Chemical Components A Lipid Soluble Components

In the last 50 years, many efforts have been made to study the chemical constituents of SM. Most of the studies have been focused on the lipophilic diter-

penoid quinones. The major lipid-soluble components that have been identified so far include tanshinone I, dihydrotanshinone I, isotanshinone I and II, tanshinone IIA, tanshinone IIB, tanshinone V, tanshinone VI, isotanshinone, hydroxytanshinone, cryptotanshinone, isocryptotanshinone, methyltanshin-onate, methylene tanshinquinone, przewaquinone A, przewaquinone B, tan-shinol A, tanshinol B, tanshinol C, isotanshinone IIA, tanshiquinone A, tanshiquinone B, tanshiquinone C, miltirone, danshenxinkun B, dimethyl lith-ospermate, and 3,(3,4-dihydroxyphenyl)lactamide, as shown in Figure 2 (3-7).

B. Water-Soluble Components

Since the 1970s water extract of SM has been used in clinical practice in certain parts of China. Therefore, in recent years, more studies have investigated its water-soluble components. This has led to the isolation of some polyphenolic

Dehydrotanshinone-1 Isotanshinone-1

Tanshinone-1

Dehydrotanshinone-1 Isotanshinone-1

Tanshinone-1

Tanshinone-IIA: R1=Ch3; R,=H Tanshinone-IIB: R,=CH2 OH; R2=H Hydroxytanshinone-IIA: R=CR3; R0=OH Methyl tanshinonate: R^COOCH^ R,=H

Tanshinone-IIA: R1=Ch3; R,=H Tanshinone-IIB: R,=CH2 OH; R2=H Hydroxytanshinone-IIA: R=CR3; R0=OH Methyl tanshinonate: R^COOCH^ R,=H

Neocryptotanshinone

Cryptotanshinone Isocryptotanshinone

Neocryptotanshinone

Cryptotanshinone Isocryptotanshinone

Isotanshinone-IIA

Tanshinone V

Tanshinone IV

Isotanshinone-IIA

Tanshinone V

Tanshinone IV

Methylene tanshiquinone 1,2-Dihydrotanshiquinone

Figure 2 Quinones isolated from SM.

Methylene tanshiquinone 1,2-Dihydrotanshiquinone

Figure 2 Quinones isolated from SM.

Miltirone Dehydromiltirone Ferruginol

3,(3,4-dihydroxyphenyl)lactamide

Dimethyl lithospermate

Figure 2 Continued.

3,(3,4-dihydroxyphenyl)lactamide

Dimethyl lithospermate

Figure 2 Continued.

acids from the aqueous extract of SM: salvianolic acid A, salvianolic acid B, salvianolic acid C, salvianolic acid D, salvianolic acid E, salvianolic acid F, salvianolic acid G, salvianolic acid H, salvianolic acid I, salvianolic acid J, isosalvianolic acid C, rosmarinic acid, lithospermic acid, protocatechuic aldehyde, protocatechuic acid, caffeic acid, and D( + )|3,4-dihydroxyphenol lactic acid (Danshensu, DA) (8,9).

III. BIOLOGICAL ACTIVITIES AND MECHANISMS A. Actions on Liver Diseases

1. Liver Fibrosis

Liver fibrosis is the result of disequilibrium between synthesis and degradation of extracellular matrix (ECM) components (10). Accumulation of components of the ECM is the main pathological feature of liver fibrosis. It is often associated with hepatocellular necrosis and inflammation (11) and is a consequence of severe liver damage that occurs in many patients with chronic liver diseases, such as persistent infection with hepatitis C and B viruses, as well as alcoholic liver disease and bile duct obstruction (12). Liver stellate cells are regarded as the primary target cells for inflammatory stimuli (13). It has been shown that activation of hepatic stellate cells in injured livers leads to their proliferation and transformation into myofibroblast-like cells. The transformed cells synthesize large quantities of the major components of the ECM, including collagen types I, III, and IV, fibronectin, laminin, and proteoglycans, leading to fibrosis.

Effects of the water extract of SM on liver fibrosis have been evaluated in experimental animal models, in which liver fibrosis was induced by chronic administration of carbon tetrachloride (CCl4) (14) or human serum albumin (15). Treatment with SM significantly reduced serum aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase activities as well as total cholesterol concentration in rats of pathological control groups. The liver hydroxyproline and malondialdehyde (MDA) contents in animals treated with SM were also reduced to control levels. Moreover, the morphological characteristics of fibrotic livers were improved in rats treated with SM, as evidenced by decreased periportal and bridging necrosis, intralobular degeneration, and lobular and peripheral inflammation. These findings suggest that SM had a protective effect against liver injury and fibrosis. Effects of the water extract of SM on liver fibrosis induced by bile duct ligation and scission (BDL) were also studied and similar results were found (16). In addition, SM was able to ameliorate the portal hypertensive state (including portal venous pressure, superior mesenteric artery blood flow, cardiac index, and total peripheral resistance) in BDL rats.

As has been well studied, the accumulation of collagen type I and III is a conspicuous feature of liver fibrosis (17). There are two possible pathways by which SM reduces collagen generation. First, SM was capable of directly inhibiting gene expression of procollagen type I and III (14). Second, as the regulation of procollagen I and III synthesis is mediated primarily by transforming growth factor-|31 (TGF-p1), the decrease in TGF-p1 gene expression by SM might also contribute to the reduction of collagen synthesis (14). The cytokine TGF-p1 plays a central role in liver inflammation and fibrosis (18,19). Upon liver injury, TGF-p1 is released at the site of injury (20). It induces ECM deposition by simultaneously stimulating the synthesis of new matrix components, increasing the synthesis of the enzymes that inhibit ECM degradation, and decreasing the synthesis of matrix-degradation proteases (21,22). Hence, the inhibition of gene expression ofTGF-p1 is one of the main mechanisms whereby SM exerts its antifibrotic action.

