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Abstract

Ten active principles (compounds 1-10) have been isolated following protein tyrosine phosphatase 1B (PTP1B) assay-guided fractionation of the methanol extract of the root of Polygonum cuspidatum. The chemical structures of the compounds were characterized mainly by nuclear magnetic resonance (NMR) spectroscopic and physicochemical data. This is the first time that 9,10-anthraquinones (compounds 5-6) have been isolated from P. cuspidatum, and this is the first record of compound 9 from the genus Polygonum. Except for compound 4, all the isolates showed potential inhibitory activity against PTP1B with half-maximal inhibitory concentration IC₅₀ values ranging from 6.3 to 28.9 µM. Furthermore, a kinetic study indicated mixed-competitive inhibition with PTP1B for compounds 2 and 9 and noncompetitive inhibition for compounds 3 and 6. In addition, compounds 2, 3, 6, and 9 also induced the 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]-d-glucose uptake stimulation in 3T3-L1 adipocytes at concentrations of 10 and 5 µM. Taken together, the results reveal that P. cuspidatum could be a new source of natural compounds for further research and development of antidiabetic agents.

Keywords

Polygonaceae anthraquinone PTP1B glucose-uptake 2-NBDG stilbene

Diabetes is a major disease of the modern world; about 90% of people suffering from this have type 2 diabetes. According to the International Diabetes Federation, an estimated 463 million adults aged 20-79 years worldwide have diabetes, and this number is expected to rise to 574 million by 2030 and 700 million by 2045.¹ Glucose-transporter proteins, especially GLUT4, play an important role in glucose uptake into cells. This transport is biologically affected by the PTP1B enzyme, a member of the protein tyrosine phosphatases (PTPs) family. The PTP1B pathway plays a central role as a negative regulator in the insulin signaling pathway implicated in metabolic diseases such as obesity and type 2 diabetes. In insulin signaling, PTP1B dephosphorylates the insulin receptor (IR) and insulin receptor substrate (IRS), whereas, in the leptin pathway, it dephosphorylates the tyrosine kinase Janus kinase 2 (JAK2).² In the insulin signaling pathway, the recruitment and phosphorylation of the IRS are triggered as a result of the binding of insulin to the IR, which forms a docking site for phosphoinositide 3-kinase (PI3K) at the membrane. Docked PI3K then induces the phosphorylation of both Akt at Thr³⁰⁸ and the 70 kDa ribosomal protein S6 kinase 1 (p70^s6k) by activation of phosphoinositide-dependent protein kinase 1 (PDK1).^3
-5 This facilitates glucose uptake in cells by allowing the translocation of GLUT4 from intracellular storage vesicles to the plasma membrane. In addition, a wealth of evidence from clinical and basic research indicates that the high expression of PTP1B can induce insulin resistance. Therefore, PTP1B is an effective target for the treatment of type 2 diabetes and possibly obesity.^6,7

In Vietnam, the traditional remedies for diabetes often involve the integrated effects of different medicinal plants—some as main ingredients and some as a supplemental factor. Polygonum cuspidatum Sieb. et Zucc., family Polygonaceae (known as knotweed in Japan and Huzhang in China), is a small perennial, straight-growing plant that usually grows to between 60 cm and 1 m high (though in some places, it can grow as high as 2.2 m).⁸ Polygonum cuspidatum grows natively in many regions across China and Southeast Asia. It can be harvested year-round, but the best time is in the monsoon season when harvesting occurs continuously for 2-3 months. In Vietnam, P. cuspidatum has been used since ancient times for the treatment of liver diseases, rheumatism, arthritis, stomachache, and leg pain, and is used especially for the treatment of hepatitis.⁸ Chemically, P. cuspidatum is a rich source of several bioactive secondary metabolites with pharmacological effects, including stilbenes, quinones, phenylpropanoid esters of sucrose, anthraquinones, and anthraquinone glucopyranosides.^9

