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PostPosted: Thu Jun 04, 2015 10:23 am 
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Oxyresveratrol (trans-2,3′,4,5′-tetrahydroxystilbene) as it is found in the Osage Orange tree of our USA is a very interesting compound and worth much study and application.

Resveratrol is a potent phenolic antioxidant found in the skin of grapes and red wine that has anti-proliferative, anti-inflammatory, and cardioprotective properties.1 Oxyresveratrol is a naturally occurring analog of resveratrol found in mulberry wood. It effectively scavenges H2O2, NO (IC50 = 45.3 μM), and the artificial free radical 2,2-diphenyl-l-picrylhydrazyl (IC50 = 28.9 μM).2 At 10 mg/kg, oxyresveratrol acts as a neuroprotectant, reducing brain infarct volume and reducing cytochrome c release and caspase-3 activation in an in vivo model of stroke.3 Oxyresveratrol also has depigmenting effects by effectively inhibiting tyrosinase activity, which catalyzes the rate-limiting step in synthesizing melanin pigments (IC50s = 1.2 and 52.7 μM in mushroom and mouse melanoma B-16 cells, respectively).4 It is 32-fold more potent than kojic acid, a depigmenting agent used in cosmetic materials with skin-whitening effects and medical agents used to treat hyperpigmentation disorders.

Analysis of osage orange (Maclura pomifera) heartwood extractives showed that two compounds were present at much higher levels than previously reported, the flavanonol dihydromorin (2.51%) and the stilbene oxyresveratrol (2.65%). All compounds present in osage orange heartwood that were tested had low activity against wood-decaying fungi. The agar plate test showed no synergistic effect, but the soil block test usinh white-rot fungi suggested synergism. The high durability of osage orange heartwood may be due to the large amounts of oxyresveratrol and dihydromorin. High levels of one or two monomeric compounds may also explain the exceptionally good durability of black locust and red mulberry heartwood


Oxidative stress is one of the major pathological factors in the cascade that leads to cell death in cerebral ischemia. Here, we investigated the neuroprotective effect of a naturally occurring antioxidant, oxyresveratrol, to reduce brain injury after cerebral stroke. We used the transient rat middle cerebral artery occlusion (MCAO) model of brain ischemia to induce a defined brain infarction. Oxyresveratrol was given twice intraperitoneally: immediately after occlusion and at the time of reperfusion. Oxyresveratrol (10 or 20 mg/kg) significantly reduced the brain infarct volume by approximately 54% and 63%, respectively, when compared to vehicle-treated MCAO rats. Also, the neurological deficits as assessed by different scoring methods improved in oxyresveratrol-treated MCAO rats. Histological analysis of apoptotic markers in the ischemic brain area revealed that oxyresveratrol treatment diminished cytochrome c release and decreased caspase-3 activation in MCAO rats. Also, staining for apoptotic DNA showed that the number of apoptotic nuclei in ischemic brain was reduced after oxyresveratrol treatment as compared to the vehicle-treated MCAO rats. This dose-dependent neuroprotective effect of oxyresveratrol in an in vivo stroke model demonstrates that this drug may prove to be beneficial for a therapeutic strategy to limit brain injury in acute brain ischemia.


THE CONSUMPTION OF NUTRIENTS rich in hydroxystilbenes (resveratrol and oxyresveratrol), such as grapes, red wine, peanuts and mulberry wood extracts (OSAGE ORANGE), has beneficial effects on human health (8, 9, 56). The cellular and the molecular mechanisms that underlie these beneficial effects are largely unknown. Several in vitro studies suggest that resveratrol suppresses the expression of genes involved in the inflammatory response to bacterial and viral stimuli (41, 57). More specifically, resveratrol or its hydroxylated form, oxyresveratrol (o-RES; trans-2,3',4,5'-tetrahydroxystilbene), reduces the immune activation of the inducible form of cyclooxygenase (COX-2), a key enzyme in the production of inflammatory prostaglandins (31, 38, 51). Such an effect is likely due to the resveratrol-induced inhibition of the NF-B signaling pathway, a signaling pathway involved in cox-2 gene expression (26, 30).

