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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 microbiota by reducing the abundance of Lactobacillus and increasing that of Bacteroides, whereas the C. kawachiensis treatment attenuated these changes. Collectively, the present results suggest that the dried peel powder of C. kawachiensis exerts neuroprotective effects in the brain and maintains the condition of the microbiome under mild stress.

Synthesis of amino acid-derived vinyl polymers with precisely controlled hydropathy by ultra-rapid reversible addition fragmentation chain transfer polymerization and their thermoresponsive behavior in water.

Citrus kawachiensis (Kawachi Bankan), is a citrus species grown in Ehime, Japan, and its peel is abundant in 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF). We have recently revealed that HMF, one of the citrus flavonoids, has anti-inflammatory activity and neuroprotective abilities in the brain against global cerebral ischemia. HMF rescued neuronal cell death in the hippocampus and suppressed the activation of microglia, whose activation have been shown to significantly aggravate neurological deficit scores for ischemic mice. In the Y-maze test, HMF showed protection against ischemia-induced short-term memory dysfunction; in addition, HMF enhanced the expression of brain-derived neurotrophic factor and accelerated neurogenesis in the hippocampus. Similarly, the powder of the peel of C. kawachiensis showed anti-inflammatory activity and neuroprotective abilities in the ischemic brain. To further examine the effect of the peel of C. kawachiensis, we administered it to senescence-accelerated-mouse prone 8 (SAMP8) mice, which show memory impairment and brain inflammation, tau hyperphosphorylation, and neuronal dysfunction. The C. kawachiensis treatment inhibited microglial activation and the hyperphosphorylation of tau protein in hippocampal neurons, and also relieved the suppression of neurogenesis in the dentate gyrus of the hippocampus in SAMP8. These results suggest that HMF and the peel of C. kawachiensis have potential effects as neuroprotective and anti-dementia agents.

We previously reported a screening method for caloric restriction mimetics (CRM), a group of plant-derived 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 activation-inhibitory 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 IC50 values-ibudilast (IC50 0.97 µM), azelastine (IC50 7.2 µM), epinastine (IC50 16 µM), and amlexanox (IC50 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.

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 anti-inflammatory 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 LPS-treated 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.

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.

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 glial activation and neuronal dysfunction were induced, while tocotrienols exerted anti-inflammatory effects and protected neurons from damage.

Coffee consumption has been shown to reduce the risk of developing type 2 diabetes mellitus (T2DM) in humans; however, the exact mechanism is not completely understood. Here, we demonstrate that N-caffeoyltryptophan (CTP), an ingredient of coffee, enhances adipogenic differentiation and promotes glucose uptake into adipocytes. CTP increased lipid accumulation and adipogenic markers (PPARγ, C/EBPα, and FABP4) expression in mouse 3T3-L1 preadipocyte cell lines and primary preadipocytes. In addition, CTP promoted glucose uptake in 3T3-L1 cells. In the oral glucose tolerance test, daily administration of CTP (30 mg/kg/day, i.p.) for a week reduced blood glucose levels in mice. In 3T3-L1 cells, adipogenic differentiation and increased adipogenic markers expression induced by CTP were inhibited by U0126, a selective MEK1/2 inhibitor. Furthermore, mRNA induction of Pparg by CTP was abrogated in SIRT1 siRNA-transfected 3T3-L1 cells. These results suggest the involvement of the MEK/ERK signaling and SIRT1 in the mechanism of adipogenic function of CTP. Taken together, CTP might contribute to the reduction in postprandial glycemia and a subsequent reduction in onset risk for T2DM.

Caloric restriction (CR) is a major contributor to good health and longevity. CR mimetics (CRMs) are a group of plant-derived compounds capable of inducing the benefits of CR. Since a longevity gene, SIRT1, inhibits T-cell activation and SIRT1 loss results in increased T-cell activation, we hypothesized that compounds capable of activating SIRT1 signaling can inhibit T-cell activation and function as CRMs. Thus we propose, in the present study, the application of a T-cell activation-inhibitory assay to screen candidate CRMs. Well-known CRMs, such as resveratrol, butein, and fisetin, suppressed the anti-CD3/CD28 antibody-induced activation of mouse spleen T-cells. We next randomly assessed 68 plant-derived compounds for screening novel candidate CRMs using this bioassay and found that all four compounds showing IC50 values