-12 In traditional Chinese medicine (TCM), this plant is used for the treatment of cancer, angiogenesis, human immunodeficiency virus (HIV), hepatitis B, obesity, and oral cancer and is known for its antimicrobial, anti-inflammatory, and neuroprotective qualities.^13,14 Choi et al reported that P. cuspidatum extract showed free radical scavenging activity and prevented obesity-associated disorders in a diabetic rat model in vivo.¹⁵ In addition, the effects of P. cuspidatum extract on advanced glycation end products (AGEs), Nε-(carboxymethyl)-l-lysine formation, protein glycation, and diabetes have been investigated. In a diabetic rat model, the levels of blood glucose, serum malondialdehyde, cholesterol, triglycerides, and low-density lipoproteins were reduced after treatment with P. cuspidatum extract.¹⁶ However, the bioactive components of Vietnamese P. cuspidatum have not yet been identified. Here we describe the purification of active compounds from P. cuspidatum and report on their stimulatory effects for glucose uptake and the enzyme inhibitory activities on both PTP1B and α-glucosidase.

Results and Discussion

The methanol extract of the root of P. cuspidatum was partitioned into n-hexane, ethyl acetate (EtOAc), and water-soluble fractions. The EtOAc fraction had the greatest inhibitory activity on PTP1B (Supplemental Material). Chromatographic purification of this fraction led to the isolation of 10 compounds (compounds 1-10) (Figure 1).

Figure 1

Chemical structure of compounds 1-10 isolated from Polygonum cuspidatum.

Comparison of the ¹H-nuclear magnetic resonance (NMR) and ¹³C-NMR data of the isolated compounds with those published in the literature led to their identification as physcion (1), aloe-emodin (2), emodin (3), 1-hydroxy-2-methyl-6-methoxyanthraquinone (5), soranjidiol (6),^17
-19 2-methoxystypandrone (4),^20,21 trans-resveratrol (7),²² trans-piceid (10),²³ which is a derivative compound of 7, dihydroresveratrol (8),^24,25 and tricuspidatin B (9)²⁶ (Figure 1 and Supplemental Material).

Isolates 1-10 were evaluated for their inhibitory activity against the PTP1B enzyme using an in vitro assay.²⁷ The results are presented in Table 1 as half-maximal inhibitory concentration (IC₅₀) values. Of these isolates, compounds 3 and 9 appeared to be the most potent inhibitors of PTP1B with IC₅₀ values of 7.6 ± 0.1 and 6.3 ± 0.2 µM, respectively. The next most potent inhibitors were compounds 2, 6, and 7 with IC₅₀ values of 13.3 ± 0.4, 12.4 ± 0.9, and 16.1 ± 1.1 µM, respectively. The other compounds showed moderate inhibitory activity with IC₅₀ values ranging from 26.1 to 28.9 µM (Table 1). Compound 4, the only stypandrone-type compound, was not active (IC₅₀ >30 µM). Among the 9,10-anthraquinone compounds, physcion (compound 1) and emodin (compound 2) were similar in structure; however, compound 2, with a hydroxyl group attached at C-6, possessed stronger activity against PTP1B (IC₅₀ 13.3 ± 0.4 µM) than compound 1 (IC₅₀ 26.1 ± 0.7 µM), with a 6-methoxy substitution. Similarly, compound 6 (1-hydroxy-2-methyl-6-hydroxyanthraquinone) also showed stronger activity (IC₅₀ 16.1 ± 1.1 µM) than 1-hydroxy-2-methyl-6-methoxyanthraquinone (compound 5: IC₅₀ 28.9 ± 1.7 µM). This observation suggests that the substitution of a methoxy moiety at the C-6 position in 9,10-anthraquinones could be responsible for a decrease in the PTP1B inhibitory action of these compounds. In stilbene type compounds (compounds 7-10), the 7α-8β configuration and the hydroxylation at these positions may play an important role in the activity against PTP1B. Thus, tricuspidatin B (compound 9), with 7,8-dihydroxylation, showed potent inhibitory activity (IC₅₀ 6.3 ± 0.2 µM), while compound 8 (dihydro-R-resveratrol), a bis-deshydroxy analog of compound 9, showed moderate inhibitory activity (IC₅₀ 28.4 ± 1.5 µM). In this assay, ursolic acid, used as a positive control, displayed an IC₅₀ value of 3.5 ± 0.2 µM. Zhao et al described the antidiabetic activity of P. cuspidatum root by investigating the PTP1B inhibitory effects of individual constituents using PTP1B profiling combined with high-performance liquid chromatography-high resolution mass spectrometry and NMR techniques.²⁸ In our assay, stypandrone (compound 4) showed weak activity with an IC₅₀ value >30 µM. This is in accordance with the value published by Zhao et al (IC₅₀ value 83.9 ± 7.45 µM). However, there were meaningful differences in the PTP1B activity for emodin (2) between our study (13.3 ± 0.4 µM) and Zhao’s (171.9 ± 35.9 µM). This discrepancy may be the result of different experimental conditions.

