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Insulin-sensitizing activities of tanshinones, diterpene compounds of the root of Salvia miltiorrhiza Bunge.

Abstract

In this study, the effects of the extract and four tanshinone compounds from the dried root of Salvia miltiorrhiza Bunge (Labiatae) on the tyrosine phosphorylation of the insulin receptor (IR) [beta]-subunit and the downstream signaling were examined in Chinese-hamster ovary cells expressing human insulin receptors (CHO/IR cells) as well as in 3T3-L1 adipocytes. In addition the translocation of the glucose transporter 4 was investigated in 3T3-L1 adipocytes. Total extract of Danshen (l-10 [micro]g/ml) and the four tanshinones (10 [micro]M) did not show any activity, but the total extract and the tanshinone I, IIA and 15, 16-dihydrotanshinone I except cryptotanshinone enhanced the activity of insulin (1 nM) on the tyrosine phosphorylation of the IR as well as the activation of the downstream kinases Akt, ERK1/2, and GSK.3[beta]. In the adipocytes the same IR-downstream signaling and the translocation of glucose transporter 4 were demonstrated by the three tanshinones in the presence of insulin. These insulin-sensitizing activities of tanshinones may be useful for developing a new class of specific IR activators as anti-diabetic agents.

[C]2008 Elsevier GmbH. All rights reserved.

Keywords: Tanshinones; Salvia miltiorrhiza; Insulin receptor tyrosine phosphorylation; Insulin signal transduction; Glucose transporter; 3T3-L1-adipocytes

Introduction

Danshen, the dried root of Salvia miltiorrhiza Bunge (Lamiaceae) is a commonly used traditional Chinese medicine for promoting blood circulation. It has been used for the treatment of cardiovascular diseases (CVD) such as coronary heart disease, hyperlipidemic, and cerebral vascular disease (Zhou et al., 2005). Various pharmacological studies in vitro and in vivo have concentrated on Danshen components such as hydrophilic phenolic compounds, danshensu, salvianolic acid B, and lipophilic diterpene compounds, tanshinones. These studies suggested that Danshen could improve microcirculations, dilate the coronary arteries, increase blood flow, and prevent myocardial ischemia (Wang et al. 2007). However, their clinical relevance needs to be established further.

Further the mode of action of Danshen needs to be established. We hypothesized that its common use in CVD may be related to the modulation of risk factors of CVD. Elevated blood glucose and/or blood pressure as well as dyslipidemia promote the process of atherosclerosis and are independent risk factors for CVD. We investigated whether Danshen has the potential to influence blood glucose levels through insulin receptor (IR) activators with insulin-mimetic and/or insulin-sensitizing activity by analyzing the effects of Danshen on IR signaling.

The IR is a tetrameric protein consisting of two identical extracellular [alpha]ts and two identical transmembrane [beta]its that have intracellular tyrosine kinase activity (Goldfine 1987; Moller and Flier 1991). Binding of insulin to the [alpha]-subunits of the IR leads to a conformational change and stimulation of the receptor kinase activity via auto-phosphorylation of tyrosine residues in the [beta]-subunits (Goldfine 1987; Kahn 1994). This triggers two major kinase-signaling cascades: the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways (Hajduch et al. 1998; Shepherd et al. 1998). Activation of PI3K, one of the earliest steps in the insulin-signaling pathway, relays the signal to several kinases including the serine/ threonine kinase, Akt and glycogen synthase kinase (GSK) 3[beta] and plays a major role in many insulin-regulated translocation of glucose transporter 4 (GLUT4) followed by glucose uptake (Cong et al. 1997; Wang et al. 1999; Bryant et al. 2002).

