Dietary Anthocyanins Mitigate High-Fat Diet-Induced Hippocampal Inflammation in Mice.

Background: Obesity and consumption of high-fat diets (HFD) are associated with intestinal permeabilization and increased paracellular transport of endotoxins, which can promote neuroinflammation. Inflammation can affect the hypothalamic pituitary adrenal (HPA) axis, which controls responses to stress and downregulates the brain-derived neurotrophic factor (BDNF), which can promote anxiety and depression, conditions frequently found in obesity. We previously showed that consumption of anthocyanins (AC) mitigate HFD-induced insulin resistance, intestinal permeability, and inflammation.

Synergistic Suppression of NF1 Malignant Peripheral Nerve Sheath Tumor Cell Growth in Culture and Orthotopic Xenografts by Combinational Treatment with Statin and Prodrug Farnesyltransferase Inhibitor PAMAM G4 Dendrimers.

Neurofibromatosis type 1 (NF1) is a disorder in which RAS is constitutively activated due to the loss of the Ras-GTPase-activating activity of neurofibromin. RAS must be prenylated (i.e.

Oligodeoxynucleotide IMT504: Effects on Central Nervous System Repair Following Demyelination.

Multiple sclerosis (MS) is an immune-mediated central nervous system (CNS) disease characterized by demyelination resulting from oligodendrocyte loss and inflammation. Cuprizone (CPZ) administration experimentally replicates MS pattern-III lesions, generating an inflammatory response through microgliosis and astrogliosis. Potentially remyelinating agents include oligodeoxynucleotides (ODN) with a specific immunomodulatory sequence consisting of the active motif PyNTTTTGT.

Naturally occurring autoimmune disease in (NZB X NZW) F1 mice is correlated with suppression of MZ B cell development due to aberrant B Cell Receptor (BCR) signaling, which is exacerbated by exposure to inorganic mercury.

Autoimmune diseases are multifactorial and include environmental as well as genetic drivers. Although much progress has been made in understanding the nature of genetic underpinnings of autoimmune disease, by comparison much less is understood regarding how environmental factors interact with genetics in the development of autoimmunity and autoimmune disease. In this report, we utilize the (NZB X NZW) F1 mouse model of Systemic Lupus Erythematosus (SLE).

Gestational zinc deficiency impairs brain astrogliogenesis in rats through multistep alterations of the JAK/STAT3 signaling pathway.

We previously showed that zinc (Zn) deficiency affects the STAT3 signaling pathway in part through redox-regulated mechanisms. Given that STAT3 is central to the process of astrogliogenesis, this study investigated the consequences of maternal marginal Zn deficiency on the developmental timing and key mechanisms of STAT3 activation, and its consequences on astrogliogenesis in the offspring. This work characterized the temporal profile of cortical STAT3 activation from the mid embryonic stage up to young adulthood in the offspring from dams fed a marginal Zn deficient diet (MZD) throughout gestation and until postnatal day (P) 2.

Demyelination-remyelination in the Central Nervous System: Ligand-dependent Participation of the Notch Signaling Pathway.

Multiple sclerosis (MS) is an immune-mediated central nervous system disease mostly affecting young people. Multiple sclerosis and other neurodegenerative and white matter disorders involve oligodendrocyte (OL) damage and demyelination. Therefore, elucidating the signaling pathways involved in the remyelination process through the maturation of OL progenitor cells (OPCs) may contribute to the development of new therapeutic approaches.

Early Developmental Marginal Zinc Deficiency Affects Neurogenesis Decreasing Neuronal Number and Altering Neuronal Specification in the Adult Rat Brain.

During pregnancy, a decreased availability of zinc to the fetus can disrupt the development of the central nervous system leading to defects ranging from severe malformations to subtle neurological and cognitive effects. We previously found that marginal zinc deficiency down-regulates the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and affects neural progenitor cell (NPC) proliferation. This study investigated if marginal zinc deficiency during gestation in rats could disrupt fetal neurogenesis and affect the number and specification of neurons in the adult offspring brain cortex.

TGF-β pro-oligodendrogenic effects on adult SVZ progenitor cultures and its interaction with the Notch signaling pathway.

Adult neural progenitor cells (NPCs) are capable of differentiating into neurons, astrocytes, and oligodendrocytes throughout life. Notch and transforming growth factor β1 (TGF-β) signaling pathways play critical roles in controlling these cell fate decisions. TGF-β has been previously shown to exert pro-neurogenic effects on hippocampal and subventricular zone (SVZ) NPCs in vitro and to interact with Notch in different cellular types.