Table 1

PTP1B Inhibitory Activity of Compounds 1-10.

Compounds	IC₅₀ (µM)^a	K _i values (µM)	Inhibition type
1	26.1 ± 0.7	-^b	-
2	13.3 ± 0.4	27.6 ± 0.9	Mixed-competitive
3	7.6 ± 0.1	15.1 ± 0.5	Noncompetitive
4	>30	-	-
5	28.9 ± 1.7	-	-
6	12.4 ± 0.9	29.6 ± 0.7	Noncompetitive
7	16.1 ± 1.1	-	-
8	28.4 ± 1.5	-	-
9	6.3 ± 0.2	51.4 ± 1.2	Mixed-competitive
10	27.7 ± 1.4	-	-
Ursolic acid	3.5 ± 0.2	-^b	-

Abbreviation: Abbreviation: IC₅₀, half-maximal inhibitory concentration.

^aResults are expressed as IC₅₀ values (µM), determined by regression analysis and expressed as the means ± SD of 3 replicates.

^bData not determined.

^cPositive control.

In our kinetic study, ursolic acid was previously determined as a mixed-competitive inhibitor.²⁹ Compounds with PTP1B inhibitory potency (compounds 2, 3, 6, and 9) were further examined to determine their inhibition type. We produced Lineweaver-Burk and Dixon plot experiments with various concentrations of para-nitrophenylphosphate (p-NPP) substrate in the presence and absence of the inhibitors (Figures 2 and 3); data were analyzed using the Sigma plot program (SPCC Inc., Chicago, IL) and are presented in Table 1. The Lineweaver-Burk plot experiment indicated the inhibition type of active compounds (2, 3, 6, and 9). Of these, compounds 2 and 9, as well as the positive control (ursolic acid), exhibited mixed-competitive inhibition, as evidenced by the fact that the lines intersected at a position in the aerial of the left y-axis and the upper x-axis. Compounds 3 and 6 exhibited noncompetitive inhibition because the lines intersected at a negative value (1/[S]) on the x-axis (1/(intensity/min) = 0). Dixon plot experiments were used to determine the K _i values of compounds 2, 3, 6, and 9 as 27.6 ± 0.9, 15.1 ± 0.5, 29.6 ± 0.7, and 51.4 ± 1.2, respectively (Table 1 and Figure 3).

Figure 2

Lineweaver-Burk plots for the inhibition of compounds (2, 3, 6, and 9) on the protein tyrosine phosphatase 1B-catalyzed hydrolysis of para-nitrophenylphosphate (p-NPP). Data are expressed as the mean reciprocal of initial velocity for n = 3 replicates at each substrate concentration.

Figure 3

Dixon plots for active compounds (2, 3, 6, and 9) used for determining the inhibition constant Ki. Ki values were determined from the negative x-axis value at the point of the intersection of 3 lines. Data are expressed as the mean reciprocal of initial velocity for n = 3 replicates at each substrate concentration.

