Cardiovascular Drug Reviews Vol. 22, No. 2, pp.

91102 2004 Neva Press, Branford, Connecticut

Pharmacological Effects of Xanthones as Cardiovascular Protective Agents

De-Jian Jiang, Zhong Dai, Yuan-Jian Li
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China

Keywords: Atherosclerosis Cardioprotection Endogenous NO synthase inhibitor Endothelial dysfunction Low-density lipoproteins Nitric oxide (NO) Xanthones.

ABSTRACT
Many epidemiological studies indicate that consumption of dietary polyphenolic compounds is beneficial in the prevention of cardiovascular diseases. Xanthones are a class of polyphenolic compounds that commonly occur in plants and have been shown to have extensive biological and pharmacological activities. Recently, the pharmacological properties of xanthones in the cardiovascular system have attracted great interest. Xanthones and xanthone derivatives have been shown to have beneficial effects on some cardiovascular diseases, including ischemic heart disease, atherosclerosis, hypertension and thrombosis. The protective effects of xanthones in the cardiovascular system may be due to their antioxidant, antiinflammatory, platelet aggregation inhibitory, antithrombotic and/or vasorelaxant activities. In particular, the antagonism of endogenous nitric oxide synthase inhibitors by xanthones may represent the basis for improved endothelial function and for reduction of events associated with atherosclerosis.

INTRODUCTION
A number of epidemiological studies indicate that consumption of dietary polyphenolic compounds is beneficial in the prevention of cardiovascular diseases. The French Paradox is the best example of such a benefit (26,27,70). French consume higher fat
Address correspondence and reprint requests to: Yuan-Jian Li, MD, Dept. of Pharmacology, School of Pharmaceutical Sciences, Central South University, Xiang-Ya Road #90, Changsha 410078, China. Tel: +86 (731) 235-5078; Fax: +86 (731) 2650442; E-mail: yuan_jianli@yahoo.com

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diets, exercise less, and smoke more than Americans. However, their mortality from cardiovascular diseases is much lower than in the USA or in most other Western societies. Polyphenolic constituents in red wine have been found to be cardioprotective and their consumption is likely to explain the French Paradox (17). Among many polyphenolic compounds, flavonoids received the most attention and their pharmacology was studied extensively. However, a large number of studies also involved other naturally occurring polyphenolic compounds, such as xanthones. Xanthones are polyphenolic compounds that commonly occur in Chinese herbs such as Swertia davidi Franch (Gentianceae), which has been used in the treatment of inflammation, allergy or hepatitis (77). Nowadays, xanthones and xanthone derivatives are isolated from plants or are chemically synthesized. A substantial number of studies demonstrated that xanthones and xanthone derivatives have extensive biological and pharmacological activities such as antiinflammatory, antihepatotoxic, antitumor and antimicrobial activities (67). Recently, cardiovascular effects of xanthones attracted considerable interest. Xanthones and xanthone derivatives have been shown to have beneficial effects in the treatment of cardiovascular diseases, including ischemic heart disease, atherosclerosis, hypertension and thrombosis. This review focuses on the protective effects and the mechanisms of action of xanthones and xanthone derivatives in the cardiovascular system.

CHEMISTRY
As Figure 1A shows, xanthene-9-one is the basic skeleton of xanthone. The carbons have been numbered according to the biosynthetic convention: carbons 14 are assigned to the acetate-derived ring A and carbons 58 to the sikimin-derived ring B (67). The xanthones isolated so far may be classified into five major groups: simple oxygenated xanthones, xanthone glycosides, prenylated and related xanthones, xanthonolignoids and miscellaneous xanthones. Xanthones have been found in some familiar fruits such as mango and mangosteen, and in some medicinal plant families such as Gentianceae and Polygalaceae. Chemical structures of several xanthone compounds are shown in Fig. 1B.

