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Role of Citrus Fruits in Alzheimer’s Disease: A Current Perspective

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Abstract

Citrus fruits are commonly consumed fruits that are known for its nutrient content, energy source, and health supplements. Citrus fruits are rich sources of several secondary metabolites like limonoids, alkaloids, coumarins, flavonoids, carotenoids, essential oils, and phenolic acids that are responsible for its beneficiary effect against various diseases. These include anti-inflammatory, cardiovascular-protective, anticancer, antioxidative, and neuroprotective effects. Present-day pharmacological therapies for the AD are deficient. Unfortunately, other strategies such as neural transplantation and stem cell transplantation remain in the experimental stage. Numerous cellular, animal, and human studies have delineated the neuroprotective effects of citrus fruits owning to their active components. Increased consumption of citrus fruits is associated with higher antioxidant status and phytochemical constituents, thus helpful against oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis that play an important role in the cause and progression of neurological disorders. The multifactorial etiology of neurodegenerative diseases suggests that drugs with multiple targets could have therapeutical potential for these pathologies.

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Accumulated evidence from experimental and epidemiological studies indicates that there is a low risk of degenerative diseases, cardiovascular disease, hypertension, cataract, stroke and, in particular, cancers in people with a high intake of fruit and vegetables. This protective effect is assumed to be associated mainly with the antioxidant activities of either individual or interacting bioactive components present in the fruits and vegetables, and with other biochemical and physical characteristics of the identified and unknown bioactive components. The implicated bioactive components present in citrus fruits include vitamin C, beta-carotene, flavonoids, limonoids, folic acid, and dietary fibre. A high intake of citrus fruits may reduce the risk of degenerative diseases.
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An HPLC analysis was performed on the concentrations of flavonoids in 42 species and cultivars of the Citrus genus and those of two Fortunella and one Poncirus species according to the classification system established by Tanaka. The composition of 8 flavanones and 9 flavone/ols for these species was determined in the albedo, flavedo, segment epidermis and juice vesicle tissues, and those in the fruit and peel tissues were calculated from the composition data of the tissues. A principal component analysis showed that such neohesperidosyl flavonoids as neoeriocitrin, naringin, neohesperidin, and rhoifolin had large factor loading values in the first principal component for each tissue. The flavonoid composition of citrus fruits was approximately the same within each section of Tanaka's system, except for the species in the Aurantium section and those with a peculiar flavonoid composition such as Bergamot (C. bergamia), Marsh grapefruit (C. paradisi), Sour orange (C. aurantium), and Shunkokan (C. shunkokan). The Aurantium section included both naringin-rich and hesperidin-rich species.
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Emerging evidences indicate hesperidin, a citrus flavanone, attenuates neurodegenerative processes and related complications. Besides its anti-oxidant properties, the other probable mechanisms which underpin its neuroprotective potential are still not clear. In light of emerging role of flavonoids in modulating oxidative stress and neuro-inflammation, the study has been designed to explore the possible neuroprotective effect of hesperidin and its combination with minocycline (microglial inhibitor), against quinolinic acid (QA) induced Huntington's disease (HD) like symptoms in rats. Unilateral intrastriatal administration of QA (300nmol/ 4µl) significantly reduced body weight, impaired behavior (locomotor activity, beam balance and memory performance), caused oxidative damage (increased lipid peroxidation, nitrite concentration, and depleted super oxide dismutase and reduced glutathione), demonstrated mitochondrial dysfunction (decreased complex-I, II, III, IV activities), increased striatal lesion volume and altered the levels of TNF- α, caspase-3 as well as BDNF expression, as compared to sham group. Meanwhile, chronic hesperidin (100mg/kg, p.o.) and minocycline (25mg/kg, p.o.) treatment for 21 days significantly attenuated the behavioral, biochemical and cellular alterations as compared to QA treated (control) animals, whereas hesperidin (50mg/kg, p.o.) treatment was found to be non-significant. However, treatment of hesperidin (50mg/kg) in combination with minocycline (25mg/kg) potentiated their neuroprotective effect, which was significant as compared to their effects per se in QA treated animals. Taken altogether, the results of the present study suggest a possible interplay of microglial modulation and anti-oxidant effect in neuroprotective potential of hesperidin against QA induced HD like symptoms in rats.
