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BackgroundThe incidence of non-alcoholic fatty liver disease (NAFLD), commonly associated with obesity and metabolic syndrome, is increasing worldwide. However, the specific mechanisms that mediate the progression from simple steatosis to non-alcoholic steatohepatitis remain largely unclear. This study aimed to investigate the timedependent changes of triglyceride (TG) and free fatty acid (FFA) levels in the blood and liver over 24 weeks in high-fat diet-induced obese rats with NAFLD and to clarify the role of high FFA levels in the progression of liver injury.MethodsMale Wistar rats were randomly divided into three groups (n = 30 per group): the Control group, fed standard chow; the High-fat diet (HFD) group, fed high-fat chow; and the Acipimox group, fed an HFD plus acipimox (100 mg/kg/d, ig) for 8, 16 and 24 weeks. After treatment, blood and liver samples were collected for biochemical analyses, western blotting analysis and a histopathological study.ResultsThe visceral fat/weight and liver/body weight ratios were higher in both the HFD and Acipimox groups than in the Control group. The TG and FFA concentrations in blood and liver were increased in the HFD group and associated with elevated serum alanine aminotransferase (ALT) and liver malondialdehyde (MDA) levels and macro/microvesicular steatosis on hepatic fragments. Although the TG levels in the liver were similar between the HFD and Acipimox groups (p > 0.05), the FFA concentrations in the blood and liver were much lower in the latter group (p < 0.05). The Acipimox group showed normal ALT and MDA levels as well as less severe hepatic histological changes than did the HFD group (NAFLD activity score: 2.14 ± 0.14, 2.43 ± 0.20 and 2.63 ± 0.26 at 8, 16 and 24 weeks, respectively; p < 0.05 versus the HFD group at 24 weeks). The diacylglycerol acyltransferase 2 (DGAT2) protein levels were similar between the HFD and Acipimox groups (p > 0.05), but the protein expression level of carnitine palmitoyltransferase 1a (CPT-1a) was higher in the Acipimox group.ConclusionsLiver TG accumulation does not cause cellular injury in the liver; rather, FFAs or their metabolites are responsible for liver injury via increased oxidative stress. It is suggested that the therapeutic efforts to prevent non-alcoholic liver injury progression should be focused on reducing the burden of fatty acids transported to the liver or those being synthesized in the liver.

In this study, we successfully developed novel tumor homing-penetrating peptide-functionalized drug-loaded phase-transformation nanoparticles (tLyP-1-10-HCPT-PFP NPs) for low intensity focused ultrasound (LIFU)-assisted tumor ultrasound molecular imaging and precise therapy. With the nanoscale particle size, tLyP-1-10-HCPT-PFP NPs could pass through the tumor vascular endothelial cell gap. Induced by tLyP-1 peptide with targeting and penetrating efficiency, tLyP-1-10-HCPT-PFP NPs could increase tumor accumulation and penetrate deeply into the extravascular tumor tissue, penetrating through extracellular matrix and the cellular membrane to the cytoplasm. With LIFU assistance, tLyP-1-10-HCPT-PFP NPs could phase-transform into microbubbles and enhance tumor ultrasound molecular imaging for tumor diagnosis. Furthermore, after further irradiation by LIFU, an intracellular "explosion effect" caused by acoustic droplet vaporization, ultrasound targeted microbubble destruction, and release of 10-HCPT could realize physicochemical synergistic antitumor therapy.

