Mitsunari Nakajima - Academia.edu (original) (raw)

Papers by Mitsunari Nakajima

Journal of Multiple Sclerosis, 2015

JMSO, an open access journal Jou rn a l o f Mul tiple S c le ro sis

NeuroSci

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Nutraceuticals

We previously reported that the dried peel powder of Citrus kawachiensis, a citrus product of Jap... more We previously reported that the dried peel powder of Citrus kawachiensis, a citrus product of Japan, exerted anti-inflammatory and neuroprotective effects in the brains of transient global cerebral ischemia model mice. It also ameliorated the hyperphosphorylation of Tau protein and the suppression of neurogenesis in the brains of the senescence-accelerated mouse-prone 8 aging model. Chronic unpredictable mild stress (CUMS) induces anxiety-like behavior, changes the composition of the gut microbiota and suppresses neurogenesis in the hippocampus. Therefore, we herein examined the effects of the dried peel powder of C. kawachiensis in a CUMS mouse model: CUMS enhanced locomotor activity, shown as the distance travelled in the open field test at the beginning of the test, while the C. kawachiensis treatment suppressed this increase. The C. kawachiensis treatment also prevented CUMS-induced decreases in hippocampal neurogenesis. The CUMS treatment changed the composition of the gut micr...

Biological and Pharmaceutical Bulletin, 2021

We previously reported a screening method for caloric restriction mimetics (CRM), a group of plan... more We previously reported a screening method for caloric restriction mimetics (CRM), a group of plantderived compounds capable of inducing good health and longevity. In the present study, we explored the possibility of using this method to screen CRM drugs for drug repositioning. The method, T-cell activationinhibitory assay, is based on inductive logic. Most of CRM such as resveratrol have been reported to suppress T-cell activation and have anti-inflammatory functions. Here, we assessed the activity of 12 antiallergic drugs through T-cell activation-inhibitory assay and selected four that showed the lowest IC 50 values-ibudilast (IC 50 0.97 µM), azelastine (IC 50 7.2 µM), epinastine (IC 50 16 µM), and amlexanox (IC 50 33 µM)-for further investigation. Because azelastine showed high cytotoxicity, we selected only the remaining three drugs to study their biological functions. We found that all the three drugs suppressed the expression of interleukin (IL)-6, an inflammatory cytokine, in lipopolysaccharide-treated macrophage cells, with ibudilast being the strongest suppressor. Ibudilast also suppressed the secretion of another inflammatory cytokine, tumor necrosis factor (TNF)-α, and the expression of an inflammatory enzyme, cyclooxygenase-2, in the cells. These results suggest that T-cell activation-inhibitory assay can be used to screen potential CRM drugs having anti-inflammatory functions for the purpose of drug repositioning.

Neuroglia, 2021

Inflammation is the cause and/or result of many diseases in peripheral tissues and the central ne... more Inflammation is the cause and/or result of many diseases in peripheral tissues and the central nervous system. Recent findings suggested that inflammation in peripheral tissue induces an inflammatory response in the brain that activates glial cells, which, in turn, induce neuronal cell dysfunction. Therefore, anti-inflammatory compounds are important for the suppression of chronic inflammation and prevention of disease. The present study revealed microglial activation in the hippocampus of the brain two days after the peripheral administration of lipopolysaccharide (LPS). Furthermore, the expression of the synaptic vesicle membrane protein, synaptophysin, in the CA3 stratum lucidum of the hippocampus was down-regulated 7 days after the LPS injection. The administration of tocotrienols, a type of vitamin E, significantly attenuated these changes in the hippocampus. Collectively, the present results demonstrated the spread of peripheral inflammatory responses to the brain, in which gl...

Phytochemistry Letters, 2020

Cynandione A (CA) is a major ingredient of Cynanchum wilfordii. Here, we report a new function of... more Cynandione A (CA) is a major ingredient of Cynanchum wilfordii. Here, we report a new function of CA in adipogenesis in 3T3-L1 cells, a preadipocyte cell line. During adipogenic differentiation in 3T3-L1 cells, CA boosted the process by enhancing the expression of key adipogenic transcription factors (Pparg and C/ebpa), brown adipocyte-related genes (Prdm16, Pgc-1a, Cidea, and Ucp1), and beige adipocyte-related genes (Tbx1 and Cited1). Additionally, CA increased mitochondrial mass and expression levels of mitochondria-related genes (Sirt3 and Tfam) in the cells. These results suggest that CA induces adipogenesis and beige adipocyte-related phenotype in adipocyte lineage cells.

International Journal of Molecular Sciences, 2019

We previously demonstrated that auraptene (AUR), a natural coumarin derived from citrus plants, e... more We previously demonstrated that auraptene (AUR), a natural coumarin derived from citrus plants, exerts anti-inflammatory effects in the brain, resulting in neuroprotection in some mouse models of brain disorders. The present study showed that treatment with AUR significantly increased the release of glial cell line-derived neurotrophic factor (GDNF), in a dose- and time-dependent manner, by rat C6 glioma cells, which release was associated with increased expression of GDNF mRNA. These results suggest that AUR acted as a neuroprotective agent in the brain via not only its anti-inflammatory action but also its induction of neurotrophic factor. We also showed that (1) the AUR-induced GDNF production was inhibited by U0126, a specific inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) 1/2, and by H89, a specific inhibitor of protein kinase A (PKA); and (2) AUR induced the phosphorylation of cAMP response element-binding protein (CREB), a transcript...

