Long term administration of loquat leaves and their major component, ursolic acid, attenuated endogenous amyloid-ß burden and memory impairment.

Loquat (Eriobotrya japonica) leaves contain many bioactive components such as ursolic acid (UA) and amygdalin. We investigated the effects of loquat leaf powder and methanol extract in human neuroglioma H4 cells stably expressing the Swedish-type APP695 (APPNL-H4 cells) and C57BL/6 J mice. Surprisingly, the extract greatly enhanced cellular amyloid-beta peptide (Aß) 42 productions in APPNL-H4 cells. Administration of leaf powder increased Aß42 levels after 3 months and decreased levels after 12 months compared to control mice. Leaf powder had no effect on working memory after 3 months, but improved working memory after 12 months. Administration of UA decreased Aß42 and P-tau levels and improved working memory after 12 months, similar to the administration of leave powder for 12 months. Amygdalin enhanced cellular Aß42 production in APPNL-H4 cells, which was the same as the extract. Three-month administration of amygdalin increased Aß42 levels slightly but did not significantly increase them, which is similar to the trend observed with the administration of leaf powder for 3 months. UA was likely the main compound contained in loquat leaves responsible for the decrease in intracerebral Aß42 and P-tau levels. Also, amygdalin might be one of the compounds responsible for the transiently increased intracerebral Aß42 levels.

Suppressive Effect of Fruiting Bodies of Medicinal Mushrooms on Demyelination and Motor Dysfunction in a Cuprizone-Induced Multiple Sclerosis Mouse Model.

Epidemiologic studies have shown a high prevalence of multiple sclerosis (MS) in Europe and North America, and a low prevalence in East Asia. Mushrooms contain various biological response modifiers (BRMs) and are widely used in traditional Chinese medicine in East Asian countries. To investigate whether mushrooms have potential beneficial effects on MS, we administered mushrooms to cuprizone (bis-cyclohexanone-oxalyldihydrazone, CPZ)-induced MS model mice. This model is used to study the processes of demyelination in the CNS. The CPZ-induced demyelination is involved in the apoptotic death of mature oligodendrocytes, neuroinflammation, and motor dysfunction. Mice were fed a powdered diet containing 5% each mushroom and CPZ diet for 5 weeks, which coincides with peak demyelination. We measured the body weight of the mice, evaluated their motor function using a rotarod, and quantified the myelin levels using Black-Gold II staining. Ganoderma lucidum and Hericium erinaceus treatments showed recovery from weight loss. Pleurotus eryngii, G. lucidum, and Flammulina velutipes treatments significantly improved CPZ-induced motor dysfunction. P. eryngii, G. lucidum, F. velutipes, and H. erinaceus treatments effectively suppressed CPZ-induced demyelination. The four medicinal mushrooms may be promising BRMs for prevention and alleviation of the symptoms of MS.

Controllable secretion of multilayer vesicles driven by microbial polymer accumulation.

Membrane vesicles (MVs) are formed in various microorganisms triggered by physiological and environmental phenomena. In this study, we have discovered that the biogenesis of MV took place in the recombinant cell of Escherichia coli BW25113 strain that intracellularly accumulates microbial polyester, polyhydroxybutyrate (PHB). This discovery was achieved as a trigger of foam formation during the microbial PHB fermentation. The purified MVs were existed as a mixture of outer MVs and outer/inner MVs, revealed by transmission electron microscopy. It should be noted that there was a good correlation between MV formation and PHB production level that can be finely controlled by varying glucose concentrations, suggesting the causal relationship in both supramolecules artificially produced in the microbial platform. Notably, the controllable secretion of MV was governed spatiotemporally through the morphological change of the E. coli cells caused by the PHB intracellular accumulation. Based on a hypothesis of PHB internal-pressure dependent envelope-disorder induced MV biogenesis, here we propose a new Polymer Intracellular Accumulation-triggered system for MV Production (designated "PIA-MVP") with presenting a mechanistic model for MV biogenesis. The PIA-MVP is a promising microbial platform that will provides us with a significance for further study focusing on biopolymer capsulation and cross-membrane transportation for different application purposes.

A peripheral lipid sensor GPR120 remotely contributes to suppression of PGD2-microglia-provoked neuroinflammation and neurodegeneration in the mouse hippocampus.

BACKGROUND: Neuroinflammation is a key pathological component of neurodegenerative disease and is characterized by microglial activation and the secretion of proinflammatory mediators. We previously reported that a surge in prostaglandin D2 (PGD2) production and PGD2-induced microglial activation could provoke neuroinflammation. We also reported that a lipid sensor GPR120 (free fatty acid receptor 4), which is expressed in intestine, could be activated by polyunsaturated fatty acids (PUFA), thereby mediating secretion of glucagon-like peptide-1 (GLP-1). Dysfunction of GPR120 results in obesity in both mice and humans. METHODS: To reveal the relationship between PGD2-microglia-provoked neuroinflammation and intestinal PUFA/GPR120 signaling, we investigated neuroinflammation and neuronal function with gene and protein expression, histological, and behavioral analysis in GPR120 knockout (KO) mice. RESULTS: In the current study, we discovered notable neuroinflammation (increased PGD2 production and microglial activation) and neurodegeneration (declines in neurogenesis, hippocampal volume, and cognitive function) in GPR120 KO mice. We also found that Hematopoietic-prostaglandin D synthase (H-PGDS) was expressed in microglia, microglia were activated by PGD2, H-PGDS expression was upregulated in GPR120 KO hippocampus, and inhibition of PGD2 production attenuated this neuroinflammation. GPR120 KO mice exhibited reduced intestinal, plasma, and intracerebral GLP-1 contents. Peripheral administration of a GLP-1 analogue, liraglutide, reduced PGD2-microglia-provoked neuroinflammation and further neurodegeneration in GPR120 KO mice. CONCLUSIONS: Our results suggest that neurological phenotypes in GPR120 KO mice are probably caused by dysfunction of intestinal GPR120. These observations raise the possibility that intestinal GLP-1 secretion, stimulated by intestinal GPR120, may remotely contributed to suppress PGD2-microglia-provoked neuroinflammation in the hippocampus.