Inducible brown-like adipocytes, also known as beige adipocytes, dissipate energy through thermogenesis. Although recent reports suggest that silent information regulator 2 homolog 1 (SIRT1) promotes beige adipocyte differentiation (beiging), the activation mechanism of SIRT1 remains unknown. Here, we report that cynandione A (CA), a major component of Cynanchum wilfordii, causes dynamic changes in SIRT1 nuclear trafficking via protein kinase cAMP-dependent (PKA) signaling and induces the beiging process in adipocyte lineage cells. SIRT1 is located in both the cytoplasm and the nucleus of 3T3-L1 cells. Using cell fractionation and RNA interference experiments, we found that the translocation of SIRT1 from the cytoplasm to the nucleus was enhanced after CA treatment and was followed by upregulation of beige adipocyte-related gene expression. Moreover, we found that CA-induced SIRT1 nuclear trafficking is dependent on the PKA signaling pathway. These results suggest a novel mechanism of CA by which PKA signaling promotes SIRT1 nuclear trafficking, which permits the docking of SIRT1 to its nuclear substrates, leading to beiging in 3T3-L1 cells.

The elderly experience numerous physiological alterations. In the brain, aging causes degeneration or loss of distinct populations of neurons, resulting in declining cognitive function, locomotor capability, etc. The pathogenic factors of such neurodegeneration are oxidative stress, mitochondrial dysfunction, inflammation, reduced energy homeostatis, decreased levels of neurotrophic factor, etc. On the other hand, numerous studies have investigated various biologically active substances in fruit and vegetables. We focused on the peel of citrus fruit to search for neuroprotective components and found that: 1) 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) and auraptene (AUR) in the peel of Kawachi Bankan (Citrus kawachiensis) exert neuroprotective effects; 2) both HMF and AUR can pass through the blood-brain barrier, suggesting that they act directly in the brain; 3) the content of AUR in the peel of K. Bankan was exceptionally high, and consequently the oral administration of the dried peel powder of K. Bankan exerts neuroprotective effects; and 4) intake of K. Bankan juice, which was enriched in AUR by adding peel paste to the raw juice, contributed to the prevention of cognitive dysfunction in aged healthy volunteers. This review summarizes our studies in terms of the isolation/characterization of HMF and AUR in K. Bankan peel, analysis of their actions in the brain, mechanisms of their actions, and trials to develop food that retains their functions.

The peel of Citrus kawachiensis (Kawachi Bankan), a citrus species grown in Ehime, Japan, is abundant in auraptene. Auraptene, a coumarin compound, have been shown to exert anti-inflammatory effects in peripheral tissues, but it was still unclear of the effect in the brain. 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 and auraptene in a hyperglycemia and global cerebral ischemia models. 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 type 2 diabetic 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 anti-inflammatory and neuroprotective effects in the brain. We attempted to demonstrate the effect of auraptene 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.

Cerebral ischemia/reperfusion leads to delayed neuronal cell death, resulting in brain damage. Auraptene (AUR) and naringin (NGIN), which exert neuroprotective effects in ischemic brain, are abundant in the peel of Citrus kawachiensis. Although parts of AUR/NGIN are transited from the peel to the juice during the squeezing of this fruit, these amounts in juice might be too low to exert effects. We thus prepared the AUR/NGIN-rich fruit juice of C. kawachiensis by addition of peel paste to the raw juice. The present study revealed that orally administration of the dried powder of this AUR/NGIN-rich fruit juice (2.5 g/kg/d) for 7 d to ischemic mice significantly suppressed the ischemia-induced neuronal cell death in the hippocampus, which was coincidently with the reduction of hyperactivation of microglia and astrocytes. These results suggest that AUR/NGIN-rich juice of C. kawachiensis may possess therapeutic potential for the prevention of neurodegenerative diseases via inhibition of inflammatory processes.

Cerebral ischemia/reperfusion is known to induce the generation of reactive oxygen species and inflammatory responses. Numerous studies have demonstrated that naringin (NGIN) has anti-oxidant and anti-inflammatory properties. We previously reported that Citrus kawachiensis contains a large quantity of NGIN in its peel. In the present study, we orally (p.o.) administered dried peel powder of C. kawachiensis to mice of a transient global ischemia model and found in the hippocampus region that it 1) suppressed neuronal cell death, 2) reversed the reduction in the level of phosphorylated calcium-calmodulin-dependent protein kinase II, 3) had the tendency to reverse the reduction in the level of glutathione, and 4) blocked excessive activation of microglia and astrocytes. These results suggested that the dried peel powder of C. kawachiensis had a neuroprotective effect against ischemic brain via anti-oxidative and anti-inflammatory effects. We also showed that these effects of the dried peel powder were more powerful than those obtained with a comparable amount of NGIN alone.