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Ten polymethoxylated flavonoids were isolated and characterized from cold pressed tangerine oil solids; they are 5,6,7,3‘,4‘-pentamethoxyflavone (sinensetin) (I); 7-hydroxy-3,5,6,3‘,4‘-pentamethoxyflavone (II); 5-hydroxy-6,7,8,3‘,4‘-pentamethoxyflavone (III); 5,6,7,8,3‘,4‘-hexamethoxyflavone (nobiletin) (IV); 5,6,7,8,4‘-pentamethoxyflavone (tangeretin) (V); 5,7,8,4‘-tetramethoxyflavone (tetra-O-methylisoscutellarein) (VI); 7-hydroxy-3,5,6,8,3‘,4‘-hexamethoxyflavone (VII); 5,6,7,4‘-tetramethoxyflavone (tetra-O-methylisoscutellarein) (VIII); 3,5,6,7,8,3‘,4‘-heptamethoxyflavone (IX); and 5,7,8,3‘,4‘-pentamethoxyflavone (X). Structures of the compounds were elucidated on the basis of spectroscopic methods and chemical data. Compounds II and VII are novel natural products; compounds IV, V, and VIII have been reported with significant activity against various strains of carcinoma cells; and compounds I and IV decrease erythrocyte aggregation and sedimentation in vitro. A biological activity screen of other compounds is in progress. Keywords: Polymethoxylated flavones; antitumor activity; Citrus; tangerine oils; Dancy tangerine
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Seeds from five varieties of Tunisian Citrus fruits, namely blood orange (Citrus sinensis), sweet orange (Citrus sinensis), lemon (Citrus limon L.), bergamot (Citrus bergamia) and bitter orange (Citrus aurantium), were examined for their composition of lipid classes and fatty acids. In addition, the oil yield, total fatty acids, palmitic, oleic and linoleic acids were determined. Petroleum ether-extracted oils of these Citrus seeds amounted to more than 78% in the case of lemon seeds. The Citrus seed oils had three lipid classes as determined by thin-layer chromatography. Triacylglycerols were the major oil class in all varieties. Gas chromatographic analyses revealed that the main fatty acids were palmitic, oleic and linoleic acids.
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Naringin, a bioflavonoid, has been reported to have potent neuro-protective effects, but its preventive effects on amyloid-β (Aβ) induced, Alzheimer's disease (AD) related, cognitive impairment, and the underlying mechanisms of these effects have not been well characterised. Three-month-old APPswe/PSΔE9 transgenic mice were randomly assigned to a vehicle group, two naringin (either 50 or 100 mg/kg/day) groups, or an Aricept (2 mg/kg/day) group. After 16 weeks of treatment, we observed beneficial effects of naringin (100 mg/kg/day), including lessening learning and memory deficits, improving locomotor activity, reducing scattered senile plaques, and ameliorating disturbances in brain energy metabolism. Furthermore, GSK-3β phosphorylation significantly increased in the naringin-treated (100 mg/kg/day) group. These findings suggest that a reduction in plaque burden and an increase in glucose uptake through the inhibition of GSK-3β activity may be one of the mechanisms by which naringin improves cognitive functioning in the APPswe/ PSΔE9 transgenic mouse model of Alzheimer's disease.
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The present study was performed to explore the effect of green tea polyphenols on the intracellular Aβ (iAβ)-induced toxicity to cultured rat primary prefrontal cortical neurons. Administration of 100nM, 1μM or 10μM of green tea polyphenols significantly inhibited the iAβ-induced toxicity to cultured rat primary prefrontal cortical neurons tested by MTT and LDH release assays. We further studied the involvement of neuroprotective pathway protein AKT in green tea polyphenols protection against iAβ-induced cytotoxicity on cultured rat primary prefrontal cortical neurons. The results demonstrated that the content of p-AKT decreased significantly after iAβ treatment, while administration of green tea polyphenols significantly inhibited the iAβ-induced decrease in the content of p-AKT. Moreover, blockade of AKT signalling inhibited the protective effects of green tea polyphenols against iAβ-induced neurotoxicity. The results suggest that green tea polyphenols may play a protective effect on cultured rat primary prefrontal cortical neurons against iAβ-induced cytotoxicity and AKT is involved in the green tea polyphenols-induced protective effects.
