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Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis and hepatocyte injury, is an obesity-induced metabolic dysregulation with few available therapeutic options. Enhancement of the mitochondrial function was considered as an effective treatment for NALFD. Unsaturated fatty acids (UFAs) have been shown to have beneficial effects on metabolic syndrome disease such as hyperlipidemia, coronary artery disease and cardiovascular diseases. The seed oil of Rosa roxburghii Tratt (ORRT) was of high quality in terms of its high amount of unsaturated fatty acids. However, the effects of ORRT on NALFD have not been reported so far. The study aimed to evaluate the protective effects and molecular mechanism of ORRT for the treatment of NAFLD in vivo and in vitro. The beneficial effects, especially improving the mitochondrial function, and the potential mechanism of ORRT on NAFLD were studied both in vivo and in vitro. Lipid levels were determined by triglyceride (TG), total cholesterol (TC), and Oil Red O staining. Oxidative stress and inflammation were assessed by detecting antioxidant enzyme activity, MDA content, and ELISA assay. Blood TG, TC, HDL-c and LDL-c levels were measured in HFD mice. Western blot analyses were used to determine the levels of the protein involved in fatty acid oxidation, oxidative metabolism, and mitochondria biogenesis and function. The mitochondrial membrane potential level was measured by JC-1 staining to teste the effect of ORRT on mitochondrial function in vitro. GW6471 (inhibitor of PPARα) was used to confirm the relationship between PPARα and PGC-1α. ORRT significantly restrained NAFLD progression by attenuating lipid accumulation, oxidative stress and inflammatory response. Furthermore, ORRT upregulated thermogenesis-related gene expressions, such as uncoupling protein 1 (UCP1) and p38 mitogen-activated protein kinase (p38 MAPK). The results showed that the expression of key genes involved in fatty acid oxidation (e.g. , CPT-1α, ACADL, PPARα) and in mitochondrial biogenesis and function (e.g. , TFAM, NRF1, PGC-1α, and COX IV) was significantly increased. Together with the observed MMP improvement, these findings suggested that ORRT activated the mitochondrial oxidative pathway. Additionally, GW6471 inhibited the ORRT on promoting the expression of PGC-1α, CPT-1α, and ACADL. In conclusion, ORRT possessed the potential to prevent lipid accumulation via the PPARα/PGC-1α signaling pathway, which could be developed as a natural health-promoting oil against NAFLD. [Display omitted] [ABSTRACT FROM AUTHOR]

The protective effect of dexamethasone (DEX) against noise-induced trauma, as reflected in hair cell destruction and elevation in auditory brainstem response (ABR) sensitivity, was assessed in guinea pigs. The animals were administered DEX (1, 10, 100, and 1000 ng/ml) or artificial perilymph (AP) via a mini-osmotic pump directly into scala tympani and, on the fourth day after pump implantation, exposed to 120 dB SPL octave band noise, centered at 4 kHz, for 24 h. Animals receiving DEX demonstrated a dose-dependent reduction in noise-induced outer hair cell loss (significant at 1, 10 and 100 ng/ml DEX animals compared to AP control animals) and a similar attenuation of the noise-induced ABR threshold shifts, observed 7 days following exposure (significant at 100 ng/ml DEX animals compared to AP control animals). These physiological and morphological results indicate that direct infusion of DEX into the perilymphatic space has protective effects against noise-induced trauma in the guinea pig cochlea. [Copyright &y& Elsevier]

Migraine headaches are often precipitated by stress and seem to involve neurogenic inflammation (NI) of the dura mater associated with the sensation of throbbing pain. Trigeminal nerve stimulation had been reported to activate rat dura mast cells and increase vascular permeability, effects inhibited by neonatal pretreatment with capsaicin implicating sensory neuropeptides, such as substance P (SP). The aim of the present study was to investigate NI, assessed by extravasation of 99-Technetium-gluceptate (99Tc-G), as well as the role of mast cells, SP and its receptor (NK-1R) in dura mater of mice in response to acute stress. Restraint stress for thirty min significantly increased 99Tc-G extravasation in the dura mater of C57BL mice. This effect was absent in W/Wv mast cell-deficient mice and NK-1 receptor knockout mice (NK-1R−/−), but was unaltered in SP knockout mice (SP−/−). Acute restraint stress also resulted in increased dura mast cell activation in C57BL mice, but not in NK-1R−/− mice. These data demonstrate for the first time that acute stress triggers NI and mast cell activation in mouse dura mater through the activation of NK-1 receptors. The fact that SP−/− mice had intact vascular permeability response to stress indicates that some other NK-1 receptor agonist may substitute for SP. These results may help explain initial events in pathogenesis of stress-induced migraines. [Copyright &y& Elsevier]

Background/Aims: Liver growth factor (LGF) is a hepatic mitogen, however, the hepatic stimulation pathway remains to be characterized. The aim of this study was to determine whether tumor necrosis factor alpha (TNF-α) stimulation constitutes a step in the mitogenic pathway of LGF.Methods: Rats were injected with 4.5 μg LGF/rat, and LGF activity was measured both by liver DNA synthesis stimulation and ‘proliferating cell nuclear antigen (PCNA)-positive’ hepatocytes in rats injected with LGF or +anti-TNF-α. TNF-α expression was evaluated by reverse-transcription polymerase chain reaction. TNF-α-producing cells were immunodetected. Human endothelial cells (HUVEC) were stimulated by LGF. TNF-α was detected in the supernatant, and the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial adhesion molecule-1 (VCAM-1) by flow cytometry analysis.Results: LGF-injected rats showed higher intrahepatic TNF-α expression. DNA synthesis and PCNA-positive hepatocytes induced by LGF were inhibited by anti-TNF-α, PCNA-positive hepatocytes being especially abundant around the central vein when LGF was injected alone, but TNF-α exhibited increased signal intensity in endothelial cells of the portal vein. LGF stimulated TNF-α secretion in HUVEC, but did not stimulate ICAM-1 or VCAM-1 up-regulation.Conclusions: The mitogenic cascade initiated by LGF in rat liver in vivo depends, at least in part, on TNF-α stimulation. Portal vein endothelial cells seem to be a source of TNF-α. [Copyright &y& Elsevier]