Galectin-1 circumvents lysolecithin-induced demyelination through the modulation of microglial polarization/phagocytosis and oligodendroglial differentiation.

Galectin-1 (Gal-1), a member of a highly conserved family of animal lectins, binds to the common disaccharide [Galβ(1-4)-GlcNAc] on both N- and O-glycans decorating cell surface glycoconjugates. Current evidence supports a role for Gal-1 in the pathophysiology of multiple sclerosis (MS), one of the most prevalent chronic inflammatory diseases. Previous studies showed that Gal-1 exerts neuroprotective effects by promoting microglial deactivation in a model of autoimmune neuroinflammation and induces axonal regeneration in spinal cord injury.

Epidermal Growth Factor Receptor Kinase Inhibitors Synergize with TCDD to Induce CYP1A1/1A2 in Human Breast Epithelial MCF10A Cells.

CYP1A1 and CYP1A2 are transcriptionally activated in the human normal breast epithelial cell line MCF10A following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Shifting MCF10A cultures to medium deficient in serum and epidermal growth factor (EGF) caused rapid reductions in the activated (i.e.

Fibulin-2 is a key mediator of the pro-neurogenic effect of TGF-beta1 on adult neural stem cells.

Transforming growth factor beta 1 (TGF-beta1), an anti-inflammatory cytokine, has been shown to have pro-neurogenic effects on adult Neural Stem Cells (aNSC) from the dentate gyrus and in vivo models. Here, we expanded the observation of the pro-neurogenic effect of TGF-beta1 on aNSC from the subventricular zone (SVZ) of adult rats and performed a functional genomic analysis to identify candidate genes to mediate its effect. 10 candidate genes were identified by microarray analysis and further validated by qRT-PCR.

Notch signaling in the pathologic adult brain.

Along the entire lifetime, Notch is actively involved in dynamic changes in the cellular architecture and function of the nervous system. It controls neurogenesis, the growth of axons and dendrites, synaptic plasticity, and ultimately neuronal death. The specific roles of Notch in adult brain plasticity and neurological disorders have begun to be unraveled in recent years, and pieces of experimental evidence suggest that Notch is operative in diverse brain pathologies including tumorigenesis, stroke, and neurological disorders such as Alzheimer's disease, Down syndrome, and multiple sclerosis.

The Notch signaling pathway: its role in focal CNS demyelination and apotransferrin-induced remyelination.

Oligodendroglial damage and demyelination are common pathological features characterizing white matter and neurodegenerative disorders. Identifying the signaling pathways involved in myelin repair through oligodendroglial progenitor maturation is essential for the development of new therapies. This article investigated the role of the Notch signaling pathway in CNS demyelination and apotransferrin-induced remyelination in a focal lysolecithin-induced demyelination model in rats.

Differential vulnerability of adult neurogenesis by adult and prenatal inflammation: role of TGF-β1.

Peripheral inflammation, both during the prenatal period and in adulthood, impairs adult neurogenesis. We hypothesized that, similar to other programming effects of prenatal treatments, only prenatal inflammation causes long-term consequences in adult neurogenesis and its neurogenic niche. To test this, pregnant Wistar rats were subcutaneously injected with lipopolysaccharide (LPS; 0.

Neuroprotective effects of human umbilical cord mesenchymal stromal cells in an immunocompetent animal model of Parkinson's disease.

Microglial activation in the substantia nigra (SN) is a ubiquitous feature in PD which could mediate toxic effects. Human mesenchymal stromal cells (hMSCs) possess immunomodulatory properties. We evaluated whether the transplantation of hMSCs obtained from umbilical cord had a neuroprotective effect in a not-immunosuppressed rat Parkinson's disease (PD) model.

p-Anilinoaniline enhancement of dioxin-induced CYP1A1 transcription and aryl hydrocarbon receptor occupancy of CYP1A1 promoter: role of the cell cycle.

The aryl hydrocarbon receptor (AhR) is targeted by ubiquitination for degradation by the proteasome shortly after its activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In silico screening identified p-anilinoaniline (pAA) as a putative inhibitor of an E2 ligase that partners with an E3 ligase implicated in AhR ubiquitination. We investigated whether pAA could modify AhR-dependent activation of its target gene CYP1A1.

Nonesterified cholesterol content of lysosomes modulates susceptibility to oxidant-induced permeabilization.

Reactive oxygen species (ROS) can induce lysosomal membrane permeabilization (LMP). Photoirradiation of murine hepatoma 1c1c7 cultures preloaded with the photosensitizer NPe6 generates singlet oxygen within acidic organelles and causes LMP and the activation of procaspases. Treatment with the cationic amphiphilic drugs (CADs) U18666A, imipramine, and clozapine stimulated the accumulation of filipin-stainable nonesterified cholesterol/sterols in late endosomes/lysosomes, but not in mitochondria.

