Neuroprotective effects of quercetin, rutin and okra (Abelmoschus esculentus Linn.) in dexamethasone-treated mice

The administration of dexamethasone, a synthetic glucocorticoid receptor agonist, causes neuronal death in the CA3 layer of the hippocampus, which has been associated with learning and memory impairments. This study aimed to examine the ability of okra (Abelmoschus esculentus Linn.) extract and its derivatives (quercetin and rutin) to protect neuronal function and improve learning and memory deficits in mice subjected to dexamethasone treatment. Learning and memory functions in mice were examined using the Morris water maze test. The results showed that the mice treated with dexamethasone had prolonged water maze performance latencies and shorter time spent in the target quadrant while mice pretreated with quercetin, rutin or okra extract prior to dexamethasone treatment showed shorter latencies and longer time spent in target quadrant. Morphological changes in pyramidal neurons were observed in the dexamethasone treated group. The number of CA3 hippocampal neurons was significantly lower while pretreated with quercetin, rutin or okra attenuated this change. Prolonged treatment with dexamethasone altered NMDA receptor expression in the hippocampus. Pretreatment with quercetin, rutin or okra extract prevented the reduction in NMDA receptor expression. Dentate gyrus (DG) cell proliferation was examined using the 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry technique. The number of BrdU-immunopositive cells was significantly reduced in dexamethasone-treated mice compared to control mice. Pretreatment with okra extract, either quercetin or rutin was found to restore BrdU-immunoreactivity in the dentate gyrus. These findings suggest that quercetin, rutin and okra extract treatments reversed cognitive deficits, including impaired dentate gyrus (DG) cell proliferation, and protected against morphological changes in the CA3 region in dexamethasone-treated mice. The precise mechanism of the neuroprotective effect of these plant extracts should be further investigated.     

Quercetin inhibits invasion, migration and signalling molecules involved in cell survival and proliferation of prostate cancer cell line (PC-3)

Urokinase-type plasminogen activator (uPA) is a serine protease that is involved in cancer progression, especially invasion and metastasis including prostate cancer. uPA activation is mediated by transactivation of uPAR and epidermal growth factor receptor (EGF-R) in prostate cancer progression. Prostate cancer (PC-3) cells have highly invasive capacity and they express uPA and uPAR gene. PC-3 cells are treated with quercetin, which inhibits invasion and migration of PC-3 cells. Quercetin downregulates uPA, uPAR and EGF, EGF-R mRNA expressions. Quercetin inhibits cell survival factor β-catenin, NF-κB and also proliferative signalling molecules such as p-EGF-R, N-Ras, Raf-1, c.Fos c.Jun and p-c.Jun protein expressions. But quercetin increased p38 mitogen-activated protein kinase protein expression. Our results suggest that quercetin inhibit migration and invasion of prostate cancer cells. It shows the value for treatment of invasive and metastasis type of prostate cancer.     

Differential responses of five cherry tomato varieties to water stress: changes on phenolic metabolites and related enzymes

Different tomato cultivars (Solanum lycopersicum L.) with differences in tolerance to drought were subjected to moderate water stress to test the effects on flavonoids and caffeoyl derivatives and related enzymes. Our results indicate that water stress resulted in decreased shikimate pathway (DAHP synthase, shikimate dehydrogenase, phenylalanine ammonium lyase, cinnamate 4-hydroxylase, 4-coumarate CoA ligase) and phenolic compounds (caffeoylquinic acid derivatives, quercetin and kaempferol) in the cultivars more sensitive to water stress. However, cv. Zarina is more tolerant, and registered a rise in querc-3-rut-pent, kaempferol-3-api-rut, and kaempferol-3-rut under the treatment of water stress. Moreover, this cultivar show increased activities of flavonoid and phenylpropanoid synthesis and decreased in degradation-related enzymes. These results show that moderate water stress can induce shikimate pathway in tolerant cultivar.     

