Mitochonic acid 5 promotes the migration of mouse microglial BV­2 cells in the presence of LPS­induced inflammation via Mfn2­associated mitophagy.

Effective strategies are needed to prevent the development of neuroinflammation, which is associated with nervous system disease,\\r\\nin patients. A previous study indicated that mitochonic acid 5 (MA­5) may promote the survival of microglial cells via mitofusin 2 (Mfn2)­associated mitophagy in response to lipopolysaccharide (LPS)­induced inflammation. The current study investigated the role and underlying mechanisms of MA­5 in the migration of BV­2 cells following LPS­mediated inflammation. The results of the present study revealed that MA­5 promoted migration and upregulated the expression of F­actin, C­X­C motif chemokine receptor (CXCR) 4 and CXCR7 in BV­2 cells in response to LPS­induced inflammation. The results also indicate that MA­5 did not promote migration or upregulate the expression of F­actin, CXCR4 or CXCR7 following the inhibition of Mfn2. Overall, the results of the present study suggest that MA­5 may promote the migration of microglial cells via Mfn2­associated mitophagy following LPS­induced inflammation.

Mitochonic acid 5 ameliorates the motor deficits in the MPTP-induced mouse Parkinson's disease model by AMPK-mediated autophagy.

Parkinson's disease (PD) is a well-known neurodegenerative disorder characterized by the degeneration of dopaminergic neurons, and oxidative stress and neuroinflammation are also associated with the pathogenesis of PD. Mitochonic acid 5 (MA-5), an analogue of indole-3-acetic acid, exerts key protective roles in inhibiting apoptosis, oxidative stress and neuroinflammation in multiple diseases. However, whether MA-5 can be beneficial for PD remains unclear. Hence, the aim of this study was to investigate the neuroprotective role of MA-5 in PD. In the current study, MPTP-challenged mice were treated as the in vivo model, and the effect of MA-5 on the motor function, neuronal survival, oxidative stress, neuroinflammation and the underlying mechanisms involved with AMPK and autophagy were determined. We revealed that MA-5 obviously up-regulated the phosphorylation of AMPK and promoted the autophagy (indicated by the increased LC3II/LC3I, parkin, pink and decreased p62) in substantia nigra (SN), ameliorated the motor deficits, up-regulated the expression of TH, suppressed the inflammation (indicated by the decreased protein levels of interleukin (IL)-1b, IL-6, tumour necrosis factor a) in SN in MPTP-induced mice. However, these patterns were reversed after the treatment of Compound C, an inhibitor of AMPK; also, after the application of CSA, an inhibitor of autophagy, MA-5 cannot play against the neurotoxicity of MPTP in mice. These combined results suggest that MA-5 can protect against MPTP-induced neurotoxicity to ameliorate the impaired motor function, which may be modulated via activation of AMPK-induced autophagy.

Tryptophan in the diet ameliorates motor deficits in a rotenone-induced rat Parkinson's disease model via activating the aromatic hydrocarbon receptor pathway.

BACKGROUND AND PURPOSE: Parkinson's disease (PD), a common neurodegenerative disorder with motor and nonmotor symptoms, does not have effective treatments. Dietary tryptophan (Trp) supplementation has potential benefits for the treatment of multiple disorders. However, whether additional Trp in the diet could be beneficial for PD remains to beinvestigated. In the present study, the neuroprotective role of dietary Trp on a rotenone-induced rat model of PD was determined. METHODS: The rotenone was injected to build the PD model, and then the rats were treated with Trp in the diet. And then, an open field test, western blot analysis, and enzyme linked immunosorbent assay (ELISA) were performed. RESULTS: We observed that dietary Trp significantly ameliorated impaired motor function, upregulated tyrosine hydroxylase expression, inhibited the nuclear transport of Nuclear factor-kappa B (NF-κB) in substantia nigra (SN), and downregulated the protein levels of IL-1ß, IL-6, and TNF-α in serum in rotenone-treated rats. However, these patterns were reversed in response to treatment with ampicillin, an agent that can clean intestinal Trp metabolism flora. Moreover, after using CH223191, an inhibitor of the aromatic hydrocarbon receptor (AhR) pathway, dietary Trp could not exert neuroprotective roles in the rotenone-induced rat model of PD. CONCLUSION: These results suggest that Trp in the diet can protect against rotenone-induced neurotoxicity to ameliorate motor deficits, which may be mediated through activating AhR pathway.

