Perilla frutescens seed oil combined with Anredera cordifolia leaf powder attenuates age-related cognitive decline by reducing serum triglyceride and glucose levels in healthy elderly Japanese individuals: a possible supplement for brain health.

We have shown that Anredera cordifolia extract improves learning and memory in a senescence-accelerated mouse model, and that α-linolenic acid (ALA)-rich Perilla frutescens seed oil (PO) improves brain function in healthy Japanese adults and elderly individuals. Herein, we present a 12-month, randomised, double-blind, parallel-armed intervention trial examining the effects of PO supplementation alone or in combination with A. cordifolia leaf powder on brain function in healthy elderly Japanese individuals. Participants were randomly divided into two groups: the PO group received 1.47 mL PO (0.88 g ALA) daily via soft gelatine capsules, and the POAC group received 1.47 mL PO and 1.12 g A. cordifolia leaf powder (1.46 mg vitexin and 1.12 mg adenosine) daily. After 12 months of intervention, the POAC group showed generally higher cognitive index scores than the PO group. The beneficial effects of combined supplementation on cognitive function were associated with increased ALA and eicosapentaenoic acid levels in red blood cell plasma membranes, increased serum biological antioxidant potential, and decreased serum triglyceride, glucose, and N-(epsilon)-carboxymethyl-lysine (CML), an advanced glycation end-product and biochemical marker of oxidative stress levels. The effects of combined supplementation on cognitive function also showed a significant negative correlation with serum CML levels after 12 months of intervention. Our findings suggest that combined long-term supplementation with PO and A. cordifolia more effectively ameliorates age-related cognitive decline than PO alone. These findings may serve as a basis for the development of new supplements for brain health. Clinical Trial Registry, UMIN000040863.

A Narrative Review of the Effects of Citrus Peels and Extracts on Human Brain Health and Metabolism.

As life expectancy increases, age-associated diseases such as Alzheimer's disease (AD) become a major health problem. The onset of AD involves neurological dysfunction due to amyloid-ß accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation in the brain. In addition, lifestyle-related diseases-such as dyslipidemia, diabetes, obesity, and vascular dysfunction-increase the risk of developing dementia. The world population ages, prompting the development of new strategies to maintain brain health and prevent the onset of dementia in older and preclinical patients. Citrus fruits are abundant polymethoxylated flavone and flavanone sources. Preclinical studies reported that these compounds have neuroprotective effects in models of dementia such as AD. Interestingly, clinical and epidemiological studies appear to support preclinical evidence and show improved cognitive function and reduced associated disease risk in healthy individuals and/or patients. This review summarizes the recent evidence of the beneficial effects of citrus peels and extracts on human cognition and related functions.

Perilla seed oil in combination with nobiletin-rich ponkan powder enhances cognitive function in healthy elderly Japanese individuals: a possible supplement for brain health in the elderly.

Perilla (Perilla frutescens) seed oil (PO), rich in α-linolenic acid (ALA), can improve cognitive function in healthy elderly Japanese people. Here, supplements containing either PO alone or PO with nobiletin-rich air-dried immature ponkan powder were examined for their effects on cognitive function in 49 healthy elderly Japanese individuals. Patients were enrolled in a 12-month randomized, double-blind, parallel-armed study. Randomized participants in the PO group received soft gelatin capsules containing 1.47 mL (0.88 g of ALA) of PO daily, and those in the PO + ponkan powder (POPP) group received soft gelatin capsules containing both 1.47 mL of PO and 1.12 g ponkan powder (2.91 mg of nobiletin) daily. At the end of intervention, the POPP group showed significantly higher cognitive index scores than the PO group. The pro-cognitive effects of POPP treatment were accompanied by increases in ALA and docosahexaenoic acid levels in red blood cell plasma membranes, serum brain-derived neurotropic factor (BDNF) levels, and biological antioxidant potential. We demonstrate that 12-month intervention with POPP enhances serum BDNF and antioxidant potential, and may improve age-related cognitive impairment in healthy elderly people by increasing red blood cell ω-3 fatty acid levels. Clinical Trial Registry, UMIN000040863.

A dandelion polysaccharide and its selenium nanoparticles: Structure features and evaluation of anti-tumor activity in zebrafish models.