PHARMACOKINETICS AND TOXICITY

Recently the pharmacokinetics of mangiferin, a xanthone glycoside isolated from the herbal root of Anemarrhena asphodeloides, in the rat was reported (46). The pharmacokinetics of mangiferin at doses of 1030 mg/kg reveal a linear relation, while doses at 30100 mg/kg magniferin shows a nonlinear pharmacokinetic phenomenon. Mangiferin was undetectable in brain dialysate. There are only a few studies on the toxicity of xanthones. Although in some studies xanthones were found to be cytotoxic in tumor cell lines (57,72), they are generally considered to have low toxicity to normal cells and tissues. In an acute toxicity study in mice, the maximal tolerated dose of 1,6-dihydroxy-3,5-dimethoxyxanthone, isolated from Canscora lucidissima, was 300 mg/kg, i.p. (85).

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A
7 6

O
8

1 2

B
5

A O
3 4

B
CH3O HO CH2OH O OH HO OH HO O OH OH

Mangostin
OH O OH O OH O HO HO O OH OH

Mangiferin
OH O OH H3CO O OH OH

Norathyriol
OH O OH

OCH3

OCH3

Demethylbellidifolin

Daviditin A

FIG. 1. A, the basic skeleton of xanthone; B, chemical structures of several xanthone derivatives.

CARDIOPROTECTIVE EFFECTS OF XANTHONES

There is a great deal of evidence in animals that xanthones prevent damage of cardiac tissue induced by various means. The three xanthones isolated from Canscora lucidissima, significantly decreased myocardial ischemia-reperfusion-induced arrhythmias in vivo. They also increased the survival rate and decreased the release of lactate dehydrogenase (LDH) in cultured cardiomyocytes subjected to anoxia/reoxygenation (23,25). In our recent study we found that the xanthone extracted from Swertia davidi Franch, as well as

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demethylbellidifolin, an isolated xanthone, significantly improved the recovery of cardiac function (coronary flow, left ventricular pressure and its first derivatives) during reperfusion, the decreased the release of creatine kinase (CK) in isolated rat hearts, and markedly decreased myocardial infarct size in vivo (40,41). Mangiferin, isolated from Rhizoma anemarhenea, has been shown to inhibit apoptosis induced by hypoxia/reoxygenation in cultured cardiomyocytes (73). Other studies have shown that some xanthones protect against the cardiac injury induced by streptozotocin or epinephrine (60,62). Gentiana kochiana Perr. et Song. (Gentianaceae) is a plant used in traditional Italian medicine as an antihypertensive remedy (3). Recently, gentiacaulein and gentiakochianin, two xanthone compounds isolated from the root of this plant, were found to relax isolated rat aortic strips, this effect may explain the antihypertensive property of Gentiana kochiana (12). Moreover, a series of synthetic xanthones and xanthone derivatives had also hypotensive acitivity in rats (83).

THE ROLE OF ANTIOXIDANT, ANTIINFLAMMATORY, ANTITHROMBOTIC AND VASODILATOR ACTIVITIES IN THE CARDIOPROTECTIVE EFFECTS OF XANTHONES
Free Radical Scavenging and Antioxidant Activities
The generation of oxygen free radicals is strongly implicated as an important pathophysiological mechanism mediating myocardial ischemia-reperfusion injury (34). Molecules involved in the free radical reactions include superoxide anion, hydroxyl radical, hydrogen peroxide, peroxynitrite and hypochlorous acid. Free radicals contain an unpaired electron and are accordingly highly reactive. Reintroduction of abundant oxygen at the very onset of reperfusion evokes a burst of free radicals as demonstrated in experimental animal models as well as in humans with acute myocardial infarction undergoing thrombolysis or percutaneous transluminal coronary angioplasty. The release of free radicals, in combination with the ischemia-induced decrease in antioxidant activity, renders the myocardium extremely vulnerable. Oxygen radicals react readily with cellular phospholipids and proteins, causing lipid peroxidation and oxidation of thiol groups with subsequent alteration of membrane ultrastructure and dysfunction of various cellular proteins. The antioxidants are known to interfere with the free radical formation, and antioxidant reserve and enzyme capacity are significantly reduced following ischemia and reperfusion. The loss of key antioxidant enzymes and antioxidant status downregulates the overall antioxidant reserve of the myocardium, and makes the heart susceptible to injury induced by ischemia reperfusion. The reduced antioxidant defense cannot provide protection against increased activities of free radicals and oxidative stress. It has been reported that some free radical scavengers and antioxidants prevent arrhythmias and cardiac injury induced by myocardial ischemia-reperfusion (18). Xanthones have been described as strong scavengers of free radicals and antioxidants. They exhibit concentration-dependent scavenging activity toward superoxide anions, hydroxyl and peroxyl radicals (24,49,87). Our recent study, as well as studies by others, showed that some xanthones scavenge 1,1-diphenyl-2-picrylhydracyl (DPPH) radicals in a concentration-dependent manner (13,38). It has been also shown that xanthones inhibit the production of lipid peroxides in normal brain, hepatic and myocardial tissues and elevate the production of lipid peroxides induced by FeSO4 + cysteine, FeCl2 + ascorbic acid or