Chronic expression of transforming growth factor-beta enhances adult neurogenesis.

Neural stem cells reside in two neurogenic regions of the adult brain: the dentate gyrus of the hippocampus (DG) and the subventricular zone (SVZ). Their proliferation, differentiation, migration and survival are modulated by intrinsic and extrinsic signals, forming a neurogenic niche. Brain cytokines have only been recently regarded as possible components of this neurogenic niche.

Brucella abortus induces the secretion of proinflammatory mediators from glial cells leading to astrocyte apoptosis.

Central nervous system (CNS) invasion by bacteria of the genus Brucella results in an inflammatory disorder called neurobrucellosis. In this study we present in vivo and in vitro evidence that B. abortus and its lipoproteins activate the innate immunity of the CNS, eliciting an inflammatory response that leads to astrogliosis, a characteristic feature of neurobrucellosis.

The more you have, the less you get: the functional role of inflammation on neuronal differentiation of endogenous and transplanted neural stem cells in the adult brain.

The differentiation of neural stem cells toward a neuronal phenotype is determined by the extracellular and intracellular factors that form the neurogenic niche. In this review, we discuss the available data on the functional role of inflammation and in particular, pro- and anti-inflammatory cytokines, on neuronal differentiation from endogenous and transplanted neural stem/progenitor cells. In addition, we discuss the role of microglial cell activation on these processes and the fact that microglial cell activation is not univocally associated with a pro-inflammatory milieu.

The chemotherapeutic agents XK469 (2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid) and SH80 (2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid) inhibit cytokinesis and promote polyploidy and induce senescence.

The therapeutic usefulness of the quinoxaline derivatives XK469 (2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid) and SH80 (2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid) has been attributed to their abilities to induce G(2)/M arrest and apoptotic or autophagic cell death. Concentrations of XK469 or SH80 > or = 5 microM were cytostatic to cultures of the normal murine melanocyte cell line Melan-a. Higher concentrations caused dose-dependent cytotoxicity.

Suppression of proliferation of two independent NF1 malignant peripheral nerve sheath tumor cell lines by the pan-ErbB inhibitor CI-1033.

Neurofibromatosis Type 1 (NF1) is characterized by the abnormal proliferation of neuroectodermal tissues and the development of certain tumors, particularly neurofibromas, which may progress into malignant peripheral nerve sheath tumors (MPNSTs). Effective pharmacological therapy for the treatment of NF1 tumors is currently unavailable and the prognosis for patients with MPNSTs is poor. Loss of neurofibromin correlates with increased expression of the epidermal growth factor receptor (EGFR) and ErbB2 tyrosine kinases and these kinases have been shown to promote NF1 tumor-associated pathologies in vivo.

Synthesis, biochemical, and cellular evaluation of farnesyl monophosphate prodrugs as farnesyltransferase inhibitors.

Certain farnesyl diphosphate (FPP) analogs are potent inhibitors of the potential anticancer drug target protein farnesyltransferase (FTase), but these compounds are not suitable as drug candidates. Thus, phosphoramidate prodrug derivatives of the monophosphate precursors of FPP-based FTase inhibitors have been synthesized. The monophosphates themselves were significantly more potent inhibitors of FTase than the corresponding FPP analogs.

The peptide specificities of the autoantibodies elicited by mouse hepatitis virus A59.

Synthetic decapeptides (N=206) covering the entire sequence of mouse liver fumarylacetoacetate hydrolase (FAH) were used to analyze the specificities of the autoantibodies (autoAb) elicited towards this enzyme in mice infected with mouse hepatitis virus (MHV). These autoAb bound mainly to N- and C-terminal FAH peptides, the most reactive sequences being 1-50 and 390-420, respectively. Surprisingly, although FAH sequence 1-50 shares a high degree of homology with various MHV proteins, the C-terminal portion does not.

Aryl hydrocarbon receptor modulation of tumor necrosis factor-alpha-induced apoptosis and lysosomal disruption in a hepatoma model that is caspase-8-independent.

Recent studies suggest that the aryl hydrocarbon receptor (AhR) modulates susceptibilities to some pro-apoptotic agents. AhR-containing murine hepatoma 1c1c7 cultures underwent apoptosis following exposure to tumor necrosis factor-alpha (TNFalpha) + cycloheximide (CHX). In contrast, Tao cells, an AhR-deficient variant of the 1c1c7 line, were refractory to this treatment.