In this study, an inulin fructan (TMP50-2) with moderate anti-tumor activity was obtained from dandelion. To further improve the anti-tumor activity of TMP50-2, a monodisperse and stable spherical nanoparticle (Tw-TMP-SeNP, 50 nm) was fabricated. Physico-chemical analysis revealed that TMP50-2 and Tween 80 were tightly wrapped on the surface of SeNPs by forming CO⋯Se bonds or through hydrogen bonding interaction (OH⋯Se). In vitro anti-tumor assay showed that Tw-TMP-SeNP treatment could significantly inhibit the proliferation of cancer cells (HepG2, A549, and HeLa) in a dose-dependent manner, while HepG2 cells were more susceptible to Tw-TMP-SeNP with an IC50 value of 46.8 µg/mL. The apoptosis induction of HepG2 cells by Tw-TMP-SeNP was evidenced by increasing the proportion of apoptotic cells ranging from 12.5% to 27.4%. Furthermore, in vivo zebrafish model confirmed the anti-tumor activity of Tw-TMP-SeNP by inhibiting the proliferation and migration of tumor cells as well as the angiogenesis of zebrafish embryos.

Anredera cordifolia extract enhances learning and memory in senescence-accelerated mouse-prone 8 (SAMP8) mice.

Learning and memory impairment may result from age-related decline in synaptic plasticity-related proteins in the hippocampus. Therefore, exploration of functional foods capable of ameliorating memory and cognition decline is an interesting endeavor in neuroscience research. We report the effects of Anredera cordifolia (AC) extract on learning and memory deficits in a senescence-accelerated mouse-prone 8 (SAMP8) mouse model, which demonstrate age-related memory deficits and related pathological changes in the brain. After 8 weeks of oral administration of AC extract, the mice were trained in the Novel Object Recognition (NOR) task, and after 7 more weeks, in the Morris Water Maze (MWM) task. Following the completion of behavioral testing, the blood biochemistry parameters, the hippocampal levels of brain-derived neurotropic factor (BDNF), PSD95, and NR2A, and the p-cAMP-response element binding (p-CREB)/CREB ratio were measured. The AC-treated group spent more time exploring the novel objects in the NOR task, and showed faster acquisition and better retention in the MWM task than the negative control (CN) group. In addition, AC enhanced the levels of the aforementioned neuronal plasticity-related proteins, and did not affect the blood biochemistry parameters. Therefore, our data suggest that the AC extract may improve learning and memory without causing any noticeable side effects in the body.

Isolation, structural elucidation, and immunoregulation properties of an arabinofuranan from the rinds of Garcinia mangostana.

In our search for bioactive polysaccharides as immunomodulatory agents, an arabinofuranan (GMP90-1) was purified and characterized from the rinds of Garcinia mangostana L. GMP90-1 (absolute molecular weight: 5.30 × 103 g/mol) was found to be composed of arabinose, galactose, and rhamnose. The backbone of GMP90-1 was determined as (1→5)-linked α-l-Araf, (1→2,3,5)-linked α-l-Araf, (1→3,5)-linked α-l-Araf, (1→6)-linked ß-d-Galp, and (1→2)-linked α-l-Rhap. Conformational analysis revealed GMP90-1 to exist as a rigid rod structure in sodium chloride solution. To explore its potential as immunomodulatory agents, an in vitro cell screening was performed and GMP90-1 was found to significantly enhance the phagocytic uptake of neutral red and improve the secreted level of nitric oxide (NO), interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α (TNF-α) of macrophages. Furthermore, the cellular immunomodulatory activities were confirmed by the in vivo zebrafish experiment, which suggested that GMP90-1 with immunomodulatory effects could be considered as a potential immunomodulatory for immune diseases.

An evaluation of the genotoxicity and subchronic toxicity of the peel extract of Ponkan cultivar 'Ohta ponkan' (Citrus reticulata Blanco) that is rich in nobiletin and tangeretin with anti-dementia activity.