Effects of flavonoid on calcium content in femoral tissue culture and parathyroid hormone-stimulated osteoclastogenesis in bone marrow culture in vitro

The effect of various flavonoids, which are present in food and plants, on bone calcium content and osteoclastogenesis were investigated to compare action of flavonoid on bone formation and bone resorption in vitro. Rat femoral-diaphyseal (cortical bone) and -metaphyseal (trabecular bone) tissues were cultured for 48 h in Dulbecco’s modified Eagle’s medium (high glucose) supplemented with antibiotics and bovine serum albumin. Amoung quercetin, myricetin, kaempferol, isorhamnetin, curcumin, hesperidin, or astaxanthin in the range of 10⁻⁷–10⁻⁵ M, culture with quercetin (10⁻⁶ or 10⁻⁵ M) caused a significant increase in diaphyseal calcium content. Such an effect was not seen in other compounds. Mouse bone marrow cells were cultured for 7 days in the presence of parathyroid hormone (PTH; 10⁻⁷ M), a bone-resorbing factor, in vitro. Culture with PTH caused a significant increase in osteoclast-like cell formation. This increase was significantly inhibited in the presence of quercetin, myricetin, kaempferol, isorhamnetin, or curcumin in the range of 10⁻⁸–10⁻⁶ M. Such an effect was not seen in the case of hesperidin or astaxanthin. In addition, culture with PTH (10⁻⁷ M) caused a significant decrease in diaphyseal calcium content. This decrease was completely prevented in the presence of quercetin, myricetin, kaempferal, or isorhamnetin of 10⁻⁶ M. This study demonstrates that various flavonoids have a potent inhibitory effect on osteoclastogenesis and bone resorption rather than bone formation in vitro. Among various flavonoids, quercetin had a stimulatory effect on bone formation and an inhibitory effect on bone resorption in vitro.     

Annona squamosa seed extract in the regulation of hyperthyroidism and lipid-peroxidation in mice: Possible involvement of quercetin

Annona squamosa (Custard apple) seeds are generally thrown away as waste materials. The extract of these seeds was evaluated for its possible ameliorative effect in the regulation of hyperthyroidism in mouse model. Serum triiodothyronine (T₃), thyroxine (T₄) concentrations, hepatic glucose-6-phospatase (G-6-Pase) and 5′-mono-deiodinase (5′DI) activity were considered as the end parameters of thyroid function. Simultaneously hepatic lipid peroxidation (LPO), superoxide dismutase (SOD) and catalase (CAT) activities were investigated to observe its hepatotoxic effect, if any.

L-T₄ administration (0.5 mg/kg/d for 12 days, i.p.) increased the levels of serum T₃ and T₄, activity of hepatic G-6-Pase, 5′DI and LPO with a parallel decrease in SOD and CAT activities. However, simultaneous administration of the Annona seed extract (200 mg/kg) or quercetin (10 mg/kg) to T₄-induced hyperthyroid animals for 10 days, reversed all these effects indicating their potential in the regulation of hyperthyroidism. Further, the seed extract did not increase, but decreased the hepatic LPO suggesting its safe and antiperoxidative nature. Quercetin also decreased hepatic LPO. When relative efficacy was compared with that of propyl thiouracil (PTU), a standard antithyroidic drug, experimental seed extract appeared to be more effective. Phytochemical analyses including HPLC revealed the presence of quercetin in the seed extract and the results on the effects of quercetin suggested the involvement of this phytochemical in the mediation of antithyroidal activity of Annona squamosa seed extract.     

