Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin-induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double-transgenic (DTG) mice with doxycycline-inducible overexpression of human FGF2 (SPC-rtTA;TRE-hFGF2) or single-transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild-type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline-induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGFβ1-induced expression of alpha smooth muscle actin (αSMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad-dependent gene expression, FGF2 inhibited TGFβ1-induced stress fiber formation and serum response factor-dependent gene expression. FGF2 inhibition of stress fiber formation and αSMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin-induced pulmonary fibrosis in vivo and reverses TGFβ1-induced collagen and αSMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

No abstract

IPRI showed promising neuroprotective effects against scopolamine-induced memory dysfunction in rats. These findings contributed to the stimulation of α-secretase enzymes, the activation of MAPK/ERK1/2, and the alleviation of oxidative stress.

In the present study we investigated the effect of the non-alcoholic fatty liver disease (NAFLD) on the alterations in the activity of neurotransmitters catabolizing enzymes and energy catabolising enzymes, prooxidants, endogenous antioxidants and proinflammatory cytokines in brain tissue of NAFLD rats. Rats were intraperitonealy injected with CCl4 solution at a dose of (0.021 mole/Kg, 20 μL, body weight) three times weekly for four weeks. Acetylcholine esterase (AChE), monoamine oxidase (MAO), prooxidant/ antioxidants status, ATPase, lipid profile and glucose level were estimated spectrophotometrically while inflammatory markers; interleukin 6 and tumor necrosis factor alpha (IL6 and TNF-α) and insulin were assessed by ELISA technique. Our results showed that the induced NAFLD and insulin resistance (IR) were accompanied with hyperglycemia and hyperlipidemia and lowered brain glucose level with elevated ATPase activity, prooxidant status (TBARS level, xanthine oxidase and cytochrome 2E1 activities), and inflammatory markers. Through the induction period AChE activity was significantly increased compared to control in blood, liver and brain tissues. Also, MAO activity was significantly increased in both brain and liver tissue but decreased in serum compared with control. These biochemical data were supported with pathophysiological analysis that showed severe neurodegeneration, pyknosis acuolations and cavitations. These observations warrant the reassessment of the conventional concept that the NAFLD with IR progression may induce disturbances in activities of neurotransmitters catabolising enzymes and energy production accompanied with oxidative stress and metabolic disorders, acting as relative risk factors for brain dysfunction and damage with the development of age-associated neurodegenerative diseases such as Alzheimer's disease.

No abstract

Numerous studies have reported neuroprotective effects of pyruvate when given in systemic injections. Impaired glucose uptake and metabolism are found in Alzheimer’s disease (AD) and in AD mouse models. We tested whether dietary pyruvate supplementation is able to provide added energy supply to brain and thereby attenuate aging- or AD-related cognitive impairment. Mice received ~800 mg/kg/day Na-pyruvate in their chow for 2–6 months. In middle-aged wild-type mice and in 6.5-month-old APP/PS1 mice, pyruvate facilitated spatial learning and increased exploration of a novel odor. However, in passive avoidance task for fear memory, the treatment group was clearly impaired. Independent of age, long-term pyruvate increased explorative behavior, which likely explains the paradoxical impairment in passive avoidance. We also assessed pyruvate effects on body weight, muscle force, and endurance, and found no effects. Metabolic postmortem assays revealed increased energy compounds in nuclear magnetic resonance spectroscopy as well as increased brain glycogen storages in the pyruvate group. Pyruvate supplementation may counteract aging-related behavioral impairment, but its beneficial effect seems related to increased explorative activity rather than direct memory enhancement.

Berberine is a plant alkaloid that has several pharmacological effects such as antioxidant, antilipidemic, and anti-inflammatory effects. Nonalcoholic steatohepatitis (NASH) triggers different aspects of disorders such as impaired endogenous lipid metabolism, hypercholesterolemia, oxidative stress, and neurotoxicity. In this study, we examined the mechanism by which NASH induces neurotoxicity and the protective effect of berberine against both NASH and its associated neurotoxicity. NASH induced rats showed significant impairments in lipid metabolism with increased serum triglycerides, cholesterol, and low-density lipoprotein (LDL). The NASH induced group also demonstrated a significant oxidative stress which is characterized by increased TBARs level and decreased antioxidant capacity such as GSH and SOD levels. Moreover, the NASH induction was associated with inflammation which was demonstrated by increased TNFα and nitric oxide levels. Hyperglycemia and hyperinsulinemia were observed in the NASH induced group. Also, our results showed a significant increase in the expression of the acetylcholine esterase (AChE) and amyloid beta precursor protein (AβPP). These changes were significantly correlated with decreased insulin degrading enzyme (IDE) and beta-amyloid40 (Aβ 40) and increased beta-amyloid42 (Aβ 42) in the hippocampal region. Daily administration of berberine (50 mg/kg) for three weeks ameliorated oxidative stress, inflammation, hyperlipidemia, hyperglycemia, hyperinsulinemia, and the observed neurotoxicity.

No abstract