However, the inflammatory responses in vivo are much more complex than can be modeled in cultured cells in vitro. As a consequence, there are conflicting data on the in vitro and in vivo effects of resveratrol (16), most likely because in vivo immune system activation sets in motion complex and intricate inflammatory responses not seen in vitro. For example, in the best-studied model of innate immune system activation (i.e., a systemic injection of LPS, a component of the outer coat of the gram-negative bacteria), LPS activates resident macrophages in a variety of tissues (17, 28, 45) to release proinflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-1, and IL-6, as well as anti-inflammatory cytokines and hormones with anti-inflammatory activity (12). A variety of transcription factors such as NF-κB and STAT-3 are consequently activated and lead to the induction of COX-2 in a variety of tissues in the body, including the brain.

One hallmark of innate immune system activation in vivo is fever, an important component of the host defense response against infection (22). At the molecular level, fever develops as a result of COX-2 induction in endothelial cells of the brain vasculature followed by a subsequent production of prostaglandin E2 (PGE2) (5, 32). PGE2 induces fever by acting on neurons located within organum vasculosum of the lateral terminalis (OVLT) and the ventral preoptic region of the hypothalamus (49, 50). In addition to fever, LPS, at higher doses, can also induce hypothermia. It is well established that LPS-induced hypothermia is mediated by the proinflammatory cytokine TNF-α (10, 11, 27, 47).

Hydroxystilbenes are available as nonprescription, complementary medications with largely undocumented claims of efficacy. It is important that the actions of such compounds be subjected to rigorous experimental assessment, so that both the accuracy of claims and the action of these nonproprietary medications are documented. The LPS fever model provides such an opportunity in light of its well-understood and characterized actions. Thus one objective of this study was to determine whether o-RES is able to alter LPS fever via an action on LPS-induced COX-2 in rat OVLT and preoptic area (OVLT/POA). We further explored whether o-RES alters levels of LPS-stimulated, blood-born inflammatory cytokines, such as TNF-α and IL-6 and the level of activation of the transcription factor NF-κB in the liver, one major target for bacterial LPS (28).


Tyrosinase is responsible for the molting process in insects, undesirable browning of fruits and vegetables, and coloring of skin, hair, and eyes in animals. To clarify the mechanism of the depigmenting property of hydroxystilbene compounds, inhibitory actions of oxyresveratrol and its analogs on tyrosinases from mushroom and murine melanoma B-16 have been elucidated in this study. Oxyresveratrol showed potent inhibitory effect with an IC(50) value of 1.2 microm on mushroom tyrosinase activity, which was 32-fold stronger inhibition than kojic acid, a depigmenting agent used as the cosmetic material with skin-whitening effect and the medical agent for hyperpigmentation disorders. Hydroxystilbene compounds of resveratrol, 3,5-dihydroxy-4'-methoxystilbene, and rhapontigenin also showed more than 50% inhibition at 100 microm on mushroom tyrosinase activity, but other methylated or glycosylated hydroxystilbenes of 3,4'-dimethoxy-5-hydroxystilbene, trimethylresveratrol, piceid, and rhaponticin did not inhibit significantly. None of the hydroxystilbene compounds except oxyresveratrol exhibited more than 50% inhibition at 100 microm on l-tyrosine oxidation by murine tyrosinase activity; oxyresveratrol showed an IC(50) value of 52.7 microm on the enzyme activity. The kinetics and mechanism for inhibition of mushroom tyrosinase exhibited the reversibility of oxyresveratrol as a noncompetitive inhibitor with l-tyrosine as the substrate. The interaction between oxyresveratrol and tyrosinase exhibited a high affinity reflected in a K(i) value of 3.2-4.2 x 10(-7) m. Oxyresveratrol did not affect the promoter activity of the tyrosinase gene in murine melanoma B-16 at 10 and 100 microm. Therefore, the depigmenting effect of oxyresveratrol works through reversible inhibition of tyrosinase activity rather than suppression of the expression and synthesis of the enzyme. The number and position of hydroxy substituents seem to play an important role in the inhibitory effects of hydroxystilbene compounds on tyrosinase activity.