Quercetin protects human granulosa cells against oxidative stress via thioredoxin system

Granulosa Cells (GCs) are sensitive to excessive production of reactive oxygen species (ROS). Quercetin (QUR) is a free radical scavenger which can alleviate oxidative stress through nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/antioxidant response element (ARE) pathway and thioredoxin (Trx) system. We aimed to explore the probable protective role of QUR on cultured human GCs treated with hydrogen peroxide (H₂O₂) as an inducer of oxidative stress. MTT assay was applied for evaluating the cell cytotoxicity of QUR and H₂O₂. The rate of apoptotic cells and intracellular ROS generation were determined by Annexin V-FITC/PI staining and 2′-7′-dichlorodihydro?uorescein diacetate ?uorescent probes (DCFH-DA), respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis and western blot analysis were used to evaluate the gene and protein expression of Nrf2 and kelch-like ech-associated protein 1 (Keap1)1. The Nrf2 and Trx activities were measured by Enzyme-linked Immunosorbent Assay (ELISA). The results indicated that QUR pretreatment can decrease ROS production and apoptosis induced by H₂O₂. In addition, QUR increased Nrf2 gene and protein expression, as well as its nuclear translocation. Moreover, in QUR-treated group, a lower level of Keap1 protein was observed, which was not reported as significant. The results also indicated a significant correlation between the expression of Nrf2 and Keap1 in QUR-treated group. Further, QUR protected GCs from oxidative stress by increasing Trx gene expression and activity. This study suggests that QUR as a supplementary factor may protect GCs from oxidative stress in diseases related to this condition.     

Protective effect of quercetin on hyperglycemia,oxidative stress and DNA damage in alloxan induced type 2 diabetic mice

Aims

Quercetin is a natural polyphenolic flavonoid and acts as a quencher for reactive oxygen species generated by any physical or chemical action. In type 2 diabetes mellitus (T2DM) the basic characteristic feature is hyperglycemia which leads to complications involving oxidative stress. In view of this, the present study was conducted to examine the effect of quercetin in T2DM.

Main methods

A total of 18 mice were divided into three groups, vis control, diabetic and diabetic treated with quercetin. Fasting blood glucose (FBG) levels and anti-oxidant enzyme activity were assayed. Creatinine, urea, lipid peroxidation, GLUT4 expression and DNA damage were also measured.

Key findings

A significant decrease in FBG level and liver and kidney marker enzymes was observed in the quercetin treated group as compared to the diabetic one. Glutathione, SOD, catalase, and glutathione-S-transferase levels were also found to be increased on quercetin supplementation. Thiobarbituric acid-reactive substance level was decreased while GLUT4 expression levels were increased in the treated group. DNA damage was also affected positively by quercetin when subjected with single cell alkaline gel electrophoresis. Thus, we may suggest an anti-oxidant potential and protective effect of quercetin in T2DM mice.

Significance

From this study, we conclude that quercetin ameliorates hyperglycemia and oxidative stress, by blunting free radical induced toxicity in T2DM.     

Isoquercitrin Suppresses Colon Cancer Cell Growth in Vitro by Targeting the Wnt/β-Catenin Signaling Pathway

Flavonoids are plant-derived polyphenolic molecules that have potential biological effects including anti-oxidative, anti-inflammatory, anti-viral, and anti-tumoral effects. These effects are related to the ability of flavonoids to modulate signaling pathways, such as the canonical Wnt signaling pathway. This pathway controls many aspects of embryonic development and tissue maintenance and has been found to be deregulated in a range of human cancers. We performed several in vivo assays in Xenopus embryos, a functional model of canonical Wnt signaling studies, and also used in vitro models, to investigate whether isoquercitrin affects Wnt/β-catenin signaling. Our data provide strong support for an inhibitory effect of isoquercitrin on Wnt/β-catenin, where the flavonoid acts downstream of β-catenin translocation to the nuclei. Isoquercitrin affects Xenopus axis establishment, reverses double axes and the LiCl hyperdorsalization phenotype, and reduces Xnr3 expression. In addition, this flavonoid shows anti-tumoral effects on colon cancer cells (SW480, DLD-1, and HCT116), whereas exerting no significant effect on non-tumor colon cell (IEC-18), suggesting a specific effect in tumor cells in vitro. Taken together, our data indicate that isoquercitrin is an inhibitor of Wnt/β-catenin and should be further investigated as a potential novel anti-tumoral agent.