In addition to the enhanced collagen production, disruption of the normal regulation of collagenase activity may also lead to progressive liver fibrosis (23). The cytokines tissue inhibitor of metalloproteinase-1 (TIMP-1) and matrix metalloproteinase-1 (MMP-1) have been implicated in the decomposition of collagen. TIMP-1 promotes the progression of hepatic fibrosis by inhibiting the degradation of collagens (24), whereas MMP-1 belongs to a class of neutral proteases and specifically degrades the native forms of interstitial collagen type I and III (25). It was demonstrated that SM could inhibit TIMP-1 gene expression and induce MMP-1 gene expression (14). Through these effects, SM was able to promote the degradation of ECM in fibrotic rat liver, and hence prevent the deposition of type I and III collagen in the liver matrix.

Moreover, SM was reported to prevent the development of experimental liver fibrosis by inhibiting the activation and transformation of hepatic stellate cell (16,26). It was also demonstrated that salvianolic acid A, a water-soluble component of SM, significantly inhibited the proliferation and collagen production and secretion of cultured hepatic stellate cells (27). Although the mechanism of liver fibrosis is not fully understood, activated hepatic stellate cells play an important role in connective tissue synthesis and deposition during fibrogenesis. Hence, the inhibitory effects on hepatic stellate cell activation and its function of collagen synthesis are among the main mechanisms of SM action against liver fibrosis.

In addition to the antifibrotic potential, effects of SM on cell proliferation and function of cultured fibroblasts have been studied. Results from flow cytometry analysis show that SM could inhibit the proliferation of fibroblasts either by arresting cells at G0-G1 phase of the cell cycle (28) or by inducing apoptosis (29). It was also found that the production of the ECM components fibronectin, laminin, and collagen type I and III by cultured fibroblasts was significantly lower in the presence of SM (30). Furthermore, magnesium lithospermate, a component isolated from the water extract of SM, was found to posttranslationally modify enzymes proline and lysine hydroxylase in collagen biosynthesis in cultured human skin fibroblasts, thus reducing collagen secretion without affecting DNA synthesis as well as noncollagen synthesis (31).

It should be noted that oxidative stress, including reactive oxygen species (ROS) formation and lipid peroxidation (LPO), is also implicated in the pathogenesis of liver fibrosis (32,33). It has recently been reported that paracrine stimuli derived from hepatocytes undergoing oxidative stress induce hepatic stellate cell proliferation and collagen synthesis (34). Hepatic stellate cells have also been shown to be activated by free radicals generated from Fe2 + /ascorbate system (35) and by LPO product MDA (36) and 4-hydroxynonenal (37). Antioxidants, on the other hand, were observed to inhibit hepatic stellate cell activation induced by type I collagen (35). SM was shown to inhibit CCl4-induced LPO in rat liver (38). In addition, it was observed that SM showed a scavenging effect on oxygen free radicals including superoxide anion and hydroxyl radical (39,40). It also increases the activity of glutathione peroxidase (GSH-Px) (41), an important enzyme in the antioxidant defense system in the liver. Based on the above evidence, it is possible that SM may exert its suppressive effects on liver fibrosis, at least in part, through its antioxidant activity.

2. Acute Liver Injury

The water extract of SM and its component lithospermate B were found to have a potent hepatoprotective activity on acute liver injuries induced by CCl4 or d-galactosamine/lipopolysaccharide (D-GaIN/LPS) (42,43). Serum LPO, AST, ALT, and lactate dehydrogenase levels were significantly lower in SM-treated group as compared to those of the pathological control group. In addition, SM could improve histological changes of liver tissue, such as alleviate necrosis and steatosis of the liver, enhance hepatocyte regeneration, improve microcirculation, eliminate stasis of blood, and enhance albumin synthesis.

The protective effect of SM on acute liver injury is mainly due to its antioxidant activity. Free radical generation and LPO are common pathways in most of the experimental liver injuries and clinical liver diseases (44,45), especially liver injury caused by CCl4, which is based on LPO of unsaturated fatty acids in cell membrane and intracellular organelle membrane. D-GaIN/ LPS, on the other hand, is known to immunologically induce liver injury and does not involve direct oxidative tissue degradation. It is rather dependent on the release of potent mediators, such as tumor necrosis factor-a and superoxide radical from activated macrophage (43). Phenolic compounds isolated from SM could inhibit LPO of rat liver microsomes and plasma membrane induced by iron/cysteine and vitamin C/NADPH, and prevent bleb of the surface of rat hepatocytes induced by iron/cysteine (8). In addition, lithospermate B was found to have a better effect on ferrous/ cysteine- and vitamin C/NADPH-induced LPO in liver mitochondria than vitamin E (46). Meanwhile, SM could enhance the enzyme activity of GSH-Px in cultured human fetal liver cells, which plays an important role in eliminating hydrogen peroxide (41). Moreover, it was observed that SM was effective in inhibiting the association of peroxidation products with DNA in liver cells and hence attenuating the decrease of cell viability (47).

3. Other Liver Diseases

In addition to experimental studies, some preliminary clinical trials have been carried out to evaluate the effect of SM in treating common liver diseases, such as chronic hepatitis (48) and portal vein hypertension (49). Although results generally support the effectiveness of SM in these cases, the mechanisms involved in its actions are far from clear.

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