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CCl4 + NADPH mixtures in rat liver homogenates (24,39). There is also direct evidence that xanthones scavenge free radicals and inhibit oxidative stress in post-ischemic myocardium. Addition of xanthine/xanthine oxidase or Fe2+/H2O2 to the reperfusion solution has been found to increase the production of oxygen free radicals and to aggravate injury induced by ischemia-reperfusion. Magniferin has been shown to attenuate this effect. As demonstrated by electron spin resonance and chemiluminescence techniques the protective effect of mangiferin can be correlated with the reduction of oxygen free radicals in myocardium (87). Furthermore, the oxidative stress in myocardial tissue has been assessed by the levels of malondialdehyde (MDA), reflecting level of lipid peroxidation. During reperfusion myocardial MDA levels were significantly increased and this increase was reduced by xanthones in vivo and in vitro (25,40,41). In addition to directly scavenging free radicals and inhibiting oxidative stress, xanthones attenuated the reperfusion-induced inhibition of antioxidant enzymes such as superoxide dismutase, which increases the antioxidant capacity of myocardium (25). Apoptosis may be the major initial form of ischemic myocardial cell death occurring within the first 2 or 3 h after an ischemic episode (9). Active oxygen species may trigger apoptotic process by adjusting the apoptosis related genes, such as bcl-2 and p53, in myocardial ischemia-reperfusion injury (1). It is well known that bcl-2 and p53 are involved in the regulation of apoptotic process. The function of bcl-2 as a survival gene is to inhibit cell death by acting as an antioxidant, triggering enhanced expression of cellular antioxidant defense and directly inhibiting the generation of oxygen radicals. As a pro-apoptotic transcription factor, p53 gene suppresses the anti-death gene bcl-2 and enhances bax induction, playing a critical role in triggering the apoptotic program of cells in hypoxia-mediated cellular apoptosis. The inhibitory effect of mangiferin on apoptosis of cardiomyocytes in hypoxia/reoxygenation process has been observed. As demonstrated by DNA electrophoresis on agarose gel mangiferin reduced the apoptosis in cardiomyocytes induced by 24-h hypoxia and 4-h reoxygenation (73). Moreover, the downregulation of bcl-2 and the upregulation of p53 in cardiomyocytes induced by hypoxia/reoxygenation were significantly attenuated by pretreantment with mangiferin (73). Low-density lipoprotein (LDL) oxidation plays a causative role in the early atherogenesis and the oxidatively modified LDL (ox-LDL) has been shown to exist in atherosclerotic lesions (45). There is evidence that intake of polyphenolic compounds is inversely related to the morbidity and mortality from coronary heart disease, and that this phenomenon is associated with the inhibition of LDL oxidation (26,35). Some xanthone compounds have been found to inhibit oxidation of LDL in vitro and in vivo (38,39,59,84). Mangostin, a prenylated xantone, prolonged in a dose-dependent manner, the lag time to either metal ion dependent (Cu2+) or independent (aqueous peroxyl radicals) oxidation of LDL. This effect has been monitored by the formation of conjugated dienes at 234 nm and by the levels of thiobarbituric reactive substances generated in LDL (84). Moreover, mangostin significantly inhibited the consumption of alpha-tocopherol in the LDL during Cu2+-induced LDL oxidation (84). More recently, we also showed that some xanthones, at low concentrations, inhibit Cu2+-induced LDL oxidation (38,39). These results suggest that xanthones can act as potent inhibitors of LDL oxidation via several mechanisms by: 1) scavenging free radicals by acting as hydrogen atom donating molecules or singlet oxygen quenchers; 2) reducing the capacity of metal to generate free radicals via chelation of transition metal ions; and 3) inhibiting the consumption of antioxidants such as -tocopherol in the LDL particles.

