Metformin-induced oxidative stress inhibits LNCaP prostate cancer cell survival.

Background: Preclinical and clinical studies over the past several decades have indicated the potential value of metformin, a widely utilized treatment for Type 2 diabetes, in prostate cancer therapy. Notably, these studies demonstrated metformin's pleiotropic effects on several molecular and metabolic pathways, such as androgen signaling, cell cycle, and cellular bioenergetics. In this study we investigated the role of metformin in regulating intracellular redox status and cell survival in LNCaP prostate cancer cells.

Combination microRNA-based cellular reprogramming with paclitaxel enhances therapeutic efficacy in a relapsed and multidrug-resistant model of epithelial ovarian cancer.

Most advanced-stage ovarian cancer patients, including those with epithelial ovarian cancer (EOC), develop recurrent disease and acquisition of resistance to chemotherapy, leading to limited treatment options. Decrease in Let7b miRNA levels in clinical ovarian cancer has been associated with chemoresistance, increased proliferation, invasion, and relapse in EOC. We have established a murine EOC relapsed model by administering paclitaxel (PTX) and stopping therapy to allow for tumor regrowth.

Decreased cortical Nrf2 gene expression in autism and its relationship to thiol and cobalamin status.

Nuclear factor erythroid 2-related factor 2 (Nrf2) promotes expression of a large number of antioxidant genes and multiple studies have described oxidative stress and impaired methylation in autism spectrum disorder (ASD), including decreased brain levels of methylcobalamin(III) (MeCbl). Here we report decreased expression of the Nrf2 gene (NFE2L2) in frontal cortex of ASD subjects, as well as differences in other genes involved in redox homeostasis. In pooled control and ASD correlation analyses, hydroxocobalamin(III) (OHCbl) was inversely correlated with NFE2L2 expression, while MeCbl and total cobalamin abundance were positively correlated with NFE2L2 expression.

Alterations in Gene Expression of Renin-Angiotensin System Components and Related Proteins in Colorectal Cancer.

Materials And Methods: Quantitative expression of the RNA of these 17 genes in normal and cancerous tissues obtained using chip arrays from the public functional genomics data repository, Gene Expression Omnibus (GEO) application, was compared statistically.

Results: Expression of four genes, (angiotensinogen), (aminopeptidase A) (neprilysin), and (prolyl endopeptidase), was significantly upregulated in CRC specimens. Expression of (renin), (thimet oligopeptidase), (neurolysin), (prolyl carboxypeptidase), (aminopeptidase N), and (Mas receptor) was downregulated in CRC specimens.

Nutritional interventions for autism spectrum disorder.

Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder with considerable clinical heterogeneity. With no cure for the disorder, treatments commonly center around speech and behavioral therapies to improve the characteristic social, behavioral, and communicative symptoms of ASD. Gastrointestinal disturbances are commonly encountered comorbidities that are thought to be not only another symptom of ASD but to also play an active role in modulating the expression of social and behavioral symptoms.

Methylation-related metabolic effects of D4 dopamine receptor expression and activation.

D4 dopamine receptor (D4R) activation uniquely promotes methylation of plasma membrane phospholipids, utilizing folate-derived methyl groups provided by methionine synthase (MS). We evaluated the impact of D4R expression on folate-dependent phospholipid methylation (PLM) and MS activity, as well as cellular redox and methylation status, in transfected CHO cells expressing human D4R variants containing 2, 4, or 7 exon III repeats (D4.2R, D4.

Cross-Generational Transmission of Early Life Stress Effects on HPA Regulators and Bdnf Are Mediated by Sex, Lineage, and Upbringing.

Early life stress (ELS) is a potent developmental disruptor and increases the risk for psychopathology. Various forms of ELS have been studied in both humans and rodents, and have been implicated in altered DNA methylation, gene transcription, stress hormone levels, and behavior. Although recent studies have focused on stress-induced epigenetic changes, the extent to which ELS alters HPA axis function and stress responsivity across generations, whether these effects are sex-specific, and how lineage interacts with upbringing to impact these effects, remain unclear.

Neuro-Immune Influences on Health Outcomes: A Nutritional Perspective.

No Abstract Available.

Alterations in DNA Methylation Status Associated with Gulf War Illness.

Gulf War Illness (GWI) affects about 25% of Persian Gulf veterans with a cluster of chronic symptoms, including immune dysfunction and neurological issues. Recent studies implicate gene expression changes in immune function to be associated with GWI. Since DNA methylation can regulate such changes in gene expression, and disruption of DNA methylation pattern is implicated in various immune and neurological diseases, we aimed to study the DNA methylation patterns in peripheral blood mononuclear cells from GWI patients.

Oxycodone Exposure: A Magnetic Resonance Imaging Study in Response to Acute and Chronic Oxycodone Treatment in Rats.