Correction to: Protective and therapeutic role of 2-carbacyclic phosphatidic acid in demyelinating disease.

After publication of the article [1], it was brought to our attention that an acknowledgement was missing from the original version.

The flavonoid Baicalein attenuates cuprizone-induced demyelination via suppression of neuroinflammation.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system characterized by recurrent and progressive demyelination/remyelination cycles, neuroinflammation, oligodendrocyte loss, and axonal pathology. Baicalein isolated from the roots of Scutellaria baicalensis has been shown to exert anti-inflammatory and antioxidant effects. The cuprizone model is an established mouse model of MS and causes demyelination and motor dysfunction and induces neuroinflammation, such as glial activation and pro-inflammatory cytokine production. To determine whether Baicalein attenuates cuprizone-induced demyelination, we administrated Baicalein to cuprizone-exposed mice. Baicalein attenuated weight loss (P<0.05) and motor dysfunction (P<0.05) in the cuprizone model mice. Baicalein treatment effectively suppressed the demyelination (P<0.01) and gene expressions of CNP (P<0.05) and MBP (P<0.05). Baicalein treatment also inhibited the cuprizone-induced increase in Iba1-positive microglia (P<0.001), GFAP-positive astrocytes (P<0.001), and the gene expressions of CD11b (P<0.01), GFAP (P<0.05), TNFα (P<0.05), IL-1ß (P<0.05), and iNOS (p<0.01). We found that Baicalein treatment attenuated cuprizone-induced demyelination, glial activation, pro-inflammatory cytokine expression, and motor dysfunction. Our results suggest that Baicalein may be a useful therapeutic agent in demyelinating diseases to suppress neuroinflammation.

Protective and therapeutic role of 2-carba-cyclic phosphatidic acid in demyelinating disease.

BACKGROUND: Multiple sclerosis is a neuroinflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by recurrent and progressive demyelination/remyelination cycles, neuroinflammation, oligodendrocyte loss, demyelination, and axonal degeneration. Cyclic phosphatidic acid (cPA) is a natural phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. We reported earlier that cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. We designed, chemically synthesized, and metabolically stabilized derivatives of cPA: 2-carba-cPA (2ccPA), a synthesized compound in which one of the phosphate oxygen molecules is replaced with a methylene group at the sn-2 position. In the present study, we investigated whether 2ccPA exerts protective effects in oligodendrocytes and suppresses pathology in the two most common mouse models of multiple sclerosis. METHODS: To evaluate whether 2ccPA has potential beneficial effects on the pathology of multiple sclerosis, we investigated the effects of 2ccPA on oligodendrocyte cell death in vitro and administrated 2ccPA to mouse models of experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. RESULTS: We demonstrated that 2ccPA suppressed the CoCl2-induced increase in the Bax/Bcl-2 protein expression ratio and phosphorylation levels of p38MAPK and JNK protein. 2ccPA treatment reduced cuprizone-induced demyelination, microglial activation, NLRP3 inflammasome, and motor dysfunction. Furthermore, 2ccPA treatment reduced autoreactive T cells and macrophages, spinal cord injury, and pathological scores in EAE, the autoimmune multiple sclerosis mouse model. CONCLUSIONS: We demonstrated that 2ccPA protected oligodendrocytes via suppression of the mitochondrial apoptosis pathway. Also, we found beneficial effects of 2ccPA in the multiperiod of cuprizone-induced demyelination and the pathology of EAE. These data indicate that 2ccPA may be a promising compound for the development of new drugs to treat demyelinating disease and ameliorate the symptoms of multiple sclerosis.

Cyclic phosphatidic acid treatment suppress cuprizone-induced demyelination and motor dysfunction in mice.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system leading to progressive cognitive and motor dysfunction, which is characterized by neuroinflammation, demyelination, astrogliosis, loss of oligodendrocytes, and axonal pathologies. Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. In this study, we investigated the effects of cPA on cuprizone-induced demyelination, which is a model of multiple sclerosis. Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, astrocyte and microglial activation, and motor dysfunction. Simultaneous administration of cPA effectively attenuated cuprizone-induced demyelination, glial activation, and motor dysfunction. These data indicate that cPA may be a useful treatment to reduce the extent of demyelination and the severity of motor dysfunction in multiple sclerosis. cPA is a potential lead compound in the development of drugs for the treatment of this devastating disease.