Sorafenib, as a multi-kinase inhibitor, was the first FDA-approved anti- hepatocellular carcinoma (HCC) drug. Rhizoma Paridis saponins (RPS) as natural products have shown antitumor activity through regulation of glycolytic and lipid metabolism which was regarded as the side effect limited the utility of sorafenib. In this research, we tried to use metabolomics to verify the probability of combinatorial treatment of RPS and Sorafenib. As a result, Sorafenib + RPS increased the antitumor effect of sorafenib and RPS in H22 mice. They mitigated the change of liver weight and the increasing levels of AST and ALT in serum, and AFP and MDA in liver tissues, which indicated their liver protective activity. They also up-regulated the activity of NOX and SDH, concentration of ATP, and down-regulated the mRNA and protein levels of HIF-1a and concentration of lactate, which suggested they protected against mitochondria damage and inhibited anaerobic glycolysis. Meanwhile, the combination group remarkably down-regulated the concentration of octadecanoic acid and hexadecanoic acid in serum, and tetradecanoic acid in liver tissues compared with model group (p < 0.05). Relative regulation mechanism included their decreasing mRNA levels of FASN, CPT1, GLUT1, Myc, Akt, mTOR and LDHA, and increasing the protein expression of p53 in tumor and liver tissues (p < 0.05). Furthermore, similar influence can be observed in protein levels of CPT1A, p-PI3K, p-mTOR and p53 in liver tissues and FASN in serum. All of that provided possibility to overcome the intolerance of sorafenib by drug compatibility through protection against mitochondria damage, inhibition of anaerobic glycolysis and suppression of lipid synthesis based on PI3K/Akt/mTOR pathway.

The present study aims to examine the protective effect of Justicia tranquebariesis on thioacetamide (TAA)-induced oxidative stress and hepatic fibrosis. Male Wister albino rats (150⁻200 g) were divided into five groups. Group 1 was normal control. Group 2 was J. tranquebariensis (400 mg/kg bw/p.o.)-treated control. Group 3 was TAA (100 mg/kg bw/s.c.)-treated control. Groups 4 and 5 were orally administered with the leaf extract of J. tranquebariensis (400 mg/kg bw) and silymarin (50 mg/kg bw) daily for 10 days with a subsequent administration of a single dose of TAA (100 mg/kg/s.c.). Blood and livers were collected and assayed for various antioxidant enzymes (SOD, CAT, GPx, GST, GSH, and GR). Treatment with J. tranquebariensis significantly reduced liver TBARS and enhanced the activities of antioxidant enzymes in TAA-induced fibrosis rats. Concurrently, pretreatment with J. tranquebariensis significantly reduced the elevated liver markers (AST, ALT, ALP, GGT, and TB) in the blood. In addition, J. tranquebariensis- and silymarin- administered rats demonstrated the restoration of normal liver histology and reduction in fibronectin and collagen deposition. Based on these findings, J. tranquebariensis has potent liver protective functions and can alleviate thioacetamide-induced oxidative stress, hepatic fibrosis and possible engross mechanisms connected to antioxidant potential.

Wild and cultured mushrooms have been extensively used for food and medicinal purposes all around the world. However, there is limited information on chemical composition, health enhancing effects and contributions on diet of some mushrooms (e.g., Agaricus arvensis) widely distributed in many countries including United Kingdom, Australia, Turkey etc. Therefore, the present study was aimed to analyse the bioactive composition and ameliorative effects of A. arvensis via evaluating in vitro and in vivo antioxidant properties in CCl4 induced rat model. The extract exhibited higher antioxidant capacities in vitro than that of the positive control (Reishi-Shiitake-Maitake standardized extract). Administration of the extract had significant regulative effects in the levels of AST, ALT, LDH, Urea and TRIG levels according to CCl4 group. Additionally, lipid peroxidation and GSH in the brain, kidney and liver tissues was regulated by extract treated groups compared to the CCI4 group. The supplementation of the extract at the dose of 100 mg/kg regulated the levels of GST, GR, CAT and GPx enzyme activities in brain and liver, but not in kidney tissue. There was approximately three fold increase in CAT enzyme activity in kidney tissue of extract treated groups compared to Control and CCl4 groups. The extract contained a rich composition of bioactive compounds including phenolics (protocatechuic acid and p-hydroxybenzoic acid), volatile compounds (benzaldehyde, palmitic acid and linoleic acid) and mineral compounds (K, Si, Mg and Na). Data obtained within this study suggests that A. arvensis might be used for food industries in order to obtain nutritional products.