The present study was designed to use blood-oxygen-level dependent (BOLD) imaging to "fingerprint" the change in activity in response to oxycodone (OXY) in drug naïve rats before and after repeated exposure to OXY. It was hypothesized that repeated exposure to OXY would initiate adaptive changes in brain organization that would be reflected in an altered response to opioid exposure. Male rats exposed to OXY repeatedly showed conditioned place preference, evidence of drug-seeking behavior and putative neuroadaptation.

Brain iron loading impairs DNA methylation and alters GABAergic function in mice.

Iron deficiency is closely associated with altered GABA metabolism and affective behavior. While mutation in the hemochromatosis ( HFE) gene disrupts iron homeostasis and promotes oxidative stress that increases the risk of neurodegeneration, it is largely unknown whether HFE mutation modifies GABAergic homeostasis and emotional behavior. The goal of our study was to investigate the impact of HFE on GABAergic neurochemistry and redox-epigenetic regulation in the brain using H67D HFE-mutant mice that recapitulates the H63D-HFE mutation in humans.

Identification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-associated DNA methylation patterns.

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition involving multiple organ systems and characterized by persistent/relapsing debilitating fatigue, immune dysfunction, neurological problems, and other symptoms not curable for at least 6 months. Disruption of DNA methylation patterns has been tied to various immune and neurological diseases; however, its status in ME/CFS remains uncertain. Our study aimed at identifying changes in the DNA methylation patterns that associate with ME/CFS.

knockout rats exhibit hippocampal neuropathology and deficits in memory.

RNASET2 deficiency in humans is associated with infant cystic leukoencephalopathy, which causes psychomotor impairment, spasticity and epilepsy. A zebrafish mutant model suggests that loss of RNASET2 function leads to neurodegeneration due to the accumulation of non-degraded RNA in the lysosomes. The goal of this study was to characterize the first rodent model of RNASET2 deficiency.

Evidence of Neurobiological Changes in the Presymptomatic PINK1 Knockout Rat.

Background: Genetic models of Parkinson's disease (PD) coupled with advanced imaging techniques can elucidate neurobiological disease progression, and can help identify early biomarkers before clinical signs emerge. PTEN-induced putative kinase 1 (PINK1) helps protect neurons from mitochondrial dysfunction, and a mutation in the associated gene is a risk factor for recessive familial PD. The PINK1 knockout (KO) rat is a novel model for familial PD that has not been neuroradiologically characterized for alterations in brain structure/function, alongside behavior, prior to 4 months of age.

Alterations in Gene Expression of Components of the Renin-Angiotensin System and Its Related Enzymes in Lung Cancer.

Objectives: The study assessed the existence and significance of associations between the expression of fifteen renin-angiotensin system component genes and lung adenocarcinoma.

Materials And Methods: NCBI's built-in statistical tool, GEO2R, was used to calculate Student's -tests for the associations found in a DNA expression study of adenocarcinoma and matched healthy lung tissue samples. The raw data was processed with GeneSpring™ and then used to generate figures with and without Sidak's multiple comparison correction.

Short-term sleep deprivation leads to decreased systemic redox metabolites and altered epigenetic status.

Sleep is critical for repair as well as the rejuvenation processes in the body and many of these functions are regulated via underlying cellular metabolic homeostasis. Changes in sleep pattern are reported to alter such metabolic function resulting in altered disease susceptibility or behavior. Here, we measured the extent to which overnight total sleep deprivation (SD) in young adult humans can influence systemic (plasma-derived) redox-metabolism including the major antioxidant, glutathione as well as DNA methylation levels.

MicroRNA-34a Encapsulated in Hyaluronic Acid Nanoparticles Induces Epigenetic Changes with Altered Mitochondrial Bioenergetics and Apoptosis in Non-Small-Cell Lung Cancer Cells.

Therapies targeting epigenetic changes for cancer treatment are in Phase I/II trials; however, all of these target only nuclear DNA. Emerging evidence suggests presence of methylation marks on mitochondrial DNA (mtDNA); but their contribution in cancer is unidentified. Expression of genes encoded on mtDNA are altered in cancer cells, along with increased glycolytic flux.

Redox-Related Epigenetic Mechanisms in Glioblastoma: Nuclear Factor (Erythroid-Derived 2)-Like 2, Cobalamin, and Dopamine Receptor Subtype 4.

Glioblastoma is an exceptionally difficult cancer to treat. Cancer is universally marked by epigenetic changes, which play key roles in sustaining a malignant phenotype, in addition to disease progression and patient survival. Studies have shown strong links between the cellular redox state and epigenetics.

Differential neurogenic effects of casein-derived opioid peptides on neuronal stem cells: implications for redox-based epigenetic changes.