European Journal of Pharmacology, 2019

4′-heptamethoxyflavone (HMF), a naturally occurring polymethoxyflavone found in citrus peel, is k... more 4′-heptamethoxyflavone (HMF), a naturally occurring polymethoxyflavone found in citrus peel, is known to have neuroprotective, anti-inflammatory, and immunomodulatory effects. However, the effects of HMF on adipogenesis remain unclear. Here, we demonstrate that HMF inhibits the early stage of adipogenesis and maturation in 3T3-L1 adipocytes. HMF treatment during preadipocyte differentiation for 8 days reduced lipid accumulation in a dose-dependent manner, and the expression levels of key adipogenic transcription factors (peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα)) and the lipogenic transcription factor, sterol regulatory element-binding protein (SREBP1), were lower after the initial 4 days of the differentiation. Moreover, PPARγ expression level was lower even after the initial 2 days, but C/EBPα and SREBP1 expression was not. HMF upregulated the phosphorylation of protein kinase A catalytic subunit α (PKACα), AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase (ACC) in 3T3-L1 cells. The phosphorylation of ACC leads to the inhibition of adipogenesis. Furthermore, the induction of phosphorylation of AMPK and ACC by HMF was abolished by RNA interference targeting PKACα. Taken together, our results suggest that HMF might inhibit the early stage of adipogenesis via the activation of PKA signaling in 3T3-L1 cells.

Journal of Nutritional Science and Vitaminology, 2019

Our previous study showed that the subcutaneous administration of auraptene (AUR) suppresses infl... more Our previous study showed that the subcutaneous administration of auraptene (AUR) suppresses inflammatory responses including the hyperactivation of microglia in the substantia nigra (SN) of the midbrain of lipopolysaccharide-induced Parkinson's disease (PD)-like mice, as well as inhibits dopaminergic neuronal cell death in this region. We also showed that the oral administration of the dried peel powder of Citrus kawachiensis, which contains relatively high amounts of AUR, suppresses inflammatory responses including the hyperactivation of microglia in the systemically inflamed brain. In the present study we showed that the oral administration of this dried peel powder successfully suppressed microglial activation and protected against dopaminergic neuronal cell death in the SN, suggesting its potential as a neuroprotective agent for the treatment of patients with PD.

PharmaNutrition, 2018

decreased the T-cell activation and growth belong to the hydrolysable tannin class, we inferred t... more decreased the T-cell activation and growth belong to the hydrolysable tannin class, we inferred that the tannins would be hydrolyzed in a culture containing fetal bovine serum to yield gallic acid and/or ellagic acid. Therefore, we assessed the effect of these two compounds on the T-cell activation and growth and cytokine secretion in the culture. Both compounds decreased the T-cell activation/growth and the secretion of interleukin-4, interleukin-10, and interferon-. These results suggested that walnuts contained compounds that either suppressed or promoted T-cell growth and that supplementation of hydrolysable tannins to walnut-containing foods might ameliorate allergic reaction by walnut consumption.

International Archives of Allergy and Immunology, 2017

In a previous study, we reported that interleukin-4 production was reduced in spleen cells of mic... more In a previous study, we reported that interleukin-4 production was reduced in spleen cells of mice administered 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF), which is a polymethoxyflavone found at high concentrations in the peel of various citrus fruits. In this study, we investigated the function of HMF on the growth of T cells cultured from the spleens of mice. HMF decreased the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) by anti-CD3/CD28 antibody-stimulated mouse spleen cells. HMF inhibited the activities of phosphodiesterase (PDE) enzymes prepared from bovine brain and human PDE4B and PDE3B enzymes. The cyclic AMP (cAMP) content in anti-CD3/CD28 antibody-stimulated spleen cells increased after HMF treatment in vitro. These results suggest that HMF inhibits T-cell growth and affects immune function via reduced PDE activity and increased cAMP content.

International Journal of Molecular Sciences, 2016

In patients with Parkinson's disease (PD), hyperactivated inflammation in the brain, particularly... more In patients with Parkinson's disease (PD), hyperactivated inflammation in the brain, particularly microglial hyperactivation in the substantia nigra (SN), is reported to be one of the triggers for the delayed loss of dopaminergic neurons and sequential motor functional impairments. We previously reported that (1) auraptene (AUR), a natural prenyloxycoumain, suppressed inflammatory responses including the hyperactivation of microglia in the ischemic brain and inflamed brain, thereby inhibiting neuronal cell death; (2) 7-isopentenyloxycoumarin (7-IP), another natural prenyloxycoumain, exerted anti-inflammatory and neuroprotective effects against excitotoxicity; and (3) 4-geranyloxyferulic acid (GOFA), a natural prenyloxycinnamic acid, also exerted anti-inflammatory effects. In the present study, using an intranigral lipopolysaccharide (LPS)-induced PD-like mouse model, we investigated whether AUR, 7-IP, and GOFA suppress microglial activation and protect against dopaminergic neuronal cell death in the SN. We successfully showed that these prenyloxyphenylpropanoids exhibited these prospective abilities, suggesting the potential of these compounds as neuroprotective agents for patients with PD.