Dimethylglycine sodium salt (DMG-Na), has exhibited excellent advantages in animal experiments and human health. The present study aimed to investigate the effects of dietary supplementation with 0.1% DMG-Na on the growth performance, hepatic antioxidant capacity and mRNA expression of mitochondria-related genes in low birth weight (LBW) piglets during weaning period. Sixteen piglets with normal birth weight (NBW) and sixteen LBW piglets were fed either a basal diet or a 0.1% DMG-Na supplemented diet from age of 21 d to 49 d. Blood and liver samples were collected at the end of the study. The results showed that compared with NBW piglets, LBW piglets exhibited greater (P < 0.05) alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase activities in the serum. LBW decreased (P < 0.05) the activity of glutathione peroxidase, and increased (P < 0.05) the contents of malondialdehyde and H2O2 in liver. DMG-Na supplementation increased (P < 0.05) body weight gain, feed intake, and feed efficiency, decreased (P < 0.05) ALT and AST activities, and reduced the content of H2O2 in LBW piglets. LBW piglets had downregulated (P < 0.05) mRNA expression of thioredoxin 2, thioredoxin reductases 2, and nuclear respiratory factor-1 (Nrf1) in the liver. However, DMG-Na supplementation increased (P < 0.05) mRNA expression of Nrf1 in the liver. In conclusion, DMG-Na supplementation has beneficial effects in alleviating LBW-induced hepatic oxidative damage and changed mitochondrial genes expression levels, which is associated with increased antioxidant enzyme activities and up-regulating mRNA gene abundance.

Telomere dysfunction drives chromosome instability through endless breakage-fusion-bridge (BFB) cycles that promote the formation of highly rearranged genomes. However, reactivation of telomerase or ALT-pathway is required for genome stabilisation and full malignant transformation. To allow the unrestricted proliferation of cells at risk of transformation, we have established a conditional system of telomere deprotection in p16INK4a-deficient MCF-10A cells with modified checkpoints. After sustained expression of a dominant negative form of the shelterin protein TRF2 (TRF2ΔBΔM), cells with telomere fusion did progress to anaphase but no signs of ongoing BFB cycles were observed, thus anticipating proliferation defects. Indeed, 96 h TRF2ΔBΔM expression resulted in noticeable growth proliferation defects in the absence of cell cycle disturbances. Further transient periods of 96 h telomere uncapping did not result in cell cycle disturbances either. And reduction of the telomere damage to short acute deprotection periods did not in any case engender cells with a reorganised karyotype. Strikingly, the growth arrest imposed in cells showing dysfunctional telomeres was not accompanied by an activation of the DNA damage response at cellular level, or by the presence of visible markers of senescence or apoptosis. We propose that the deprotection of many telomeres simultaneously, even for a short time, results in a local activation of the cellular stress response which consequently triggers gradual cell withdrawal from cell cycle, restraining the onset of genomic instability.

The seizing of locking screws is a frequently encountered clinical problem during implant removal of locking compression plates (LCP) after completion of fracture healing. The aim of this study was to investigate the effect of two different locking mechanisms on the seizing of locking screws. Specifically, the removal torques before and after cyclic dynamic loading were assessed for screws inserted at the manufacturer-recommended torque or at an increased insertion torque. The seizing of 3.5-mm angular stable screws was assessed as a function of insertion torque for two different locking mechanisms (Thread & Conus and Thread Only). Locking screws (n=10 for each configuration) were inserted either according to the manufacturer-recommended torque or at an increased torque of 150% to simulate an over-insertion of the screw. Half of the screws were removed directly after insertion and the remaining half was removed after a dynamic load protocol of 100,000 cycles. The removal torques of locking screws exceeded the insertion torques for all tested conditions confirming the adequacy of the test setup in mimicking screw seizing in locked plating. Screw seizing was more pronounced for Thread Only design (+37%) compared to Thread & Conus design (+14%; P<0.0001). Cyclic loading of the locking construct consistently resulted in an increased seizing of the locking screws (P<0.0001). Clinical observations from patients treated with the Thread & Conus locking design confirm the biomechanical findings of reduction in seizing effect by using a Thread & Conus design. In conclusion, both over-tightening and cyclic loading are potential causes for screw seizing in locking plate implants. Both effects were found to be less pronounced in the Thread & Conus design as compared to the traditional Thread Only design.