In type 2 diabetes, the decreased ability of insulin to stimulate translocation of intracellular vesicles that store GLUT4 to the plasma membrane and the reduced glucose uptake into muscle or adipose tissues in response to insulin, results in a condition called insulin resistance (Kahn 1994). Although the molecular basis of type 2 diabetes is poorly understood, it is well established that insulin signaling, including activation of IR tyrosine kinase activity, is impaired in most type 2 diabetics (Thies et al. 1990; Goldfine 1999). Recently, small non-peptide molecules known as IR activators have been developed that restore IR auto-phosphorylation in insulin-resistant cells (Zhang et al. 1999; Manchem et al. 2001; Ding et al. 2002; Pender et al. 2002; Jung et al. 2007). Such pharmacological agents that enhance IR [beta]-subunit tyrosine kinase activity could be useful for treating type 2 diabetes (Zhang and Moller 2000; Salituro et al. 2001).

Our search for IR activators from medicinal herbs has identified that diterpenoid components of medicinal plants greatly stimulate the effect of insulin on IR signaling (Jung et al., unpublished data). In the present study, we employed CHO/IR cells (Chinese-hamster ovary cells expressing modest amounts of human IR) (Frattali et al. 1991), as well as 3T3-L1 primary adipocytes, to evaluate whether tanshinone compounds work as IR activators with insulin-mimetic and/or insulin-sensitizing activity. Among various diterpenoid tanshinones that possess a variety of pharamacological activities such as antibacterial, antioxidant, anti-inflammatory, and antineoplastic (Wang et al. 2007), we selected tanshinone I (T-I), tanshinone IIA (T-IIA), 15, 16-dihydrotanshinone I (DHT-I), and cryptotanshinone (CT). These four tanshinones are the major constituents of the plant, and the biological studies have mainly focused on these relatively abundant tanshinones: activities as coronary artery dilators and protective effects against myocardial ischemia are known (Yagi et al. 1994; Wang et al. 2007).

Materials and methods

Antibodies (Abs) and reagents

Dulbecco's modified Eagle's medium (DMEM), [alpha]-minimal Eagle's medium ([alpha]MEM)+, fetal bovine serum (FBS), bovine calf serum, L-glutamine, penicillin, and streptomycin were purchased from Gibco BRL (Grand Island, NY, USA). Trypsin-EDTA, insulin, dexamethasone, 3-isobutyl-l-methylxanthine, and -o phenylenediamine dihydrochloride were obtained from Sigma Chemical Co. (St. Louis, MO, USA). Blotting antibodies (Abs) against the IR [beta] chain (IR[beta], C-19), GLUT4 (H-61), and extracellular signal-regulated kinase (ERK) were from Santa Cruz Biotechnology Inc. (Santa Cruz, CA, USA). Abs against phospho-Akt (pAkt, Ser 473), phospho-GSK3[beta] (pGSK3[beta], Ser 9), and phospho-ERKl/2 (pERK, Thr202/Tyr204) were from Cell Signaling Technology Inc. (Beverly, MA, USA). Blotting Ab against phosphotyrosine (pTyr, clone 4G10) and biotin-conjugated Ab 4G10 were from Upstate Biotechnology Inc. (Lake Placid, NY, USA). Monoclonal anti-human IR [beta]-subunit Ab for coating, and streptavidin conjugated to horseradish peroxidase (HRP), were obtained from Biosource International (Camarillo, CA, USA). HRP-conjugated second Abs, affinity purified mouse anti-rabbit IgG and rabbit anti-mouse IgG were purchased from Bio-Rad Laboratories (Hercules, CA, USA), and the enhanced chemilumine-sence (ECL) kit was from Amersham Biosciences Ltd. (Piscataway, NJ, USA).