Abstract: The anti-herpes simplex virus (HSV) compound, oxyresveratrol, purified from a Thai traditional medicinal plant of Artocarpus lakoocha, was evaluated for its anti-varicella-zoste r virus (VZV) activity. This compound exhibited IC(50) values (50%-inhibitory concentrations for virus plaque formation) of 12.82, 12.80, 12.99 and 12.82 microg/ml against wild type, thymidine kinase-deficient and two types of DNA polymerase mutants with acyclovir-resistance , respectively. Thus oxyresveratrol showed a broad spectrum of anti-VZV activity with a mechanism of action different from that of acyclovir.


Oxyresveratrol (OXY) is a polyhydroxylated stilbene existing in mulberry (osage orange). Increasing lines of evidence have shown its neuroprotective effects against Alzheimer disease and stroke. However, little is known about its neuroprotective effect in Parkinson disease (PD). Owing to its antioxidant activity, blood-brain barrier permeativity, and water solubility, we hypothesized that OXY may exert neuroprotective effects against parkinsonian mimetic 6-hydroxydopamine (6-OHDA) neurotoxicity. Neuroblastoma SH-SY5Y cells have long been used as dopaminergic neurons in PD research. We found that both pretreatment and posttreatment with OXY on SH-SY5Y cells significantly reduced the release of lactate dehydrogenase, the activity of caspase-3, and the generation of intracellular reactive oxygen species triggered by 6-OHDA. Compared to resveratrol, OXY exhibited a wider effective dosage range. We proved that OXY could penetrate the cell membrane by HPLC analysis of cell extracts. These results suggest that OXY may act as an intracellular antioxidant to reduce oxidative stress induced by 6-OHDA. Western blot analysis demonstrated that OXY markedly attenuated 6-OHDA-induced phosphorylation of JNK and c-Jun. Furthermore, we proved that OXY increased the basal levels of SIRT1, which may disclose new pathways accounting for the neuroprotective effects of OXY. Taken together, our results suggest OXY, a dietary phenolic compound, as a potential nutritional candidate for protection against neurodegeneration in PD.



Hydroxystilbenes are naturally occurring polyphenols with protective effects against reactive oxygen and nitrogen species (ROS/RNS). Here, we investigated oxyresveratrol (OXY), which is contained in high amounts in mulberry wood, (osage orange) in comparison to the antioxidant resveratrol (RES). We found that OXY is a more effective scavenger for 2,2-diphenyl-1-picryl-hydrazyl (DPPH, 100μM) used as a general free radical model, compared to RES or trans-4-hydroxystilbene (IC50=28.9, 38.5, and 39.6μM, respectively). When primary glial cell cultures were loaded with the ROS/RNS-sensitive fluorochrome 2,7-dichlorodihydrofluorescein, the lowest rise in the fluorescence signal after H2O2 exposure was seen when the cells were pretreated with OXY. Using 4,5-diaminofluorescein (DAF-2) to monitor free nitric oxide levels (7.7 μM NO) in a spectrofluorimetric cell-free assay, we found again that OXY (at 5μM) is a more effective scavenger. Accordingly, cultures of the murine microglial cell line N9 and primary mixed glial cultures were used to test the drug effects of NO production upon expression of the inducible isoform of nitric oxide synthase (iNOS). We found that both compounds considerably diminished NO (nitrite) levels, RES more effectively than OXY (IC50=22.36 and 45.31μM). RES but not OXY down-regulated the expression of iNOS protein, but both did not alter iNOS activity. Furthermore, OXY displayed a generally lower cytotoxicity than RES. The radical and ROS scavenging properties, as well as the lower cytotoxicity towards microglia and the known good water solubility suggest OXY as a potential protectant against ROS/RNS.


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