In Vivo Genotoxicity and Oxidative Stress Evaluation of an Ethanolic Extract from Piquia (Caryocar villosum) Pulp

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)In this study, the ethanolic extract obtained from piquia pulp was assessed for genotoxicity and oxidative stress by employing the micronucleus test in bone marrow and peripheral blood cells in addition to comet, thiobarbituric-acid-reactive substances (TBARS), and reduced glutathione assays in the liver, kidney, and heart. Additionally, phytochemical analyses were performed to identify and quantify the chemical constituents of the piquia extract. Wistar rats were treated by gavage with an ethanolic extract from piquia pulp (75 mg/kg body weight) for 14 days, and 24 h prior to euthanasia, they received an injection of saline or doxorubicin (15 mg/kg body weight, intraperoneally). The results demonstrated that piquia extract at the tested dose was genotoxic but not mutagenic, and it increased the TBARS levels in the heart. Further studies are required to fully elucidate how the properties of ethanolic extract of piquia pulp can affect human health.o TEXTO COMPLETO DESTE ARTIGO, ESTARÁ DISPONÍVEL À PARTIR DE AGOSTO DE 2015.163268271Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2009/15692-0, 2005/59552-6

Effects of sulforaphane on the oxidative response, apoptosis, and the transcriptional profile of human stomach mucosa cells in vitro

Oxidative stress is a critical factor in the pathogenesis of several gastrointestinal diseases. Sulforaphane (SFN), a bioactive compound found in cruciferous vegetables, activates the redox-sensitive nuclear erythroid 2-related factor 2 (NRF2). In addition to its protective role, SFN exerts cytotoxic effects on cancer cells. However, there is a lack of information concerning the toxicity of SFN in normal cells. We investigated the effects of SFN on cell viability, antioxidant defenses, and gene expression in human stomach mucosa cells (MNP01). SFN reduced ROS formation and protected the cells against induced oxidative stress but high concentrations increased apoptosis. An intermediate SFN concentration (8 μM) was chosen for RNA sequencing studies. We observed upregulation of genes of the NRF2 (antioxidant) pathway, the DNA damage response, and apoptosis signaling; whereas SFN downregulated cell cycle and DNA repair pathway genes. SFN may be cytoprotective at low concentrations and cytotoxic at high concentrations

Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells

Abnormal epigenetic alterations are one of the keystones of cancer development. Epigenetic targeting drugs have become a promising and effective cancer therapy strategy. However, due to the high toxicity and unclear mechanisms of action of these drugs, natural compounds that cause epigenetic modulation have also been studied. Sulforaphane (SFN) is a promising bioactive compound for epigenetic targeting therapy. In this study, we investigate the effects of SFN on gene expression and DNA methylation in human hepatocellular carcinoma cells (HepG2). Using high throughput technologies in combination with cell-based assays, we find SFN is a potent anticancer agent, as it induces DNA damage, mitotic spindle abnormalities followed by apoptosis and proliferation inhibition in HepG2 cells. Our results show the upregulation of DNA damage response and cell cycle checkpoint genes. Also, we find the downregulation of cellular pathways frequently overexpressed in human cancer. As expected, SFN exerts epigenetic modulation effects by inhibiting histone deacetylases (HDACs). SFN might affect the activity of oncogenic transcription factors through methylation of its binding sites motifs. Our findings offer insights into SFN chemopreventive molecular effects in HepG2 cells and highlight SFN as a valuable natural approach to cancer therapy for future investigatio

New patterns of magnetic resonance images in high-grade glioma patients treated with bevacizumab (Avastin®)

Objectives: To identify new magnetic resonance imaging (MRI) patterns in patients with high-grade glioma treated with bevacizumab (Avastin®). Methods: The retrospective study was approved by the institutional review board. An extended case series of 27 patients (19 men, 8 women) with age range of 22–76 years and an average age 52 years were studied by 1.5T/3T MRI (Siemens scanner Erlangen, Germany). Protocol included axial T1-wi spin echo (SE), axial T2-wi fast SE, three-dimensional fluid-attenuated inversion recovery (3D FLAIR), axial diffusion tensor imaging, axial T2-wi gradient echo (GE), dynamic-susceptibility contrast T2-perfusion, axial T1-wi post-gadolinium (Gd) (0.2 ml/kg of body weight) and 3D T1-wi (weighted) GE post-Gd. Evaluation comprised oedema or low-grade tumour infiltration using FLAIR sequences, perfusion using relative cerebral blood volume (rCBV) and enhancement using T1-wi post-medium contrast images. Results: At baseline, the study included 27 patients, of which 14 patients were excluded and 13 patients analysed. One patient under treatment showed persistent hyperperfusion, three mixed perfusion, six hypoperfusion and three normal perfusion. FLAIR sequences were used in oedema analysis. When treated, 10 patients showed decrease in perilesional oedema, 1 showed increase in perilesional oedema and 2 had stability in perilesionnal oedema. Lesion enhancement was analysed using axial T1-wi SE post-Gd images; 12 patients showed decrease and 1 patient showed stability in lesion enhancement. Conclusions: Bevacizumab (Avastin) alters the process of angiogenesis resulting in different perfusion patterns in patients with disease progression that must be known in order to avoid erroneous interpretation

A multifunctional therapeutic approach to disease modification in multiple familial mouse models and a novel sporadic model of Alzheimer's disease.

BACKGROUND: Clinical failures singularly targeting amyloid-β pathology indicate a critical need for alternative Alzheimer's disease (AD) therapeutic strategies. The mixed pathology reported in a large population of AD patients demands a multifunctional drug approach. Since activation of cAMP response element binding protein (CREB) plays a crucial role in synaptic strengthening and memory formation, we retooled a clinical drug with known neuroprotective and anti-inflammatory activity to activate CREB, and validated this novel multifunctional drug, NMZ, in 4 different mouse models of AD. RESULTS: NMZ was tested in three mouse models of familial AD and one model of sporadic AD. In 3 × Tg hippocampal slices, NMZ restored LTP. In vivo, memory was improved with NMZ in all animal models with robust cognitive deficits. NMZ treatment lowered neurotoxic forms of Aβ in both APP/PS1 and 3 × Tg transgenic mice while also restoring neuronal plasticity biomarkers in the 3 × Tg mice. In EFAD mice, incorporation of the major genetic AD risk factor, hAPOE4, did not mute the beneficial drug effects. In a novel sporadic mouse model that manifests AD-like pathology caused by accelerated oxidative stress in the absence of any familial AD mutation, oral administration of NMZ attenuated hallmark AD pathology and restored biomarkers of synaptic and neuronal function. CONCLUSIONS: The multifunctional approach, embodied by NMZ, was successful in mouse models of AD incorporating Aβ pathology (APP/PS1), tau pathology (3xTg), and APOE4, the major human genetic risk factor for AD (EFAD). The efficacy observed in a novel model of sporadic AD (Aldh2 (-/-) ) demonstrates that the therapeutic approach is not limited to rare, familial AD genetic mutations. The multifunctional drug, NMZ, was not designed directly to target Aβ and tau pathology; however, the attenuation of this hallmark pathology suggests the approach to be a highly promising, disease-modifying strategy for AD and mixed pathology dementia