In vitro screening methods using cultured Neuro2a cells to examine the activation (phosphorylation) of extracellular signal-regulated kinase (ERK) 1/2 and promotion of neurite outgrowth revealed that the extracts of 5 Kampo (Japanese traditional) formulations have potential as medicines for the treatment of behavioral abnormalities. Since sansoninto (SAT) extract exerted stronger effects than the other candidates tested, we investigated whether its oral administration ameliorates the pathologies of some mouse models of behavioral impairments. The results obtained suggested that SAT extract exerted anti-depression-like effects in the forced swim test, which may be mediated by the up-regulated expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. They may also be mediated by the enhanced phosphorylation of the cAMP response element-binding protein (CREB) via the mitogen-activated protein kinase (MAPK) cascade and Ca2+/calmodulin-dependent protein kinase II (CaMK II) cascade, a downstream signaling cascade of the N-methyl-D-aspartate (NMDA) receptor. These results indicate that the extract of SAT has potential as a new remedial medicine in the treatment of depression-like behavior.

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.

Brain-derived neurotrophic factor (BDNF) is associated with onset of several central nervous system disorders, e.g., Parkinson’s disease, Alzheimer’s disease, depression, epilepsy, and chronic pain. In our previous in vivo studies using ischemic and depression mouse models, we revealed that citrus flavonoid 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF) exerts neuroprotective effects by enhancing the expression of BDNF in astrocytes within the hippocampus. Therefore, in the present study, we examined the mechanism of BDNF induction by HMF in vitro using rat C6 glioma cells. C6 glioma cells were treated with HMF (10 μM) or HMF + U0126 (10 μM), HMF + H89 (1 μM), or HMF + K252a (200 nM) for 48 h. The protein level of mature BDNF (m-BDNF), phosphorylated-ERK (p-ERK) and phosphorylated-cAMP-response element binding protein (p-CREB) were measured using western blot analysis. To clarify the mechanism of HMF for increasing m-BDNF, the inhibitory effect of phosphodiesterase 4B (PDE4B) and PDE4D, and intracellular cAMP levels were examined by ELISA. Our findings revealed that the m-BDNF-inducing activity of HMF was abolished by U0126 but not by H89 or K252a. HMF was found to phosphorylate (activate) ERK and cAMP-response element binding protein (CREB), a BDNF transcription factor. HMF inhibited PDE4B and PDE4D activity. Moreover, 10 μM HMF elevated intracellular cAMP levels in C6 cells. These findings suggest that HMF might exert its neuroprotective effects by inducing m-BDNF expression in C6 cells, model cell line of astrocytes, via the activation of cAMP/ERK/CREB signaling and inhibiting PDE4B or PDE4D.

We previously reported that the dried peel powder of Citrus kawachiensis exerted anti-inflammatory effects in the brain in several animal models. Hyperglycemia induces inflammation and oxidative stress and causes massive damage in the brain; therefore, we herein examined the anti-inflammatory and other effects of the dried peel powder of C. kawachiensis in the streptozotocin-induced hyperglycemia mice model and in the type 2 diabetic db/db mice model. The C. kawachiensis administration inhibited microglial activation in the hippocampus in the streptozotocin-injected mice. Moreover, The C. kawachiensis treatment inhibited astroglial activation in the hippocampus and the hyperphosphorylation of tau at 231 of threonine and 396 of serine in hippocampal neurons, and also relieved the suppression of neurogenesis in the dentate gyrus of the hippocampus in the db/db mice. It was suggested that the dried peel powder of C. kawachiensis exerts anti-inflammatory and neuroprotective effects in the brain.

We previously reported that the dried peel powder of Citrus kawachiensis, one of the citrus products of Ehime, Japan, exerted anti-inflammatory effects in the brain of a lipopolysaccharide-injected systemic inflammation animal model. Inflammation is one of the main mechanisms underlying aging in the brain; therefore, we herein evaluated the anti-inflammatory and other effects of the dried peel powder of C. kawachiensis in the senescence-accelerated mouse-prone 8 (SAMP8) model. The C. kawachiensis treatment inhibited microglial activation in the hippocampus, the hyper-phosphorylation of tau at 231 of threonine in hippocampal neurons, and ameliorated the suppression of neurogenesis in the dentate gyrus of the hippocampus. These results suggest that the dried peel powder of C. kawachiensis exert anti-inflammatory and neuroprotective effects.

