Structure, anti-tumor activity, and potential anti-tumor mechanism of a fungus polysaccharide from Fomes officinalis.

In our ongoing process of discovering bioactive macromolecules, a homogeneous polysaccharide (FOP80-1) was first purified from Fomes officinalis. FOP80-1 with molecular weight of 4560 Da was mainly composed of →3)-d-Galp-(1→, →4)-ß-d-Manp-(1→, →6)-α-d-Glcp-(1→, →3,6)-d-Glcp-(1→, and t--d-Glcp. Besides the structure features, the anti-tumor activity and potential mechanism of FOP80-1 were also investigated. The cellular and zebrafish experiments revealed that FOP80-1 inhibited tumor proliferation, invasion, and metastasis by increasing ROS, arresting cell cycle, inducing apoptosis, and suppressing angiogenesis. Corresponding to the inhibition of angiogenesis, the surface plasmon resonance (SPR) experiments revealed that FOP80-1 had good affinity with VEGF, a crucial protein to regulate angiogenesis. Molecular docking indicated that FOP80-1 could interact with the protein VEGF.

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.

Structural analysis and biological effects of a neutral polysaccharide from the fruits of Rosa laevigata.

A neutral water-soluble polysaccharide (RLP50-2) was extracted and purified from the fruits of Rosa laevigata. The absolute molecular weight was determined as 1.26 × 104 g/mol. Monosaccharide composition analysis showed that RLP50-2 mainly consisted of glucose, arabinose, and galactose. Structural analysis revealed that RLP50-2 consisted of →5)-α-L-Araf-(1→, →2,5)-α-L-Araf-(1→, →3,5)-α-L-Araf-(1→, →4)-α-D-Glcp-(1→, →6)-α-D-Glcp-(1→, →3,6)-ß-D-Glcp-(1→, →4)-α-D-Galp-(1→, →6)-ß-D-Galp-(1→, →2)-ß-D-Xylp-(1→, terminal α-L-arabinose, and terminal ß-D-mannose. Biological assays showed that RLP50-2 had immunomodulatory activities using cell and zebrafish models. Moreover, RLP50-2 showed significantly antitumor activities by inhibiting tumor cell proliferation and migration and blocking angiogenesis. These results suggested that RLP50-2 could be developed as a potential immunomodulatory agent or antitumor candidate drug in biomedicine field.

Cytotoxic and Antiangiogenetic Xanthones Inhibiting Tumor Proliferation and Metastasis from Garcinia xipshuanbannaensis.

Eight prenylated xanthones including four new analogues were extracted and purified from the leaves of Garcinia xipshuanbannaensis. Multiple techniques including UV, 1D and 2D NMR, and HRESIMS were used to determine the structures of the isolated xanthones. These xanthones were evaluated for their cytotoxicity toward human cancer cells, and compound 4 exhibited activity against HeLa cells. A cytotoxic mechanism examination revealed the active compound induced cell apoptosis by arresting the cell cycle, increasing the levels of ROS, and inhibiting the expression of p-STAT3 in HeLa cells. In in vivo zebrafish experiments, compound 4 was found to block tumor proliferation and migration and have antiangiogenetic activity, and thus seems worthy of further laboratory evaluation.

Beneficial Effects of Citrus-Derived Polymethoxylated Flavones for Central Nervous System Disorders.

The number of patients with central nervous system disorders is increasing. Despite diligent laboratory and clinical research over the past 30 years, most pharmacologic options for the prevention and long-term treatment of central nervous system disorders and neurodegenerative disorders have been unsuccessful. Therefore, the development of drugs and/or functional foods to prevent the onset of neurodegenerative disorders is highly expected. Several reports have shown that polymethoxylated flavones (PMFs) derived from citrus fruit, such as nobiletin, tangeretin, and 3,3',4',5,6,7,8-heptamethoxyflavone, are promising molecules for the prevention of neurodegenerative and neurological disorders. In various animal models, PMFs have been shown to have a neuroprotective effect and improve cognitive dysfunction with regard to neurological disorders by exerting favorable effects against their pathological features, including oxidative stress, neuroinflammation, neurodegeneration, and synaptic dysfunction as well as its related mechanisms. In this review, we describe the profitable and ameliorating effects of citrus-derived PMFs on cognitive impairment and neural dysfunction in various rat and murine models or in several models of central nervous system disorders and identify their mechanisms of action.

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.

An active heteropolysaccharide from the rinds of Garcinia mangostana Linn.: Structural characterization and immunomodulation activity evaluation.