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Nobiletin is a citrus flavonoid which possesses the flavone structure with six methoxy groups. Although nobiletin has been reported to display anti-inflammatory, anti-tumor, and anti-diabetes activities, its effect on adipocyte differentiation remained unclear. In the present study, we investigated the effect of nobiletin on the differentiation of 3T3-L1 preadipocytes into adipocytes. 3T3-L1 preadipocytes were treated with nobiletin under various differentiation conditions. The effect of nobiletin on adipocyte differentiation was evaluated by oil red O staining, real-time RT-PCR, and Western blotting. Nobiletin significantly suppressed the differentiation of 3T3-L1 preadipocytes into adipocytes, upon induction with insulin together with a cAMP elevator such as 3-isobutyl-1-methylxanthine (IBMX), by downregulating the expression of the gene encoding peroxisome proliferator-activated receptor (PPAR) γ2. In addition, nobiletin decreased the phosphorylation of cAMP-response element-binding protein (CREB) and strongly enhanced the phophorylation of signal transducer and activator of transcription (STAT) 5. Nobiletin has a suppressive effect on the differentiation of preadipocytes into adipocytes when cells were induced with a general differentiation cocktail such as insulin, IBMX, and dexamethasone.
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β-Amyloid (Aβ) plaques in Alzheimer (AD) brains are surrounded by severe dendritic and axonal changes, including local spine loss, axonal swellings and distorted neurite trajectories. Whether and how plaques induce these neuropil abnormalities remains unknown. We tested the hypothesis that oligomeric assemblies of Aβ, seen in the periphery of plaques, mediate the neurodegenerative phenotype of AD by triggering activation of the enzyme GSK-3β, which in turn appears to inhibit a transcriptional program mediated by CREB. We detect increased activity of GSK-3β after exposure to oligomeric Aβ in neurons in culture, in the brain of double transgenic APP/tau mice and in AD brains. Activation of GSK-3β, even in the absence of Aβ, is sufficient to produce a phenocopy of Aβ-induced dendritic spine loss in neurons in culture, while pharmacological inhibition of GSK-3β prevents spine loss and increases expression of CREB-target genes like BDNF. Of note, in transgenic mice GSK-3β inhibition ameliorated plaque-related neuritic changes and increased CREB-mediated gene expression. Moreover, GSK-3β inhibition robustly decreased the oligomeric Aβ load in the mouse brain. All these findings support the idea that GSK3β is aberrantly activated by the presence of Aβ, and contributes, at least in part, to the neuronal anatomical derangement associated with Aβ plaques in AD brains and to Aβ pathology itself.
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Traditional Chinese medicinal herbs are a rich source of compounds with reported anti-inflammatory and anti-carcinogenic effects. Growing evidence shows the codependence of chronic inflammation and angiogenesis, and the potential benefits of targeting angiogenesis in the treatment of chronic inflammation and targeting inflammation in the treatment of diseases with impaired angiogenesis. We hypothesized that the anti-inflammatory activity of the natural compounds may owe at least some of its efficacy to their anti-angiogenic activity and hence we investigated the anti-angiogenic activity of these compounds in vivo in zebrafish embryos and in vitro in human umbilical vein endothelial cells (HUVECs). Nobiletin, a polymethoxylated flavonoid from citrus fruits, showed anti-angiogenic activity in both assays. Nobiletin inhibited the formation of intersegmental vessels (ISVs) in live transgenic zebrafish embryos expressing green fluorescent protein (GFP) in the vasculature. Cell cycle analysis of dissociated zebrafish embryo cells showed that nobiletin induced G0/G1 phase accumulation in a dose-dependent manner in GFP-positive endothelial cells. Nobiletin also dose-dependently induced VEGF-A mRNA expression. In HUVECs, nobiletin inhibited endothelial cell proliferation and, to a greater extent, tube formation in a dose-dependent manner. As in the in vivo study, nobiletin induced G0/G1 cell cycle arrest in HUVECs. However, this arrest was not accompanied by an increase in apoptosis, indicating a cytostatic effect of nobiletin. This study, for the first time, identifies nobiletin as having potent anti-angiogenic activity and suggests that nobiletin has a great potential for future research and development as a cytostatic anti-proliferative agent.
