No abstract

Background: Urolithin A (URA) is an intestinal microbiota metabolic product from ellagitannin-containing foods with multiple biological activities. However, its role in autoimmune diseases is largely unknown. Here, for first time, we demonstrate the therapeutic effect of URA in an experimental autoimmune encephalomyelitis (EAE) animal model. Methods: Therapeutic effect was evaluated via an active and passive EAE animal model in vivo. The function of URA on bone marrow-derived dendritic cells (BM-DCs), T cells, and microglia were tested in vitro. Findings: Oral URA (25 mg/kg/d) suppressed disease progression at prevention, induction, and effector phases of preclinical EAE. Histological evaluation showed that significantly fewer inflammatory cells, decreased demyelination, lower numbers of M1-type microglia and activated DCs, as well as reduced infiltrating Th1/ Th17 cells were present in the central nervous system (CNS) of the URA-treated group. URA treatment at 25 mM inhibited the activation of BM-DCs in vitro, restrained Th17 cell differentiation in T cell polarization conditions, and in a DC-CD4 + T cell co-culture system. Moreover, we confirmed URA inhibited pathogenicity of Th17 cells in adoptive EAE. Mechanism of URA action was directly targeting Aryl Hydrocarbon Receptor (AhR) and modulating the signaling pathways. Interpretation: Collectively, our study offers new evidence that URA, as a human microbial metabolite, is valuable to use as a prospective therapeutic candidate for autoimmune diseases.

No abstract

No abstract

The free radical nitric oxide (NO), a main member of neuroinflammatory cytokine and a gaseous molecule produced by activated microglia, has many physiological functions, including neuroinflammation. In the present study, we evaluated the effects of serial 16-dehydropregnenolone-3-acetate derivatives on lipopolysaccharide (LPS)-induced NO production and inducible nitric oxide synthase (iNOS) expression in BV-2 microglial cells. Among the six derivatives tested, the increases in NO production and iNOS expression observed in BV-2 microglial cells after LPS stimulation were significantly inhibited by treatment with 16α, 17α-epoxypregnenolone-20-oxime. Moreover, the inhibitory effect of 16α,17α-epoxypregnenolone-20-oxime on NO production was similar to that of S-methylisothiourea sulfate (SMT), an iNOS inhibitor. Further studies showed that 16α,17α-epoxypregnenolone-20-oxime inhibited c-Jun N-terminal kinase (JNK) phosphorylation but not inhibitor kappa B (IκB)-α degradation. Our data in LPS-stimulated microglia cells suggest that 16α,17α-epoxypregnenolone-20-oxime might be a candidate therapeutic for treatment of NO induced neuroinflammation and could be a novel iNOS inhibitor. Key words microglia; nitric oxide; neuroinflammationMicroglial cells, the tissue macrophages of the central nervous system (CNS), 1-3) play a crucial role in the recognition and phagocytic removal of apoptotic neurons. Microglial cell activation is regarded as a marker of brain injury development in many neuronal diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). 4,5) Neuron inflammation also accompanies neuron degeneration in these diseases. During neuroinflammation, microglias are activated and secrete various cytokines. Microglial cells respond to inflammatory agonists, such as bacterial lipopolysaccharide (LPS), the human immunodeficiency virus (HIV) coat protein gp120, and β-amyloidrelated peptides, by producing many inflammatory factors, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β) and nitric oxide (NO). These microglial products are thought to be responsible for glia-mediated neurotoxicity. 6,7)The free radical NO, a gaseous molecule produced by activated microglia, has many physiological functions, including neuroinflammation. In the brain, NO serves as a neurotransmitter and a second messenger molecule mediating a variety of neuronal functions. 8) Deletion of Osteopontin (OPN) in mice increased thalamic neurodegeneration through regulation inducible nitric oxide synthase (iNOS) expression, 9) an enzyme that produces NO. The interactions of NO are not restricted to a single receptor, it can react with other inorganic molecules (such as oxygen, superoxide or transition metals), structures in DNA (pyrimidine bases), prosthetic groups (such as heme) and proteins (leading to S-nitrosylation of thiol groups, nitration of tyrosine residues or disruption of metal-sulfide clusters such as zinc-finger domains and ironsulfide complexes).10) In addition, a recent repor...