In the oral cavity, titanium is an excellent biocompatible material. However, it is reported that high ratios of intracellular titanium particles can cause cell apoptosis or necrosis by as-yet unknown mechanisms. The purpose of this study was to investigate the response of tumor necrosis factor alpha (TNF-α)-resistant L929 fibroblasts to titanium particles. Cells were cultured in Eagle''s medium supplemented with fetal bovine serum and l-glutamine. Titanium particle sizes were less than 9 μ. Cytotoxicity was assayed by a cell counting kit, trypan blue dye exclusion test and lactate dehydrogenase (LDH) leakage. The production of reactive oxygen species (ROS) was detected by a confocal laser scanning microscope (CLSM) using dichlorofluorescein diacetate as a fluorescent probe. Morphology was viewed by a CLSM and with an X-ray microanalyser (XMA). When titanium particles were added to cells, the viability decreased to around 50% at a particle concentration of 2.0%. The number of dead cells and LDH activity in the culture media increased significantly between 1 and 2 days. However, formation of active oxygen species did not occur, since no dichlorofluorescein fluorescence was observed. A scanning electron photomicrograph (SEM) revealed a large number of particles covering or adhering to cellular components in lysed cells compared with flattened control cells attached to the substrate. The XMA showed that the titanium accumulation was coincident with the deformed cell shape. The CLSM also confirmed that particles were within the cells. From these results it was concluded that titanium particles ingested in large quantities into the cell induced necrosis by a pathway other than by producing ROS. [Copyright &y& Elsevier]

Background/Aims: Recently, we have reported that macrophage inflammatory protein-2 (MIP-2) plays a pivotal role in concanavalin A (Con A)-induced liver injury. In this study, we investigated the effect of antithrombin III (AT-III) on liver damage, and production of MIP-2 and prostacyclin in this model.Methods: Liver injury was induced by intravenous injection of Con A (15 mg/kg) and AT-III was administered (50, 250 and 500 units/kg, iv) 30 mm before Con A injection. Plasma levels of alanine aminotransferase (ALT), MIP-2 and 6-keto-prostaglandin F1α (6k-PG-F1α), stable metabolite of prostaglandin I2 (prostacyclin), were determined.Results: The elevated plasma ALT levels 8, 16, 24 h after Con A injection were inhibited by AT-III pretreatment. The elevated plasma MIP-2 levels were significantly inhibited by AT-III pretreatment compared with vehicle treatment. The inhibitory effect of AT-III on plasma ALT and MIP-2 in Con A-induced liver injury was attenuated by indomethacin (5 mg/kg, ip). Plasma concentration of 6k-PG-F1α at 2 h after AT-III injection was significantly elevated compared with baseline and vehicle pretreatment.Conclusions: These findings suggest that AT-III prevents Con A-induced liver injury through an inhibition of MIP-2 release and a production of prostacyclin. [Copyright &y& Elsevier]

Acoustic trauma induces an inflammatory response in the cochlea, resulting in debilitating hearing function. Clinically, amelioration of inflammation substantially prevents noise-induced hearing loss. The Limulus factor C, Cochlin, and Lgl1 (LCCL) peptide plays an important role in innate immunity during bacteria-induced inflammation in the cochlea. We aimed to investigate the LCCL-induced innate immune response to noise exposure and its impact on hearing function. Methods: We used Coch (encodes cochlin harboring LCCL peptide) knock-out and p.G88E knock-in mice to compare the immune responses before and after noise exposure. We explored their hearing function and hair cell degeneration. Moreover, we investigated distinct characteristics of immune responses upon noise exposure using flow cytometry and RNA sequencing. Results: One day after noise exposure, the LCCL peptide cleaved from cochlin increased over time in the perilymph space. Both Coch −/− and Coch G88E/G88E mutant mice revealed more preserved hearing following acoustic trauma compared to wild-type mice. The outer hair cells were more preserved in Coch −/− than in wild-type mice upon noise exposure. The RNA sequencing data demonstrated significantly upregulated cell migration gene ontology in wild-type mice than in Coch −/− mice following noise exposure, indicating that the infiltration of immune cells was dependent on cochlin. Notably, infiltrated monocytes from blood (C11b+/Ly6G−/Ly6C+) were remarkably higher in wild-type mice than in Coch −/− mice at 1 day after noise exposure. Conclusions: Noise-induced hearing loss was attributed to over-stimulated cochlin, and led to the cleavage and secretion of LCCL peptide in the cochlea. The LCCL peptide recruited more monocytes from the blood vessels upon noise stimulation, thus highlighting a novel therapeutic target for noise-induced hearing loss. l LCCL peptide is cleaved and secreted in the cochlea after noise exposure. l The concentration of LCCL in the perilymph peaks at 1 day after noise exposure. l The presence of LCCL aggravates the noise-induced hearing loss. l LCCL regulates monocyte infiltration after noise exposure. [ABSTRACT FROM AUTHOR]