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Epidemiological studies suggest that higher flavonoid intake from fruits and vegetables is associated with decreased risk for the development of cardiovascular disease. The mechanisms explaining this observation remain unclear, but current evidence suggests that flavonoids may exert their effects through the improvement of cardiovascular risk factors. The present review summarizes data suggesting that flavonoids improve endothelial function. inhibit low-density lipoprotein oxidation, decrease blood pressure and improve dyslipidemia. A large number of studies have reported the impact of consuming flavonoid-rich foods on biomarkers of cardiovascular disease risk in healthy volunteers or at-risk individuals. Most studies have focused on cocoa, soy, and green and black tea. Recent evidence suggests that some polyphenols in their purified form, including resveratrol, berberine and naringenin, have beneficial effects on dyslipidemia in humans and/or animal models. In a mouse model of cardiovascular disease, naringenin treatment, through correction of dyslipidemia, hyperinsulinemia and obesity, attenuated atherosclerosis. Therefore, the beneficial effects of flavonoids on multiple risk factors may explain, in part, the observed beneficial effects of flavonoids on cardiovascular disease.
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Nobiletin is a polymethoxylated flavone found in certain citrus fruits that exhibits various pharmacological effects including anti-inflammatory, antitumor and neuroprotective properties. The present study investigated the effects of nobiletin on insulin sensitivity in obese diabetic ob/ob mice, and the possible mechanisms involved. The ob/ob mice were treated with nobiletin (200mg/kg) for 5 weeks. Nobiletin significantly improved the plasma glucose levels, homeostasis model assessment index, glucose tolerance in an oral glucose tolerance test and plasma adiponectin levels. In white adipose tissue (WAT), nobiletin significantly decreased the mRNA expression levels of inflammatory adipokines such as interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 and increased the mRNA expression levels of adiponectin, peroxisome proliferator-activated receptor (PPAR)-gamma and its target genes. At the same time, nobiletin increased the glucose transporter (Glut) 4 expression levels in the whole plasma membrane, and Glut1 and phospho-Akt expression in the whole cell lysates in WAT and muscle. Nobiletin also increased Glut4 protein expression level in the whole cell lysates of the muscle. Taken together, the present results suggest that nobiletin improved the hyperglycemia and insulin resistance in obese diabetic ob/ob mice by regulating expression of Glut1 and Glut4 in WAT and muscle, and expression of adipokines in WAT.
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A comparative study between the antioxidant properties of peel (flavedo and albedo) and juice of some commercially grown citrus fruit (Rutaceae), grapefruit (Citrus paradisi), lemon (Citrus limon), lime (Citrusxaurantiifolia) and sweet orange (Citrus sinensis) was performed. Different in vitro assays were applied to the volatile and polar fractions of peels and to crude and polar fraction of juices: 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity, reducing power and inhibition of lipid peroxidation using beta-carotene-linoleate model system in liposomes and thiobarbituric acid reactive substances (TBARS) assay in brain homogenates. Reducing sugars and phenolics were the main antioxidant compounds found in all the extracts. Peels polar fractions revealed the highest contents in phenolics, flavonoids, ascorbic acid, carotenoids and reducing sugars, which certainly contribute to the highest antioxidant potential found in these fractions. Peels volatile fractions were clearly separated using discriminant analysis, which is in agreement with their lowest antioxidant potential.