Plant compounds

The dried roots of Salvia miltiorrhiza Bunge (Lamiaceae) were purchased from the Sung-Lim Company, Korea and authenticated by Professor J.H. Lee (College of Pharmacy, Kyung Hee University, Seoul, Korea). The dried roots (17.45 kg) were percolated with 70% ethanol (EtOH) three times and the EtOH extract concentrated in vacuo (2.4 kg) was suspended in [H.sub.2]O, partitioned successively with hexane, [CH.sub.2][C1.sub.2], EtOAc, and butanol (BuOH). A portion of the hexane and [CH.sub.2][C1.sub.2] fractions (76.7 g) were chromatographed on a silica gel column (hexane-[CH.sub.2][Cl.sub.2], 80:20-40:60) to yield eleven subfractions (HC1-HC11). Tanshinone IIA (T-IIA) and tanshinone I (T-I) were purified by a recrystallization step with MeOH from subtractions HC4 and HC6, respectively. Further chromatography of the subfractions, HC8-HC10 (2.0 g) on a silica gel column (hexane-[CH.sub.2][Cl.sub.2], 40:60-60:40) yielded six fractions (HC8.1 -HC8.6). Cryptotanshinone (CT) and 15, 16-dihydrotanshinone I (DHT-I) were isolated by a recrystallization step with MeOH from HC8.3 and HC8.6, respectively. The structures of T-IIA, T-I, CT, and DHT-1 (Fig. 1) were verified by comparing NMR data with those reported in the literature (Ryu et al. 1997) and their chemical purities were 96.1%, 97.4%, 96.1%, and 97.0%, respectively (data not shown). The compounds were dissolved in dimethylsulfoxide (DMSO) and diluted with cell culture medium (final DMSO concentration [less than or equal to]0.01% (v/v)).

[FIGURE 1 OMITTED]

Cell culture

3T3-L1 adipocytes (American Type Culture Collection, Manassas, VA, USA) were grown and differentiated as described previously (Jung et al. 2007). Briefly, 3T3-L1 pre-adipocytes were grown to confluence and induced to differentiate into adipocytes in a medium supplemented with 0.25 [micro]M dexamethasone, 0.5 mM 3-isobutyl-l-methylxanthine, and 100 nM insulin. The adipocytes were transferred to the same medium containing insulin (l0[micro]g/ml) for 4 days; thereafter they were grown in a fresh medium without insulin with fresh medium added every 4 days. The cells were normally used 12 days post-differentiation, since the full adipocyte phenotype appears 5-8 days after transfer to differentiation medium. CHO/IR cells (Frattali et al. 1991) were kindly provided by Dr. Jeffery Pessin (University of Iowa, Iowa City, IA, USA). At 90% confluence the cells were trypsinized and transferred to a new dish for the next passage.

Enzyme-linked immunosorbent assay (ELISA) for whole-cell IR auto-phosphorylation

The ELISA for tyrosine phosphorylation of the IR [beta]-subunit was performed as described previously (Jung et al. 2007). Briefly, equal amounts of cell lysate (40 [micro]g of protein) were applied to 96-well immulon-1 flat-bottomed plates coated with monoclonal anti-human IR[beta] Ab in carbonate-bicarbonate buffer (15 mM [Na.sub.2][CO.sub.3], 35 mM [NaHCO.sub.3]; pH 9.6) at 4[degrees]C overnight. IR[beta] was allowed to bind overnight at 4[degrees]C. Next, the plates were washed with phosphate-buffered saline (PBS) containing 0.05% Tween 20 (T-PBS), and biotin-conjugated anti-pTyr Ab was added to the wells for 1 h at room temperature. The wells were again washed and streptavidin-HRP was added. Following the addition of the peroxidase substrate, [alpha]-phenylenediamine dihydrochloride, tyrosine phosphorylation was quantified by measuring absorbance at 490 nm with a microplate reader (Molecular Devices, Spectra MAX 190).

Subcellular fractionation

After washing in ice-cold PBS, 3T3-L1 adipocytes were incubated in 300 [micro].1 of ice-cold hypotonic buffer SI (10 mM HEPES/KOH, pH 7.4, 38 mM NaCl, with a panel of protease and phosphatase inhibitors) and subjected to four freeze-thaw cycles. The resulting suspension was centrifuged at 800g for 10 min to remove nuclei and intact cells, and the supernatant was centrifuged at 100,000g for 1 h at 4[degrees]C in a TLA 120.2 rotor (Beckman Coulter, Inc.). The supernatant (S100) was collected, and the membrane pellet (M) was resuspended in 50 [micro]l of 6 M urea before adding SDS sample buffer.