Mitochonic acid 5 regulates mitofusin 2 to protect microglia.

Microglial apoptosis is associated with neuroinflammation and no effective strategies are currently available to protect microglia against inflammation-induced apoptosis. Mouse microglial BV-2 cells (5 × 106) were incubated with 10 µg/mL lipopolysaccharides for 12 hours to mimic an inflammatory environment. Then the cells were co-cultured with mitochonic acid 5 (MA-5) for another 12 hours. MA-5 improved the survival of lipopolysaccharide-exposed cells. MA-5 decreased the activity of caspase-3, which is associated with apoptosis. MA-5 reduced the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells, and increased adenosine triphosphate levels in cells. MA-5 decreased the open state of the mitochondrial permeability transition pore and reduced calcium overload and diffusion of second mitochondria-derived activator of caspase (Smac). MA-5 decreased the expression of apoptosis-related proteins (mitochondrial Smac, cytoplasmic Smac, pro-caspase-3, cleaved-caspase-3, and caspase-9), and increased the levels of anti-apoptotic proteins (Bcl2 and X-linked inhibitor of apoptosis protein), mitochondria-related proteins (mitochondrial fusion protein 2, mitochondrial microtubule-associated proteins 1A/1B light chain 3B II), and autophagy-related proteins (Beclin1, p62 and autophagy related 5). However, MA-5 did not promote mitochondrial homeostasis or decrease microglial apoptosis when Mitofusin 2 expression was silenced. This shows that MA-5 increased Mitofusin 2-related mitophagy, reversed cellular energy production and maintained energy metabolism in BV-2 cells in response to lipopolysaccharide-induced inflammation. These findings indicate that MA-5 may promote the survival of microglial cells via Mitofusin 2-related mitophagy in response to lipopolysaccharide-induced inflammation.

Genistein exerts a cell-protective effect via Nrf2/HO-1/ /PI3K signaling in Ab25-35-induced Alzheimer's disease models in vitro.

INTRODUCTION: Alzheimer's disease (AD), a very common neurodegenerative disorder, is mainly characterized by the deposition of b-amyloid protein (Ab) and extensive neuronal cell death. Currently, there are no satisfactory therapeutic approaches for AD. Although neuroprotective effects of genistein against Ab-induced toxicity have been reported, the underlying molecular mechanisms remain unclear. Furthermore, the PI3K/Akt/Nrf2 signaling pathway is associated with AD. The aim of the study was to investigate whether genistein can modulate Nrf2/HO-1/PI3K signaling to treat AD. MATERIALS AND METHODS: Cell viability assay, the measurement of heme oxygenase-1 (HO-1) expression by reverse transcription-polymerase chain reaction (RT-qPCR), and western blot were performed on the SH-SY5Y cells induced by Ab25-35 in response to the treatment with genistein. Moreover, PI3K p85 phosphorylation was measured. RESULTS: Genistein enhanced the HO-1expression at both the mRNA and protein levels, as well as the PI3K p85 phosphorylation level. In addition, genistein increased the survival of SH-SY5Y cells treated with Ab25-35via HO-1 signaling. However, following transfection with Nrf2 small interfering RNA (siRNA) and treatment with LY294002, an inhibitor of PI3K p85, genistein could not upregulate HO-1 to exert neuroprotective effects on SH-SY5Y cells treated with Ab25-35. CONCLUSIONS: These results suggest that genistein exerts a neuroprotective effect on SH-SY5Y cells in vitro via Nrf2/ HO-1/PI3K signaling, providing a foundation for the application of genistein in the treatment of neurodegenerative diseases related to Nrf2/HO-1/PI3K signaling.

The characterization of the mitochondrial genome of Calineuria stigmatica (Plecoptera: Perlidae).

The nearly complete sequence of the mitochondrial DNA of Calineuria stigmatica has been completed and annotated in this study. The circular genome is 15,070 bp in length with an A + T content of 61.8% and contains 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, and two ribosomal RNA (rRNA) genes. The control region can only be assembled partially. All PCGs use normal start codon ATN, while COI, ND1, and ND5 use CCG, TTG, and GTG as start codon, respectively. Meanwhile, 10 PCGs use the typical termination codons TAN, except COII, ND4, ND5, which stopped with the incomplete terminaton signal T--. Based on 13 PCGs and two rRNAs using the Bayesian (BI) method supported that C. stigmatica was closely grouped with four other Acroneuriinae species. Our results provide basic data for further study of phylogeny in Plecoptera.