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Inhibition of Inflammatory Response

Myocardial reperfusion injury has recently been considered to involve a type of inflammatory response, and myocardial infarction has been associated with the coordinated activation of a series of inflammatory responses, including complement activation, an increase in the expression of cytokines and adhesion molecules, as well as neutrophil infiltration and recruitment (21). The cytokine cascade in the infarcted myocardium is triggered by a number of agents, including cytokines (such as TNF- and IL-1) and by free radicals. It has been recently reported that mast cell is an important source of preformed and newly synthesized cytokines, chemokines and growth factors, and that TNF-, released by degranulation of cardiac mast cell following myocardial ischemia, may be an upstream cytokine responsible for initiation of the inflammatory cascade (20). Elevation of inflammation factors and increase of vascular permeability have been thought to play a crucial role in recruiting neutrophils in the ischemic and reperfused myocardium (43). Recruited neutrophils exert potent cytotoxic effects through the release of proteolytic enzymes and the adhesion to the intercellular adhesion molecule-1 (ICAM-1) that is expressed in the endothelial cells and cardiomyocytes (43). It has been suggested that adherence to CD11b/CD18-ICAM-1 activates the neutrophil respiratory burst, resulting in a highly compartmented iron-dependent oxidative injury of cardiomyocytes (19). Xanthones have been shown to have a strong antiinflammatory activity, such as inhibition of allergy, decrease of histamine release and reduction of some prostanoids synthesis via inhibition of cyclooxygenase (COX) activity (63,64,71). Norathyriol has antiinflammatory effects mediated partly through suppression of mast cell degranulation (51). Moreover, it has been reported that norathyriol attenuates the increased permeability of heart endothelial cells and the respiratory burst of neutrophils induced by some inflammatory agonists by inhibiting the activation of protein kinase C or phospholipase C (29,47). Some synthetic xanthones have been shown to inhibit the increased expression of ICAM-1 induced by TNF- in cultured endothelial cells (58). More recently, we have shown that, in isolated rat hearts subjected to 20 min of global ischemia, followed by 40 min of reperfusion, 3,4,5,6-tetrahydroxyxanthone attenuates the inhibition of cardiac function, the increase in the release of CK in the coronary effluent, as well as the increased levels of TNF- in myocardium (16). The same compound also markedly decreased the infarct size and the release of CK and TNF- in myocardium induced by coronary artery occlusion for 60 min, followed by 180 min of reperfusion in vivo (16). These results suggest that the protective effects of xanthones in myocardial ischemia/reperfusion injury may be related to inhibition of inflammatory response in myocardial infarction, especially a reduction of TNF- production. The antiinflammatory roles of xanthones may also be of particular interest with respect to atherosclerosis, which is being increasingly viewed as a disease with complex inflammatory responses (50). The earliest stages of atherogenesis are associated with the enhanced expression of pro-inflammatory cytokines such as TNF-. Numerous pathophysiological phenomena may stimulate cytokine release, including ox-LDL, free radicals, hemodynamic stress, hypertension, or infectious organisms. Many of the early atherogenic processes, triggered by inflammatory cytokines, alter endothelial function, enhance the expression of leukocyte adhesion molecules and chemokines, promote monocyte and T-cell recruitment, and foster formation of monocyte- and smooth muscle cellderived foam cells.

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As mentioned above, xanthones significantly inhibit TNF--induced increase of ICAM-1 expression in cultured endothelial cells (58). Our study showed that xanthones significantly inhibit the increased adhesion of monocytes to endothelial cells and attenuate the increased levels of TNF- and monocyte chemoattractant protein (MCP-1) induced by ox-LDL in cultured endothelial cells (36,39). Recently, it has been shown that mangiferin decreases TNF- mRNA levels in rat macrophages stimulated in vivo with 3% thioglycollate and in vitro with 100 ng/mL lipopolysaccharide (49). These antiinflammatory effects of xanthones may contribute to their protection against atherogenesis.