A previously undescribed polysaccharide, GMP70-1, was isolated from the rinds of Garcinia mangostana Lin. Physicochemical characterization analysis showed that GMP70-1 (absolute molecular weight: 2.01 × 104 g/mol) is a multi-branched acidic heteropolysaccharide with a compact coil chain conformation in sodium chloride solution. The repeated unit of GMP70-1 was mainly composed of (1 → 5)-linked α-L-Araf, (1 → 3, 5)-linked α-L-Araf, (1 → 2, 4)-linked α-L-Rhap, (1 → 4)-linked ß-D-Galp, terminating with t-α-L-Araf, t-α-D-GalpA, and t-ß-D-Galp. To explore the medicinal potential responsible for the bioactivity of G. mangostana, an immunomodulatory assay was performed. The in vitro cell test showed that GMP70-1 possessed a prominent immunoregulatory activity by enhancing the phagocytic uptake of neutral red and promoting the secretion of nitric oxide (NO), reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1ß of macrophages. Furthermore, an in vivo zebrafish evaluation revealed that the production of ROS and NO was significantly increased after treated with GMP70-1.

A fructan from Anemarrhena asphodeloides Bunge showing neuroprotective and immunoregulatory effects.

A novel polysaccharide, AAP70-1, was isolated from Anemarrhena asphodeloides for the first time. The primary structural analysis revealed that AAP70-1 was composed of glucose and fructose, had an absolute molecular weight of 2720 Da, and contained a (2→6)-linked ß-D-fructofuranose (Fruf) backbone and a (2→1,6)-linked ß-D-Fruf side chain with an internal α-D-glucopyranose (Glcp) in the form of a neokestose. To explore the potential factors responsible for the medicinally relevant bioactivities of A. asphodeloides, a biological assay was performed. Using flow cytometry analysis, AAP70-1 was experimentally shown to have neuroprotective effects, and it can prevent and ameliorate neurological damage via reducing apoptosis. The immunomodulation assay further revealed that AAP70-1 can significantly improve immune function by promoting phagocytic capacity and the secretion of cytokines (IL-6, IL-1ß and TNF-α) in RAW264.7 cells. These results suggest that AAP70-1 has potential as a therapeutic agent for central nervous system diseases or as an immunomodulatory agent.

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.

Bioactive Diterpenoids from the Stems of Euphorbia antiquorum.

A total of 18 diterpenoids, including 10 new analogues (1-10), were isolated from Euphorbia antiquorum. The structures were characterized by spectroscopic techniques, and circular dichroism data analysis was adopted to confirm the absolute configurations of 1-10. Compounds 1-9 were classified as ent-atisane diterpenoids, and 10 was assigned as an ent-kaurane diterpenoid. The biological evaluation of nitric oxide (NO) production inhibition was conducted, and all of these isolates showed the property of inhibiting NO generation in lipopolysaccharide-induced BV-2 cells. Further research on molecular docking disclosed the affinities between the diterpenoids obtained and inducible nitric oxide synthase.

Cytotoxic diterpenoids as potential anticancer agents from the twigs of Casearia kurzii.

A search for bioactive natural products as anticancer lead compounds has led to the isolation of five new clerodane diterpenoids (1-5) from the twigs of Casearia kurzii. Their structures were elucidated by extensive analysis of their NMR, IR, and HRESIMS data, and the absolute configurations were determined by experimental and calculated electronic circular dichroism (ECD) data analysis. The isolates were biologically evaluated and showed cytotoxic activities toward human lung cancer cells (A549), human cervical cancer cells (HeLa), and human hepatocellular carcinoma cells (HepG2). The most active compound (5) with an IC50 value of 5.3 µM against HeLa cells, was found to induce apoptosis and arrest the HeLa cell cycle at G0/G1 stage to exert cytotoxic effects.

Withanolides from Physalis peruviana showing nitric oxide inhibitory effects and affinities with iNOS.

A phytochemical study to obtain new nitric oxide (NO) inhibitors resulted in the isolation of five new withanolides from the whole plants of Physalis peruviana. The structures were determined on the basis of extensive NMR spectroscopic data analysis as well as the time-dependent density functional theory (TDDFT) electronic circular dichroism (ECD) calculations. The NO inhibitory effects were examined by inhibiting NO release in lipopolysaccharide-stimulated murine microglial BV-2 cells. Molecular docking studies showed the strong interactions of bioactive compounds with the inducible nitric oxide synthase (iNOS) protein, revealing the potential mechanism of NO inhibition of bioactive compounds.

Bioactive terpenoids from Euonymus verrucosus var. pauciflorus showing NO inhibitory activities.

In our continuous search for new nitric oxide (NO) inhibitory compounds as potential anti-inflammatory agents or lead compounds for inflammatory diseases, the chemical constituents of Euonymus verrucosus var. pauciflorus were investigated, leading to the isolation of eleven terpenoids including six new diterpenoids, designated as euonymupenes A-F. The structures were elucidated on the basis of NMR and ECD data analysis. Euonymupenes A, C, and F feature rare labdane-type norditerpenoid skeletons. The NO inhibitory effects were evaluated and all of the isolates were found to inhibit lipopolysaccharide (LPS)-induced NO production in murine microglial BV-2 cells. Western blotting analysis indicated that the most active compound (5) can regulate iNOS (inducible nitric oxide synthase) expression. The further molecular docking studies exhibited the affinities of bioactive compounds with iNOS.

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.