Food-derived peptides, such as β-casomorphin BCM7, have potential to cross the gastrointestinal tract and blood-brain barrier and are associated with neurological disorders and neurodevelopmental disorders. We previously established a novel mechanism through which BCM7 affects the antioxidant levels in neuronal cells leading to inflammatory consequences. In the current study, we elucidated the effects of casein-derived peptides on neuronal development by using the neurogenesis of neural stem cells (NSCs) as an experimental model.

Clinical evaluation of glutathione concentrations after consumption of milk containing different subtypes of β-casein: results from a randomized, cross-over clinical trial.

Unlabelled: This study reports the plasma glutathione concentrations in a double-blind, randomized, controlled, 2 × 2 cross-over study in which healthy participants consumed conventional milk (2 × 250 mL per day) containing both A1 and A2 types of β-casein, or milk containing only A2 type β-casein. Beta-casomorphin-7 (BCM-7), a peptide uniquely derived from the A1 type of β-casein, was previously reported to downregulate glutathione expression in human gut epithelial and neuronal cell lines by limiting cysteine uptake. The current human study demonstrates that consumption of milk containing only A2 β-casein was associated with a greater increase in plasma glutathione concentrations compared with the consumption of milk containing both β-casein types, and did not increase plasma BCM-7 concentrations compared with the washout diet in the study participants.

Renin-angiotensin system gene expression and neurodegenerative diseases.

Hypothesis: Single nucleotide polymorphisms and altered gene expression of components of the renin-angiotensin system (RAS) are associated with neurodegenerative diseases.

Introduction: Drugs that interact with the RAS have been shown to affect the course of neurodegenerative disease, suggesting that abnormalities in the RAS may contribute to neurodegenerative disease.

Materials And Methods: A meta-analysis of genome-wide association studies and gene expression data for 14 RAS-related proteins was carried out for five neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, narcolepsy, amyotrophic lateral sclerosis and multiple sclerosis.

Neuregulin 1 Promotes Glutathione-Dependent Neuronal Cobalamin Metabolism by Stimulating Cysteine Uptake.

Neuregulin 1 (NRG-1) is a key neurotrophic factor involved in energy homeostasis and CNS development, and impaired NRG-1 signaling is associated with neurological disorders. Cobalamin (Cbl), also known as vitamin B12, is an essential micronutrient which mammals must acquire through diet, and neurologic dysfunction is a primary clinical manifestation of Cbl deficiency. Here we show that NRG-1 stimulates synthesis of the two bioactive Cbl species adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) in human neuroblastoma cells by both promoting conversion of inactive to active Cbl species and increasing neuronal Cbl uptake.

Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia.

Many studies indicate a crucial role for the vitamin B12 and folate-dependent enzyme methionine synthase (MS) in brain development and function, but vitamin B12 status in the brain across the lifespan has not been previously investigated. Vitamin B12 (cobalamin, Cbl) exists in multiple forms, including methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), serving as cofactors for MS and methylmalonylCoA mutase, respectively. We measured levels of five Cbl species in postmortem human frontal cortex of 43 control subjects, from 19 weeks of fetal development through 80 years of age, and 12 autistic and 9 schizophrenic subjects.

Combination wt-p53 and MicroRNA-125b Transfection in a Genetically Engineered Lung Cancer Model Using Dual CD44/EGFR-targeting Nanoparticles.

Mutations in KRAS and p53 signaling pathways contribute to loss of responsiveness to current therapies and a decreased survival in lung cancer. In this study, we have investigated the delivery and transfection of wild-type (wt-) p53 and microRNA-125b (miR-125b) expressing plasmid DNA, in SK-LU-1 human lung adenocarcinoma cells as well as in Kras(G12D)/p53(fl/fl) (KP) genetically engineered mouse model of lung cancer. Systemic plasmid DNA delivery with dual CD44/EGFR-targeted hyaluronic acid (HA)-based nanoparticles (NPs) resulted in a 2- to 20-fold increase in wt-p53 and miR-125b gene expression in SK-LU-1 cells.

Epigenetic effects of casein-derived opioid peptides in SH-SY5Y human neuroblastoma cells.

Background: Casein-free, gluten-free diets have been reported to mitigate some of the inflammatory gastrointestinal and behavioral traits associated with autism, but the mechanism for this palliative effect has not been elucidated. We recently showed that the opioid peptide beta-casomorphin-7, derived from bovine (bBCM7) milk, decreases cysteine uptake, lowers levels of the antioxidant glutathione (GSH) and decreases the methyl donor S-adenosylmethionine (SAM) in both Caco-2 human GI epithelial cells and SH-SY5Y human neuroblastoma cells. While human breast milk can also release a similar peptide (hBCM-7), the bBCM7 and hBCM-7 vary greatly in potency; as the bBCM-7 is highly potent and similar to morphine in it's effects.