Nobiletin and tangeretin are major components of polymethoxylated flavones in the peels of citrus fruits such as Citrus reticulata. Because nobiletin and tangeretin have attracted attention due to their beneficial health properties, citrus peel extracts, in which they are concentrated, have the potential to serve as a functional food ingredient to prevent diseases. In this study, a series of toxicological studies on the peel extract of Ponkan cultivar 'Ohta ponkan' (Citrus reticulata Blanco), was conducted. No mutagenic activity was observed in a bacterial reverse mutation test, whereas chromosomal aberrations were induced in an in vitro mammalian chromosomal aberration test. No genotoxicity was observed in an in vivo mammalian micronucleus test. In a 90-day study at daily doses of 54, 180, or 540 mg/kg body weight (bw)/day, hyaline droplet nephropathy, which specifically occurs in adult male rats, was observed in males of 540 mg/kg bw/day group. No other adverse effects were observed in the 90-day study. The no adverse effect level in the 90-day study was considered to be 540 mg/kg bw/day for female rats and less than 540 mg/kg bw/day for male rats.

Potential Benefits of Nobiletin, A Citrus Flavonoid, against Alzheimer's Disease and Parkinson's Disease.

Alzheimer's disease (AD), which is characterized by the presence of amyloid-ß (Aß) plaques and neurofibrillary tangles, accompanied by neurodegeneration, is the most common form of age-related neurodegenerative disease. Parkinson's disease (PD) is the second most common neurodegenerative disease after AD, and is characterized by early prominent loss of dopaminergic neurons in the substantia nigra pars compacta. As currently available treatments are not able to significantly alter the progression of these diseases, successful therapeutic and preventive interventions are strongly needed. In the course of our survey of substances from natural resources having anti-dementia and neuroprotective activity, we found nobiletin, a polymethoxylated flavone from the peel of Citrus depressa. Nobiletin improved cognitive deficits and the pathological features of AD, such as Aß pathology, hyperphosphorylation of tau, and oxidative stress, in animal models of AD. In addition, nobiletin improved motor and cognitive deficits in PD animal models. These observations suggest that nobiletin has the potential to become a novel drug for the treatment and prevention of neurodegenerative diseases such as AD and PD.

Clerodane diterpenoids from Casearia kurzii and their cytotoxic activities.

A search for bioactive natural products as anticancer lead compounds resulted in the isolation of one previously undescribed and three known clerodane diterpenoids (1-4) from Casearia kurzii. The structures of these compounds were established by analysis of their NMR, MS, and electronic circular dichroism data. The cytotoxic activities of four compounds against three human cancer cell lines were evaluated. Compound 2 was found to be the most active with an IC50 value of 4.1 µM against HeLa cells, and was selected to investigate the possible cytotoxic mechanism.

NO inhibitory phytochemicals as potential anti-inflammatory agents from the twigs of Trigonostemon heterophyllus.

Studies on the relationship of nitric oxide (NO) and inflammation have revealed that compounds with NO inhibitory effects are potentially useful for inflammation and related inflammatory disorders. A phytochemical investigation to obtain new NO inhibitors resulted in the isolation of two new cleistanthane diterpenoids (1 and 2) and 11 known terpenoids (3-13) from Trigonostemon heterophyllus. The structures of these terpenoids were established by analysis of their NMR, MS, and electronic circular dichroism (ECD) data. Compounds 1 and 2 possess rare 3,4-seco-cleistanthane diterpenoid skeletons. All of the isolates were evaluated biologically for their NO inhibitory effects in lipopolysaccharide (LPS)-induced murine microglial BV-2 cells and compounds 1, 6, and 8-10 showed strong NO inhibitory effects with IC50 values less than 40 µM. Using Western blotting experiments and molecular docking, the possible mechanism of NO inhibition was investigated.

Bioactive Diterpenoids from the Stems of Euphorbia royleana.

Two ingenane- (1 and 2), two ent-atisane- (3 and 4), two ent-kaurane- (5 and 6), two ent-abietane- (7 and 8), and one ent-isopimarane-type (9) diterpenoid and 12 known analogues have been isolated from the methanolic extract of the stems of Euphorbia royleana. Their structures, including absolute configurations, were determined by extensive spectroscopic methods and ECD data analysis. The nitric oxide inhibitory activities of those diterpenoids were examined biologically in lipopolysaccharide-stimulated BV-2 cells, with compounds 1, 2, 5-7, 10, and 12 having IC50 values lower than 40 µM. Molecular docking was used to investigated the possible mechanism of compounds 1, 2, 5-7, 10, and 12.

Seco-labdane diterpenoids from the leaves of Callicarpa nudiflora showing nitric oxide inhibitory activity.