Western blotting

Total cell lysates were prepared in 1% Triton-X 100 lysis buffer that contained inhibitors for proteases and phosphatases, as described previously (Jung et al. 2007). For Western blot analysis, the same amount of protein of each sample was loaded on the gel: total cell lysates (20 [micro]g) and membrane (M) fraction (30 [micro]g) were subjected to SDS/8% PAGE. The proteins were transferred to nitrocellulose filters and incubated with Ab against pTyr (1:10,000), phosphorylated proteins (Akt, GSK3[beta] or ERK; 1:1000), and GLUT4 (1:1000). Anti-IR[beta] (1:1000) and anti-ERK2 (1:1000) polyclonal Abs were used to assess total protein levels. After incubation with HRP-conjugated secondary Ab, signals were detected with an ECL kit.

Other methods

Protein concentrations were determined with the Bradford reagent (Bio-Rad laboratories). The effects of samples in combination with insulin were examined by one-way analysis of variance. Post hoc analysis was by paired t tests when a significant interaction was obtained. Analysis of variance was performed using the Prism program (Graphpad Software Inc., San Diego, CA). Values of p<0.05 were considered significant.

Results

The effects of insulin on IR [beta]-subunit auto-phosphorylation were measured by a specific ELISA (Fig. 2). Insulin at 5 nM had an approximately three-fold greater effect than at 1 nM. The effects of Danshen extracts (70% EtOH) on IR auto-phosphorylation in CHO/IR cells were also measured. As shown in Fig. 2, the extracts had no effect on IR auto-phosphorylation at concentrations up to 10[micro]g/ml in the absence of insulin, while the significant IR-sensitizing effect of the extracts at low-dose (1 nM) insulin started at 1 [micro]g/ml (p< 0.001) and greatly increased at 10[micro]g/ml (p<0.001).

[FIGURE 2 OMITTED]

We investigated further the effects of four diterpene tanshinones (T-IIA, T-I, CT, and DHT-I) on IR auto-phosphorylation in CHO/IR cells (Fig. 3A). The IR-sensitizing effects of these tanthinones were observed at concentrations of 2-20 [micro]M; at 10[micro]M we detected consistent effects of all four tanshinones on IR auto-phosphorylation (data not shown). None of these tanshinone compounds, at concentrations of 10[micro]M, induced phosphorylation on the IR [beta]-subunit (Fig. 3A). On the other hand, three tanshinones (T-IIA, T-I, and DHT-I), but not CT tended to enhance low-dose (1 nM) insulin-mediated tyrosine phosphorylation of the IR [beta] subunit. The effects of all three tanshinones on insulin-mediated IR activation were significant (p< 0.001) as shown in Fig. 3A. The effects of tanshinones on IR [beta] subunit auto-phosphorylation were also determined by blotting cell lysates with anti-pY Ab (Fig. 3B). Tyrosine phosphorylation of the IR [beta]-subunit took place in response to insulin in a dose-dependent manner. As also shown in Fig. 3B, three tanshinone compounds (T-IIA, T-I, and DHT-I), at concentrations of 10 [micro]M, induced phosphorylation on the IR [beta]-subunit at low dose (1 nM) insulin, while these compounds had no effect on IR auto-phosphorylation in the absence of insulin.