We previously reported that the subcutaneous administration of 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF), a citrus polymethoxyflavone, attenuated depressive-like behavior and increased the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of a corticosterone-induced depression-like mouse model. We herein demonstrated that (1) HMF was detectable in the brain 10 and 30 min after its oral administration, (2) orally administered HMF improved chronic unpredictable mild stress (CUMS)-induced pathological conditions, including body weight loss and depressive-like behavior, and CUMS-induced neurochemical changes, such as reduction in BDNF expression, decrease in neurogenesis, and decreased level of phosphorylated calcium-calmodulin-dependent protein kinase II in the hippocampus, and (3) these effects of HMF were inhibited by the pre-administration of U0126, a mitogen-activated protein (MAP) kinase inhibitor. These results suggest that orally administered HMF is beneficial for the upregulation of BDNF in the hippocampus via the extracellular signal-regulated kinase1/2 (ERK1/2)/MAP system, which may account for its antidepression effects.

3,5,6,7,8,3',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.

Walnut is an allergenic food in some populations. Although some allergenic proteins have been identified in walnuts, few small molecule components in the food have been evaluated for their immunomodulatory functions. To examine the immunomodulatory functions, we cultured T-cells from the spleen of mice with small molecule compounds in walnut, measured 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction in the cells and assessed the T-cell activation and growth. Of the nine compounds of walnut, three compounds decreased the T-cell activation and growth in anti-CD3/CD28 antibody-stimulated spleen cells of mice, whereas five compounds increased that. Because the three compounds, pedunculagin, casuarictin, and pentagalloylglucose that 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-γ. 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.

Accumulating data have indicated that citrus polymethoxyflavones (PMFs) have the ability to affect brain function. In the present study, we showed that 3,5,6,7,8,3',4'-heptamethoxy- flavone (HMF) given intraperitoneally to mice was immediately detected in the brain and that the permeability of the brain tissues to it was significantly higher than that of other citrus PMFs (nobiletin, tangeretin, and natsudaidain). The permeation of these PMFs into the brain well correlated with their abilities to suppress MK-801-induced locomotive hyperactivity, suggesting that HMF had the ability to act directly in the brain. We also obtained data suggesting that the suppressive effect of HMF on MK-801-induced locomotive hyperactivity was mediated by phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the hippocampus.

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.

We previously reported that the citrus flavonoid 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF) increased the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of a transient global ischemia mouse model. Since the BDNF hypothesis of depression postulates that a reduction in BDNF is directly involved in the pathophysiology of depression, we evaluated the anti-depressive effects of HMF in mice with subcutaneously administered corticosterone at a dose of 20 mg/kg/day for 25 days. We demonstrated that the HMF treatment ameliorated (1) corticosterone-induced body weight loss, (2) corticosterone-induced depression-like behavior, and (3) corticosterone-induced reductions in BDNF production in the hippocampus. We also showed that the HMF treatment restored (4) corticosterone-induced reductions in neurogenesis in the dentate gyrus subgranular zone and (5) corticosterone-induced reductions in the expression levels of phosphorylated calcium-calmodulin-dependent protein kinase II and extracellular signal-regulated kinase1/2. These results suggest that HMF exerts its effects as an anti-depressant drug by inducing the expression of BDNF.

Ambipolar organic field effect transistors with heterojunction structures have been fabricated using a biphenyl-capped thiophene oligomer (BP2T) and a naphthalene derivative (GS1b) for p-type and n-type organic semiconductors, respectively. Asymmetric electrode structures with Au source and Al–Li drain resulted in better performances than that of a symmetric device due to improved electron injection by the low work-function drain metal.

The present study evaluated the effects of treatment with the citrus flavonoid, 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF) on protection against memory impairment and neuronal death in a global cerebral ischemia mouse model. The results showed that HMF, administrated for three days immediately after ischemic surgery, protected against ischemia-induced memory dysfunction, rescued neuronal cell death in the CA1 cell layer, increased the production of BDNF, stimulated the autophosphorylation of CaMK II and suppressed microglial activation in the hippocampus. These results suggest that HMF has a neuroprotective effect after brain ischemia by inducing BDNF production and anti-inflammatory effects.

The authors report on gate-controlled light emission from an organic field effect transistor composed of a vapor-deposited thin film of α,ω-bis(biphenyl-4-yl)-terthiophene (BP3T) with an electron injection layer of pentacene for the drain electrode. A n-triacontane thin film vapor deposited on a Si∕SiO2 wafer was used as a buffer layer for the gate dielectric. The location of emission zones within the channel where both injected carriers recombine was controlled by the gate voltage. The insertion of the pentacene and n-triacontane layers improved the threshold voltage and mobility for electrons, resulting in balanced ambipolar carrier injection and transport.