Nine previously undescribed seco-labdane diterpenoids, nudiflopenes A-I, were isolated from the leaves of Callicarpa nudiflora. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analysis, and the absolute configurations of these compounds were established by the modified Mosher's method and experimental and calculated electronic circular dichroism spectra. Nudiflopenes A-I belong to the class of seco-labdane diterpenoids. All of the isolates showed inhibitory activities on lipopolysaccharide-induced nitric oxide (NO) production in murine microglial BV-2 cells. The possible mechanism of NO inhibition of some bioactive compounds was also investigated using molecular docking, which revealed interactions of bioactive compounds with the inducible nitric oxide synthase (iNOS) protein.

NO inhibitors function as potential anti-neuroinflammatory agents for AD from the flowers of Inula japonica.

The extensive pathology studies revealed that Alzheimer's disease (AD) is closely related to neuroinflammation and anti-neuroinflammatory agents may be potentially useful for the treatment of AD. Inula japonica is a member of the Asteraceae plant family and its flowers have been used as a healthy tea and a traditional Chinese medicine. Our continuous search for new nitric oxide (NO) inhibitory substances as anti-neuroinflammatory agents for AD resulted in the isolation of two new sesquiterpenes and ten known terpenes from the flowers of I. japonica. Their structures were established on the basis of extensive analysis of NMR and MS spectroscopic data, as well as calculated and experimental electronic circular dichroism (ECD) spectra. Among these isolates, compound 1 is a new sesquiterpene with a rare tricyclic fused skeleton, and 2 processes a 1,10-seco-eudesmane skeleton. The anti-neuroinflammatory effects were examined by inhibiting NO release in LPS-induced murine microglial BV-2 cells. The possible mechanism of NO inhibition was also investigated using molecular docking, which revealed the interactions of bioactive compounds with the iNOS protein. The present study disclosed that the flowers of I. japonica as a healthy tea are potentially useful for AD and related neuroinflammatory diseases.

Polycyclic phloroglucinols as PTP1B inhibitors from Hypericum longistylum: Structures, PTP1B inhibitory activities, and interactions with PTP1B.

Protein tyrosine phosphatase 1B (PTP1B) has been regarded asa target for the research and development of new drugs to treat type II diabetes and PTP1B inhibitors are potential lead compounds for this type of new drugs. A phytochemical investigation to obtain new PTP1B inhibitors resulted in the isolation of four new phloroglucinols, longistyliones A-D (1-4) from the aerial parts of Hypericum longistylum. The structures of 1-4 were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analysis, and the absolute configurations of these compounds were established by comparing their experimental electronic circular dichroism (ECD) spectra with those calculated by the time-dependent density functional theory method. Compounds 1-4 possess a rare polycyclic phloroglucinol skeleton. The following biological evaluation revealed that all of the compounds showed PTP1B inhibitory effects. The further molecular docking studies indicated the strong interactions between these bioactive compounds with the PTP1B protein, which revealed the possible mechanism of PTP1B inhibition of bioactive compounds. All of the results implied that these compounds are potentially useful for the treatment of type II diabetes.

Extraction of nobiletin from Citrus Unshiu peels by supercritical fluid and its CRE-mediated transcriptional activity.

BACKGROUND: Polymethoxyflavone (PMF) is one of bioactive compounds in Citrus Unshiu and included mainly in the peels rather than the fruits, seeds and leaves. HYPOTHESIS/PURPOSE: Supercritical CO2 extraction is one candidate for selective extraction of polymethoxyflavone and in this study, supercritical CO2 extraction with/without ethanol entrainer from Citrus Unshiu peels was examined at a temperature of 333K and a pressure of 30MPa. METHODS: CRE (cyclic AMP response element)-mediated transcriptional assay was examined by using the extracts from supercritical fluid extraction. RESULTS: The results showed that extracts including nobiletin increased with increasing ethanol concentration in supercritical CO2 and the elapsed extraction time. Extracts at ethanol concentration of 5 mol% showed high CRE-mediated transcription activity. This can be caused by activity of the extract including nobiletin in addition to the other methoxylated flavonoid species such as tangeretin. Extracts at ethanol concentration of 50% showed the highest CRE-mediated transcription activity, which can be attributed to flavonoid glycoside such as hesperidin. From our investigations, flavonoid glycoside can be one of promoters of CRE-mediated transcription activity.