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Alzheimer's disease is a progressive and fatal neurodegenerative disease characterized by a build up of amyloid beta (Abeta) deposits, elevated oxidative stress, and deterioration of the cholinergic system. The present study investigated short-term cognitive-enhancing effects of acute intraperitoneal (i.p.) Vitamin C (ascorbate) treatment in APP/PSEN1 mice, a mouse model of Alzheimer's disease. Middle-aged (12 months) and very old (24 months) APP/PSEN1 bigenic and wild-type mice were treated with ascorbate (125 mg/kg i.p.) or the vehicle 1 h before testing on Y-maze spontaneous alternation and Morris water maze tasks. Very old mice performed more poorly on cognitive tasks than middle-aged mice. Ascorbate treatment improved Y-maze alternation rates and swim accuracy in the water maze in both wild-type and APP/PSEN1 mice. Abeta deposits and oxidative stress both increased with age, and acetylcholinesterase (AChE) activity was significantly reduced in APP/PSEN1 compared to wild-type mice. However, the short course of acute ascorbate treatment did not alter Alzheimer-like neuropathological features of plaque deposition, oxidative stress, or AChE activity. These data suggest that ascorbate may have noötropic functions when administered parenterally in high doses and that the mode of action is via an acute, pharmacological-like mechanism that likely modulates neurotransmitter function.
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The chemical composition of several commercial Italian Limoncellos, lemon-peel-based alcoholic beverages, was studied by chromatographic techniques. These methods allowed a rapid monitoring of Limoncello, giving information on quality markers and possible adulteration of the product. Quantitative data for more than 60 compounds are reported. Limoncellos were characterized by the presence of selected volatile (terpenes, aldehydes, alcohols) and nonvolatile compounds (psoralens, coumarins, phenolics, carbohydrates and acids). On the basis of their composition, the samples were grouped by PCA analysis in two sets; the first group showed a composition similar to lemon essential oils, with a high content of b-pinene, myrcene, trans-a-bergamottene, and b-bisabolene, and a low content in neral and geranial. The composition of the second group suggested the occurrence of oxidative phenomena and/or the addition of flavors. The presence of ethyl acetate, acetaldehyde, 2-methyl-1-propanol and glycerol showed that a fermentation probably occurred in the sugar syrup used to dilute the Limoncello after the extraction process.
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In order to assess peripheral levels and activities of a broad spectrum of non-enzymatic and enzymatic antioxidants in elderly subjects with mild cognitive impairment (MCI) and Alzheimer's disease (AD), plasma levels of water-soluble (Vitamin C and uric acid) and of lipophilic (Vitamin A, Vitamin E and carotenoids including lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha- and beta-carotene) antioxidant micronutrients as well as activities of plasma and red blood cell (RBC) superoxide dismutase (SOD) and of plasma glutathione peroxidase (GPx) were measured in 25 patients with MCI, 63 AD patients and 53 controls. Peripheral levels and activities of antioxidants were similarly lower in MCI and AD patients as compared to controls. As MCI may represent a prodromal stage of AD, and oxidative damage appears to occur as one of the earliest pathophysiological events in AD, an increased intake of antioxidants in patients with MCI could be helpful in lowering the risk of conversion to dementia.
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive and memory deterioration. Production and accumulation of beta-amyloid peptide (Abeta) is central to the pathogenesis of AD. Recent studies have demonstrated that PKA/CREB-dependent signaling pathway and long-term potentiation are inhibited by sublethal concentrations of Abeta(1-42) in cultured hippocampus neurons. Here, we examined the effects of nobiletin on the Abeta-induced inhibition of CREB phosphorylation in cultured rat hippocampus neurons. A sublethal concentration of Abeta(1-42) or Abeta(1-40) decreased glutamate-induced CREB phosphorylation, whereas pretreatment with nobiletin reversed the Abeta-induced decrease in CREB phosphorylation. The effects of nobiletin on impairment of learning ability were also examined in chronically Abeta(1-40) infused AD model rats using the eight-arm radial maze. In the AD model rats, nobiletin showed protective effects on Abeta(1-40)-induced impairment of learning ability. These results suggest that nobiletin has the potential for becoming a novel lead compound for drug development for AD.