with unresectable PC were enrolled in this study, including 20 male and 12 female patients. A total of 105 cycles of TAI (mean=3.3 cycles/patient) were performed. Of 32 patients, partial remission was achieved in eight (25.0%), stable disease in 13 (40.6%), and progressive disease in 11 (34.4%). The overall response rate was 25.0%. The median survival time was 10.0 months (range=4-21 months). Grade III-IV toxicity, vomiting, occurred with a rate of 21.9%. Grade I-II neutropenia, thrombocytopenia, peripheral nerve toxicity, elevated serum transaminases levels, and serum total bilirubin were observed. TAI with gemcitabine and oxaliplatin is well tolerated and highly effective in patients with unresectable PC.

Fine needle aspirating and cutting is superior to Tru-cut core needle in liver biopsy.

BACKGROUND: Liver biopsy is the "gold standard" for evaluating liver disorders, but controversies over the potential risk of complications and patient discomfort still exist. Using a 21G fine needle, we developed a new biopsy procedure, fine needle aspirating and cutting (FNAC). Our procedure obtains enough tissue for pathological examination and meanwhile, reduces the risk of biopsy complications. The present study was to determine the safety and efficiency of 21G FNAC compared with 18G Tru-cut core needle (TCN) in liver tumor biopsies. METHODS: Ninety-four patients with unresectable malignant tumors were included in this study. Patients were divided into 2 groups: 18G TCN and 21G FNAC. The total positive rate (TPR) and safety of both groups were compared. RESULTS: TPR was not different between the two groups. Liver puncture track subcapsular hemorrhage and arteriovenous shunt were reported with 18G TCN but not with 21G FNAC. The incidence of pain caused by biopsy was higher for the 18G TCN group compared to the 21G FNAC group (P<0.05). About 82.6% of the patients in the 18G TCN group had a sample length >0.5 cm, but 52.1% in the 21G FNAC group (P<0.05). More than 50% of patients in both groups had sufficient tissue for immunohistochemical examination. CONCLUSIONS: TPR is not different between the 21G FNAC and 18G TCN biopsy procedures, but the safety of 21G FNAC is superior to that of 18G TCN. Tissues obtained by either of these two procedures are sufficient for a pathological diagnosis.

Damage to pig bile duct caused by intraluminal brachytherapy using a (125)I ribbon.

BACKGROUND: Stent occlusion by tumor ingrowth or overgrowth is the main cause of jaundice recurrence after metal stent insertion in patients with malignant obstructive jaundice (MOJ). The application of intraluminal brachytherapy (ILBT) in patients with MOJ results in local control of malignant tumors, which prolong stent patency. PURPOSE: To evaluate the safety of ILBT in pig bile ducts using ribbons of iodine-125 ((125)I) seeds. MATERIAL AND METHODS: Sixteen healthy pigs were randomly assigned to four groups of four pigs each. A (125)I seed ribbon was implanted into the common bile duct of each animal through an incision in the duct wall, and was fixed by suturing. The four groups of animals were sacrificed at 15, 30, 60, and 120 days after ribbon implantation, respectively. Serum bilirubin concentrations, alanine aminotransferase concentrations, and white blood cell counts before and after implantation were compared within each group. Pathological changes to the bile duct wall were observed using a light microscope. Morphological changes in biliary epithelial cells and organelles were observed with electron microscopy. RESULTS: (125)I ribbons were successfully implanted in all animals without surgery-related death. We found no significant difference in pre- and post-implant serum bilirubin, alanine aminotransferase, or white blood cell counts. Light and electron microscopy showed that the most severe bile duct damage occurred in the 15-day group, which exhibited necrosis and detachment of numerous epithelial cells, and infiltration of inflammatory cells. Repair and proliferation of the bile duct epithelium began 30 days after implantation and was nearly complete at 60 days. CONCLUSION: This study demonstrated the safety of ILBT using a (125)I ribbon in the pig bile duct. (125)I seed ribbons may be used in the treatment of MOJ in humans.