Inhibition of Platelet Aggregation and Antithrombotic Effects

Intravascular thrombosis is involved in the pathogenesis of several cardiovascular diseases. The initiation of intraluminal thrombosis is believed to involve platelet adherence and aggregation. In the normal circulation, platelets do not aggregate in the absence of stimulation. When a blood vessel is damaged, platelets adhere to the disrupted surface and then release several biologically active mediators such as platelet-activating factor (PAF) that promotes platelet aggregation (61). Platelet aggregation plays probably a crucial role in the development of an atherosclerotic lesion, unstable angina, or acute myocardial infarction (14,22). The effects of natural or synthetic xanthones and xanthone derivatives on platelet aggregation have been evaluated in washed rabbit platelets or human platelet-rich plasma. Xanthones and xanthone derivatives inhibited platelet aggregation and ATP release induced by a variety of agonists, including ADP, arachidonic acid, PAF, collagen, ionophore A23187 and thrombin (10,5254,56,69,79). The inhibitory effect of xanthones and xanthone derivatives on platelet aggregation may be related to the reduction of phosphoinositide breakdown and/or decrease of thromboxane formation via inhibition of COX (10,52,69,79). Moreover, some xanthones block the PAF receptor and inhibit PAF binding to rabbit platelets in vitro (32,33). Jacarelhyperols A and B, two new bisxanthones extracted from Hypericum japonicum, showed significant inhibitory effects against PAF-induced hypotension (30). In vivo, at 30 min after intraperitoneal administration of norathyriol, tail-bleeding time of mice was markedly prolonged in a dose-dependent manner (78). In endotoxin-induced experimental disseminated intravascular coagulation in rats, norathyriol prevented the decrease in platelet counts and fibrinogen, and the prolongation of plasma prothrombin time (78). However, norathyriol could not prevent acute thromboembolic death in mice.

Vasorelaxant Actions
The vasorelaxant actions of several xanthones have been examined in rat thoracic aorta (3,11,12,44). The norepinephrine (NE)- and high K+-induced vasoconstriction was inhibited concentration-dependently in aorta pretreated with xanthone or norathyriol (11,44). This relaxant effect of xanthone and norathyriol persisted in endothelium-denuded aorta, suggesting that the relaxation induced by xanthones is endothelium-independent. The 45Ca2+ influx caused by either NE or high-K+ was inhibited by xanthone or norathyriol in a concentration-dependent manner, suggesting that xanthones might act as blockers of both receptor-operated and voltage-dependent Ca2+ channels. Moreover, the relaxant effect of norathyriol was not antagonized by methylene blue or indomethacin. These data suggested that the mechanism of xanthone-induced vasorelaxation might in-

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volve the block of Ca2+ channels. However, although xanthone caused an increase in the levels of intracellular cyclic adenosine 3,5-monophosphate (cAMP) but not cyclic guanosine 3,5-monophosphate (cGMP), norathyriol (at a high concentration of 400 M) increased cGMP but not cAMP levels.

EFFECTS OF XANTHONES ON ENDOTHELIAL FUNCTION AND ON THE LEVELS OF ENDOGENOUS NITRIC OXIDE SYNTHASE INHIBITOR
Endothelial Dysfunction and Endogenous Nitric Oxide Synthase Inhibitors
It has been shown that endothelium-dependent vasodilation is attenuated in many risk factors of atherosclerosis, such as hypercholesterolemia, hypertension, and diabetes mellitus, and endothelial dysfunction is recognized as an early event in the pathogenesis of atherosclerosis (68). Nitric oxide (NO), synthesized from L-arginine by NO synthase (NOS) in endothelial cells, has been thought to play a key role in the maintenance of vascular tone and structure. NO possesses complex cardiovascular actions such as protection of endothelial cells, decrease of the endothelial adhesiveness and inhibition of the adhesion of monocytes to endothelial cells, and it is generally described as an endogenous anti-atherosclerotic molecule (65). Recently, it has been found that L-arginine analogs such as asymmetric dimethylarginine (ADMA), which is present in the blood of both humans and animals, can inhibit NOS in vivo and in vitro (81,82). ADMA has been shown to concentration-dependently inhibit vasodilator responses to acetylcholine in isolated aortic rings, upregulate expression of MCP-1 and enhance adhesion of monocytes in cultured endothelial cells (2,6). There is growing evidence that endothelial dysfunction in some cardiovascular diseases, such as hypercholesterolemia, heart failure and hypertension, is associated with elevation of ADMA levels, and that its levels could predict endothelial dysfunction (15,74,80,86).