[FIGURE 3 OMITTED]

We next investigated whether activation of IR by tanshinone compounds results in increased phosphorylation of a number of other proteins that are involved in IR signal transduction, namely ERK, Akt, and GSK3[beta]. CHO/IR cells were treated with each tanshinone compound in the absence or presence of low dose (1 nM) insulin, and lysates were Western blotted with phosphoprotein-specific Abs. As shown in Fig. 4, phosphorylation of these proteins was higher in cells incubated with T-IIA, T-I, or DHT-I plus insulin than in cells incubated with CT plus insulin. Phosphorylation of Akt, which are activated by PI3K, was higher in cells incubated with T-I or DHT-I plus insulin than in cells incubated with T-IIA plus insulin (Fig. 4). ERK phosphorylation was induced in cells incubated with T-IIA or T-I plus insulin, but not in cells incubated with either compound alone. Phosphorylation of ERK in cells incubated with DHT-I plus insulin was greater than in cells incubated with DHT-I alone (Fig. 4).

[FIGURE 4 OMITTED]

We next examined the effects of tanshinone compounds on the insulin signaling in 3T3-L1 adipocytes formed from pre-adipocytes. As shown in Fig. 5A, three tanshinone compounds (T-IIA, T-I, and DHT-I) stimulated tyrosine phosphorylation of the IR [beta]-subunit as well as phosphorylation of Akt, GSK-3[beta] and ERK. Phosphorylation of these proteins was higher in cells

[FIGURE 5 OMITTED]

incubated with T-I or DHT-I plus insulin than in cells incubated with T-IIA plus insulin. Phosphorylation of ERK was also induced in cells incubated with DHT-I alone similarly as shown in CHO/IR cells.

We further enquired whether the action of tanshinone compounds on the IR affected the classical insulin effect on glucose transport. Because CHO/IR cells do not have an insulin-sensitive glucose transport system, we used 3T3-L1 adipocytes that do have one. To examine insulin-stimulated translocation of GLUT4 to the plasma membrane, the membrane pellet (M) was separated from the supernatant (S100). Insulin stimulation of 3T3-L1 adipocytes caused translocation of GLUT4 to the membrane fraction (Fig. 5B). Incubation with 1 nM insulin plus DHT-I led to a similar extent of GLUT4 translocation to the plasma membrane as achieved with 100nM insulin on its own. In contrast, incubation with 1 nM insulin plus CT failed to induce translocation of GLUT4 to the membrane (Fig. 5B).

Discussion

With respect to the prevention of the risk factors associated with CVD, we have investigated whether Danshen that has been used for the treatment of CVD contains IR activators by analyzing its effects on IR signaling, and have identified several components of Danshen that greatly stimulate the effect of insulin on IR signaling.

Danshen extracts did not act as an insulin-mimetic agent at levels tested up to l0[micro]g/ml, but showed effective insulin-sensitizing effects at doses above 1 [micro]g/ ml. We found significant enhancement effects of the insulin-stimulated auto-phosphorylation of IR [beta]-sub-unit with a combination of Danshen EtOH extracts and a relatively low dose of insulin (1 nM). We further compared the effects of four tanshinones (T-IIA, T-I, DHT-I, and CT), diterpene compounds isolated from the lipophilic fractions, which constituted approximately 3% of the EtOH extracts, as agreed to a recent report determining the major lipophilic diterpene compounds in Danshen (Zheng et al. 2008). Similarly, these tanthinone compounds showed insulin-sensitizing effects, but not insulin-mimetic effects. These results suggest that tanthinones do not act on the IR-binding site, but rather on the IR [beta] and that they specifically enhance IR [beta] auto-phosphorylation and subsequent downstream signaling. We also showed that the extent of stimulation of insulin-mediated tyrosine phosphorylation of the IR depended on details of their structures. T-I (tanshinone I) and DHT-I (15, 16-dihydrotanshi-none I), at 10 [micro]M gave the greatest enhancement and CT (cryptotanshinone) the least. Our findings show that stimulation of the effect of insulin on receptor-mediated signal transduction depends on specific structural features of these compounds.