Bioactive Terpenoids from Salvia plebeia: Structures, NO Inhibitory Activities, and Interactions with iNOS.

A phytochemical investigation to obtain new NO inhibitors resulted in the identification of six new (1-6) and four known (7-10) terpenoids from Salvia plebeia. Compounds 1 and 2 are new diterpenoids, 3-5 are new meroditerpenoids, 6-9 are sesquiterpenoids, and 10 is a known meroditerpenoid. The structures of these isolates were determined by routine NMR experiments and X-ray diffraction, as well as the electronic circular dichroism spectra. Compounds 1-4 are diterpenoids carrying an oxygen bridge, and 6 is a rare copane-type sesquiterpenoid with a bridged tricyclic framework. The isolates inhibited NO generation induced by lipopolysaccharide in BV-2 cells. The possible mechanism of NO inhibition of some bioactive compounds was also investigated using molecular docking, which revealed interactions of bioactive compounds with the iNOS protein.

Diterpenoids from Callicarpa kwangtungensis and their NO inhibitory effects.

A phytochemical investigation of the leaves of Callicarpa kwangtungensis led to the isolation of three new diterpenoids (1-3), callipenes A-C, and eleven known analogues (4-14). Their structures were established on the basis of extensive analysis of NMR spectroscopic data, X-ray diffraction data, and experimental and calculated electronic circular dichroism spectra. Compounds 1 and 2 are rare abietane diterpenoids possessing a peroxide bridge. All of the isolates were found to inhibit LPS-induced NO production in BV-2 cells.

Characterization of diterpenoids from Caesalpinia decapetala and their anti-TMV activities.

Caesalpinia decapetala is a versatile medicinal plant belonging to the Fabaceae plant family. In our survey on plant secondary metabolites to obtain bioactive substances for the development of new agricultural anti-TMV agents, the chemical constituents of C. decapetala were investigated. This investigation led to the isolation of three new and ten known diterpenoids. Their structures including absolute configurations were elucidated based on the extensive NMR spectroscopic data analyses and the time-dependent density functional theory calculations. The following biological screenings revealed that most of these diterpenoids possessed anti-TMV activities.

Nerve growth factor enhances the CRE-dependent transcriptional activity activated by nobiletin in PC12 cells.

Prevention and treatment of Alzheimer disease are urgent problems for elderly people in developed countries. We previously reported that nobiletin, a poly-methoxylated flavone from the citrus peel, improved the symptoms in various types of animal models of memory loss and activated the cAMP responsive element (CRE)-dependent transcription in PC12 cells. Nobiletin activated the cAMP/PKA/MEK/Erk/MAPK signaling pathway without using the TrkA signaling activated by nerve growth factor (NGF). Here, we examined the effect of combination of nobiletin and NGF on the CRE-dependent transcription in PC12 cells. Although NGF alone had little effect on the CRE-dependent transcription, NGF markedly enhanced the CRE-dependent transcription induced by nobiletin. The NGF-induced enhancement was neutralized by a TrkA antagonist, K252a. This effect of NGF was effective on the early signaling event elicited by nobiletin. These results suggested that there was crosstalk between NGF and nobiletin signaling in activating the CRE-dependent transcription in PC12 cells.

Di- and Triterpenoids from the Leaves of Casearia balansae and Neurite Outgrowth Promoting Effects of PC12 Cells.

A bioassay-guided phytochemical investigation of the leaves of Casearia balansae led to the isolation of six new cucurbitane-type triterpenoid derivatives (balanterpenes A-F, 1-6) and four new clerdoane-type diterpenoids (balanterpenes G-J, 7-10). The structures of 1-10 were established on the basis of extensive analysis of NMR spectroscopic data, X-ray crystallography, and experimental and calculated electronic circular dichroism spectra. Compound 1 features a ring-expanded triterpenoid skeleton with the C-19 methyl involved in the ring formation, compound 6 possesses a rare hexanortriterpenoid scaffold, and compounds 7-10 may be four new diterpenoid artifacts presumably formed during the extraction and purification processes. Compounds 3 and 7-10 showed promoting effects on neurite outgrowth of PC12 cells with EC50 values in the range 2.9-10.0 µM.