Xanthones Protect against Endothelial Dysfunction by Reducing the Levels of Endogenous Nitric Oxide Synthase Inhibitors
Vasodilator responses to acetylcholine in rings of the isolated thoracic aorta have been shown to be impaired in the presence of lysophosphatidylcholine (LPC), a major component of ox-LDL. Daviditin A significantly attenuated inhibition of endothelium-dependent relaxation by LPC (38). Previous observations and our recent studies have shown that a single injection of native LDL causes a rapid accumulation and oxidation of LDL in the arterial wall. This effect is followed by an acute inflammatory response, such as an increase of ICAM-1 expression at 6 to 12 h after injection of LDL, which leads to endothelial dysfunction concomitantly with an elevation of ADMA level (8,42). Pretreatment with xanthones attenuated the endothelial dysfunction and the elevation of ADMA level elicited by injection of LDL in vivo (37). Moreover, in cultured endothelial cells xanthones inhibited the increase in the release of LDH, the upregulation of MCP-1 expression and the enhancement of monocytes adhesion concomitantly with a reduction of ADMA levels (36,39). These findings suggest that xanthones protect against endothelial damage induced by high-lipid levels, and that the protective effect of xanthones on the endothelium is related to a reduction of ADMA concentration.

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Mechanism of the Inhibitory Effect of Xanthones on ADMA Levels

ADMA is synthesized by protein arginine methyltransferases (PRMTs), which utilize S-adenosylmethionine as methyl group donor, and is degraded by dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyzes ADMA to L-citrulline and dimethylamine (7, 66). Two different isoforms of DDAH are known, DDAH-1 and DDAH-2. DDAH-1 is typically found in tissues expressing neuronal NOS, whereas DDAH-2 predominates in tissues containing the endothelial isoform of NOS (48). There is evidence that lipid-induced dysregulation of DDAH may be an important factor contributing to the elevation of ADMA in hypercholesterelemia and hyperhomocysteinemia (5,75). Others have reported that in cultured endothelial cells treated with ox-LDL or TNF the elevated content of ADMA is also related to the decreased activity of DDAH, but not to its protein expression (31). DDAH has been thought to be an oxidant-sensitive enzyme that has sulfhydryl groups in its structure. Though it is not yet understood in detail, oxidative stress induced by lipid and/or inflammation factors may contribute to the decrease of DDAH activity (4). Some antioxidants have been shown to attenuate homocysteine- or high glucose-induced ADMA accumulation by reversing the decrease in DDAH activity (55,76). Our results in cultured endothelial cells treated with LDL, ox-LDL or LPC also showed that xanthones significantly decreased the level of ADMA concomitantly with an improvement in DDAH activity (3639). As mentioned above, xanthones can significantly attenuate the levels of lipid peroxides and of TNF- induced by ox-LDL (3639). These findings suggest that xanthones-induced decreased level of ADMA is related to an increase of DDAH activity due to inhibition of oxidative stress via antioxidant and/or antiinflammatory activities.

SUMMARY
There is substantial evidence to suggest that xanthones and xanthone derivatives may be potentially useful as pharmacological agents in the treatment or prevention of cardiovascular diseases, including ischemic heart disease, atherosclerosis and hypertension. The protective effects of xanthones in the cardiovascular system may be due to their antioxidant, anti-inflammatory, platelet aggregation inhibitory, antithrombotic and/or vasorelaxant activities. In particular, the antagonism of endogenous NOS inhibitors by xanthones may represent the basis for improved endothelial function and for reduction of events associated with atherosclerosis. However, the precise effects of xanthones need to be further elucidated in animal experiments in vivo and in humans. Moreover, pharmacokinetics, toxicity and structural optimization of xanthones should also be explored.
Acknowledgments. This study was supported by a grant from the Provincial Natural Science Foundation of Hunan, China, No. 02jjy2046.

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