Purpose The purpose of this study was to carry out a metaanalysis for a comprehensive understanding and estimation of the association between sperm DNA Fragmentation Index (DFI) and pregnancy outcome after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. Methods Studies concerning the link of DFI with pregnancy outcome were included after literature search of database PUBMED, EMBASE, MEDLINE. Related information was extracted from the eligible studies by two independent authors and a meta-analysis was conducted by using STATA 12.0 software. Pregnancy outcomes consisted of biochemical pregnancy (BP), clinical pregnancy (CP) and pregnancy loss (PL). The studies included for meta-analysis were divided into three groups according to the DFI threshold value (DFI >27 %, 15-27 %, ≤15 % group). The odds ratio (OR ) and their 95 % confidence intervals (95 % CIs) were used to evaluate the association between DFI and pregnancy outcome. Results Twenty articles were included in our meta-analysis. The results indicated that infertile couples were more likely to get pregnant if DFI was less than threshold value (For threshold value > 27 % and 15-27 % group, combined overall OR (95 % CI) = 1.437 (1.186-1.742), 1.639 (1.093-2.459) respectively). However, when stratified by DFI detection methods, using sperm chromatin structure assay (SCSA) as the DFI test method, the results indicated a similar CP rate between groups with a high DFI or a lower DFI value (SCSA, For threshold value >27 % and 15-27 % group, combined overall OR (95 % CI) = 1.242(0.978-1.577), 1.480(0.921-2.377) respectively). The meta-analysis based on BP (overall OR (95 % CI) = 0.952 (0.697-1.302)) and PL((For DFI >27 %, 15-27 %, ≤15 % group, OR (95 % CI) = 0.786 (0.491-1.258), 1.509 (0.655-3.476), (0.538 (0.264-1.097) respectively) outcome yielded nonsignificant results. Conclusions The predication value of DFI for IVF or ICSI outcome is not confirmed in our meta-analysis. Further better designed studies with larger subjects involved are needed to better address this issue.

Objective: Prepare a multifunctional ultrasound molecular probe, hyaluronic acid-mediated cell-penetrating peptide-modified 10-hydroxycamptothecin-loaded phase-transformation lipid nanoparticles (HA/CPPs-10-HCPT-NPs), and to combine HA/CPPs-10-HCPT-NPs with low-intensity focused ultrasound (LIFU) for precision theranostics against hepatocellular carcinoma (HCC).Methods: HA/CPPs-10-HCPT-NPs were prepared using thin-film dispersion, ultrasound emulsification, and electrostatic effects. HA/CPPs-10-HCPT-NPs were characterized for particle size, zeta potential, encapsulation efficiency and drug-loading efficiency. In vitro, HA/CPPs-10-HCPT-NPs were tested for acoustic droplet vaporization (ADV) at different time points/acoustic intensities; the ability of HA/CPPs-10-HCPT-NPs to target SMMC-7721 cells was detected by confocal laser scanning microscopy (CLSM); the penetrating ability of CG-TAT-GC-modified NPs was verified by CLSM in a 3D multicellular tumor spheroid (MCTS) model; the effect of HA/CPPs-10-HCPT-NPs combined with LIFU on killing SMMC-7721 cells was measured by CCK-8 and flow cytometry. In vivo, the tumor-target efficiency of HA/CPPs-10-HCPT-NPs was evaluated by a small-animal fluorescence imaging system and CLSM; the enhanced ultrasound imaging efficiency of HA/CPPs-10-HCPT-NPs combined with LIFU was measured by an ultrasound imaging analyzer; the therapeutic effect of HA/CPPs-10-HCPT-NPs combined with LIFU was evaluated by tumor volume, tumor inhibition rate, and staining (hematoxylin and eosin (H & E), proliferating cell nuclear antigen (PCNA) and TUNEL).Results: Mean particle size and mean zeta potential of HA/CPPs-10-HCPT-NPs were 284.2±13.3 nm and - 16.55±1.50 mV, respectively. HA/CPPs-10-HCPT-NPs could bind to SMMC-7721 cells more readily than CPPs-10-HCPT-NPs. Penetration depth into 3D MCTS of HA/CPPs-10-HCPT-NPs was 2.76-fold larger than that of NPs without CG-TAT-GC. HA/CPPs-10-HCPT-NPs could enhance ultrasound imaging by undergoing ADV triggered by LIFU. HA/CPPs-10-HCPT-NPs+LIFU group demonstrated significantly higher efficiency of anti-proliferation and apoptosis percentage than all other groups. In mouse liver tumor xenografts, HA/CPPs-10-HCPT-NPs could target tumor sites and enhance ultrasound imaging under LIFU. HA/CPPs-10-HCPT-NPs+LIFU group had a significantly smaller tumor volume, lower proliferative index (PI), and higher tumor inhibition and apoptotic index (AI) than all other groups.Conclusions: Combined application of HA/CPPs-10-HCPT-NPs and LIFU should be a valuable and promising strategy for precise HCC theranostics.