Additional experiments showed that the effects of tanshinone compounds as insulin sensitizers on the insulin-mediated tyrosine phosphorylation of the IR also correlated with the stimulation of downstream IR signaling events by these compounds. T-I and DHT-I at the dose of 10 [micro]M, but not CT, with a combination of a relatively low dose of insulin (1 nM) increased two major kinase-signaling cascades, MAPK and PI3K pathways (Hajduch et al. 1998; Shepherd et al. 1998). These enhancement signals eventually resulted in the insulin-regulated glucose uptake by the translocation of GLUT4 (Cong et al. 1997; Wang et al. 1999; Bryant et al. 2002). Our findings show that the extent of stimulation of insulin action may depend on the saturation degree of the rings in these compounds: unsaturated ring A in T-IIA reduce the effect on insulin stimulation and unsaturated rings, A and D in CT further reduce the effect as an insulin sensitizer (Fig. 1). Insulin-dependent activation of the IR and stimulation of downstream signaling events by tanthinones in our study may also minimize unwanted side effects, such as induction of cytotoxicity and apoptosis by T-IIA shown in other cell systems (Yang et al. 2005; Kuo et al. 2006).

Impaired insulin signaling, including decreased IR phosphorylation and decreased PI3K activity leads to hyperglycemia (Taylor 1999). Such defects in the IR and its signal transduction pathway have been found in insulin-resistant patients (Dozio et al. 1992; Goodyear et al. 1995). Therefore pharmacological agents that enhance IR [beta]-subunit tyrosine kinase activity could also be useful in the treatment of insulin resistance in target tissues (Pessin and Saltiel 2000). Recent efforts discovered small non-peptide molecules that enhance insulin action in cultured cells and mice, acting as direct IR agonists (Zhang et al. 1999; Ding et al. 2002; Pender et al. 2002) or as IR sensitizers (Manchem et al. 2001). Previously, we also reported a specific pentacyclic triterpenoid isolated from Campsis grandiflora as an IR activator (Jung et al. 2007). The results of the present study demonstrate that specific diterpene tanshinone compounds also exert insulin-sensitizing effects as IR activators in CHO/IR cells and adipocytes.

Although the detailed mechanisms of action need to be investigated further, our results suggest a new class of compounds as possible IR activators for the treatment of diabetes. Compared to the compounds reported previously as IR activators, T-I and DHT-I, among four tanshinone compounds tested, at 10[micro]M had greater sensitizing effects on the activity of insulin at concentrations as low as 1 nM. In addition, tanshinones are derived from medicinal plants, which are often used as traditional remedies for the treatment of CVD. The identification of a significant IR activator in these medicinal plants may provide the opportunity to develop a novel class of anti-diabetic agents, which also provide possible treatments of several cardiovascular risk factors. The enhancement of insulin activity by tanshinones may be useful for developing specific IR activators in the treatment of high blood sugar levels in type 2 diabetes or CVD.

Acknowledgements

This study was supported by a grant from the KFDA through the NCSHM, a Grant (R04-2004-000-10077-0) from the Korea Research Foundation, and the NCRC Program (R15-2006-020) of the MEST and the KOSEF through the Center for Cell Signaling & Drug Discovery Research at Ewha Womans University. This study was also supported in part by research funding to J.R.L. from the Yangyoung Foundation. S.H.J, and H.J.S. were supported in part by the BK 21 Program of the Korea Ministry of Education.

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Seung Hee Jung (a), Hee Jung Seol (a), Su Jin Jeon (b), Kun Ho Son (b), Jong Ran Lee (a), (c), *

(a) Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea

(b) Food Science and Nutrition, Andong National University. Andong 760-749, Republic of Korea

(c) Department of Life Science, College of Natural Sciences and Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, Seoul 120-750, Republic of Korea

* Corresponding author at: Department of Life Science, College of Natural Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea. Tel.: +82232773762; fax: +82232773760.

E-mail address: jrlee@ewha.ac.kr (J.R. Lee).

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doi:10.1016/j.phymed.2008.12.017
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Author:Jung, Seung Hee; Seol, Hee Jung; Jeon, Su Jin; Son, Kun Ho; Lee, Jong Ran
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9SOUT
Date:Apr 1, 2009
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