Biological and Pharmaceutical Bulletin

In Japan, ibudilast (IBD) is a therapeutic agent used to treat asthma, allergic conjunctivitis, a... more In Japan, ibudilast (IBD) is a therapeutic agent used to treat asthma, allergic conjunctivitis, and dizziness caused by cerebrovascular disease. Previously, we have reported that IBD could reduce the secretion of proinflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor (TNF)-α, in lipopolysaccharide (LPS)-treated RAW264.7 monocyte-linage cells in vitro. In the present study, we examined the antiinflammatory effects of IBD in vivo. As IL-6 is a biomarker for sepsis and has been suggested to exacerbate symptoms, we determined whether IBD reduces IL-6 levels in vivo and improves sepsis symptoms in animal models. We observed that IBD treatment reduced IL-6 levels in the lungs of LPS-treated mice and improved LPS-induced hypothermia, one of the symptoms of sepsis. In addition, IBD reduced IL-6 and attenuated plasminogen activator inhibitor-1 (PAI-1) and alanine aminotransferase (ALT) levels in the serum of LPStreated mice. Elevated PAI-1 levels exacerbate sepsis-induced disseminated intravascular coagulation (DIC), and ALT is a biomarker for liver dysfunction. IBD improved the survival of mice administered a lethal dose of LPS. IBD administration ameliorated kidney pathology of model mice. Overall, these results suggest that IBD exerts anti-inflammatory functions in vivo and could be a drug candidate for treating endotoxemia, including sepsis.

Plants

Folia Pharmacologica Japonica

Proceedings for Annual Meeting of The Japanese Pharmacological Society

The peel of Citrus kawachiensis (Kawachi Bankan), a citrus species grown in Ehime, Japan, is abun... more The peel of Citrus kawachiensis (Kawachi Bankan), a citrus species grown in Ehime, Japan, is abundant in auraptene. Hyperglycemia and brain ischemia induce inflammation and oxidative stress and cause massive damage in the brain; therefore, we examined the anti-inflammatory and other effects of the dried peel powder of C. kawachiensis in the type 2 diabetic db/db mice model and global cerebral ischemia mice. The C. kawachiensis treatment inhibited astroglial activation in the hippocampus and the hyperphosphorylation of tau protein in hippocampal neurons, and also relieved the suppression of neurogenesis in the dentate gyrus of the hippocampus in the db/db mice. The C. kawachiensis treatment inhibited microglial and astroglial activation, and neuronal cell death in the hippocampus of transient global cerebral ischemia mice. It was suggested that the dried peel powder of C. kawachiensis exerts antiinflammatory and neuroprotective effects in the brain. Auraptene, a coumarin compound, have been shown to exert anti-inflammatory effects in peripheral tissues; therefore, we attempted to demonstrate the effect in the brains in streptozotocin-induced hyperglycemic mice and transient global cerebral ischemia mice. Auraptene administration showed the similar effects as the peel of C. kawachiensis in the hippocampus of these mice models. These results suggested that auraptene have potential effects as a neuroprotective agent in the peel of C. kawachiensis.

Molecules

(1) Background: Our published data have indicated that (1) auraptene (AUR), a citrus ingredient, ... more (1) Background: Our published data have indicated that (1) auraptene (AUR), a citrus ingredient, has neuroprotective effects on the mouse brain, owing to its ability to suppress inflammation, such as causing a reduction in hyperactivation of microglia and astrocytes; (2) AUR has the ability to trigger phosphorylation (activation) of extracellular signal-related kinase (ERK) and cAMP response element-binding protein (CREB) in neuronal cells; (3) AUR has the ability to induce glial cell line-derived neurotrophic factor (GDNF) synthesis/secretion in rat C6 glioma cells. The well-established fact that the ERK-CREB pathway plays an important role in the production of neurotrophic factors, including GDNF and brain-derived neurotrophic factor (BDNF), prompted us to investigate whether AUR would also have the ability to induce BDNF expression in neuronal cells. (2) Methods: Mouse neuroblastoma neuro2a cells were cultured and the effects of AUR on BDNF mRNA expression and protein content were evaluated by RT-PCR and ELISA, respectively. (3) Results: The levels of BDNF mRNA and secreted BDNF were significantly increased by AUR in a dose-and time-dependent manner in neuro2a cells. (4) Conclusion: The induction of BDNF in neuronal cells might be, in part, one of the mechanisms accounting for the neuroprotective effects of AUR.