Glucose transporters are a large group of membrane proteins that facilitate the transport of glucose across the plasma membrane. Among the 14 glucose transporters, GLUT4 is a well-characterized insulin-regulated glucose transporter expressed mainly in adipose tissues and striated muscle (ie, skeletal and cardiac muscle). The translocation of GLUT4 to the plasma membrane in muscle and adipocytes directly facilitates glucose uptake into the cells. This action is dependent mainly on the regulation of 2 physiological pathways: the AMP-activated protein kinase (AMPK) and the insulin signaling pathway.³ PTP1B negatively regulates the insulin signaling pathway by dephosphorylating the insulin receptor (IR) and insulin receptor substrate (IRS), leading to the inactivation of PDK1 and Akt, the proteins that directly allow the translocation of GLUT4.^2,30 Therefore, the facilitation of the insulin signaling pathway by inhibition of PTP1B activity and/or reduction of its expression level can stimulate glucose uptake in adipocytes. To investigate this possibility, the stimulatory effects of compounds 2, 3, 6, and 9 on glucose uptake were further investigated in 3T3-L1 adipocyte cells using 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]-d-glucose (2-NBDG) as a substrate. Figure 4 illustrates the compounds’ stimulation of 2-NBDG uptake at both 10 and 5 µM concentrations. In comparison with the control (dimethylsulfoxide [DMSO]), compound 9—the most potent inhibitor of PTP1B in this study—stimulated 2-NBDG more strongly than insulin (the positive control) with inductions of 1.67 (±0.05)-fold and 1.75 (±0.08)-fold at 5 and 10 µM, respectively. Insulin showed an induction of 1.56-fold at a concentration of 100 nM. Similar to the positive control, aloe-emodin (compound 3) showed an induction of 1.63 (±0.05)-fold at a concentration of 10 µM. Emodin (compound 2) and sojanjidiol (compound 6), which had similar PTP1B inhibitory activities, also showed similar stimulatory effects on 2-NBDG uptake with 1.24 (±0.06), 1.31 (±0.08), 1.21 (±0.07), and 1.38 (±0.06)-fold at concentrations of 5 and 10 µM, respectively. To avoid any cytotoxicity of the tested compounds to their 2-NBDG uptake stimulation result, we used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay to measure 3T3-L1 adipocyte cell viability in the presence of compounds 2, 3, 6, and 9. At both 5 and 10 µM, each of these compounds showed minimal cytotoxicity (Supplemental Figure 1, Supplemental Material) indicating that the 2-NBDG uptake effects of these compounds were not affected by cytotoxicity. Our data suggest that compounds 2, 3, 6, and 9 might induce glucose uptake in 3T3-L1 adipocyte cells through the insulin-signaling pathway via inhibition of PTP1B enzyme activity.

Figure 4

Stimulatory effects of the potential protein tyrosine phosphatase 1B inhibitors (2, 3, 6, and 9) on 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]-d-glucose (2-NBDG) uptake in 3T3-L1 adipocyte cells (control: dimethylsulfoxide; insulin: positive control). Fully differentiated 3T3-L1 adipocytes were treated with 5 and 10 µM of each compound and insulin (100 nM) followed by treatment with 2-NBDG.

Conclusion

A study of the chemical constituents of the methanol extract of P. cuspidatum root—collected in 2018 from Thai Nguyen Province, Vietnam—has led to the purification and identification of 10 natural bioactive principles. The chemical structures were confirmed by NMR spectroscopic and mass spectrometric analyses and comparison with published data. This is the first time that 9,10-anthraquinones (compounds 5 and 6) have been isolated from P. cuspidatum, and compound 9 is identified from a Polygonum species. Except for compound 4 (IC₅₀ >30 µM), all isolates showed potential inhibitory activity against PTP1B, with IC₅₀ values ranging from 6.3 to 28.9 µM. A kinetic study to assess the compounds’ potencies showed mixed-competitive inhibition for compounds 2 and 9 and noncompetitive inhibition for compounds 3 and 6. In addition, the PTP1B inhibitors 2, 3, 6, and 9 also induced 2-NBDG uptake stimulation in 3T3-L1 adipocytes at both 10 and 5 mM concentrations. Together, our results suggest potential bioactive components from P. cuspidatum—including 9,10-anthraquinones and α,β-dihydroxystilbenes—as new natural products for research and development of antidiabetic agents.

Materials and Methods

General Experimental Procedures

¹H-NMR (400 MHz) and ¹³C-NMR (100 MHz) were measured on a Varian Unity Inova 400 MHz spectrometer. Electrospray ionization-MS was obtained from a Varian FT-MS spectrometer and MicroQ-TOF III (Bruker Daltonics, Ettlingen Germany). Other spectroscopic measurements and chromatographic techniques are presented in Supplemental Material.

Plant Material

The roots of P. cuspidatum were collected in February 2018 from Thai Nguyen province, Vietnam. The sample was identified by Dr Nguyen Quoc Binh (Vietnam National Museum of Nature, Vietnam Academy of Science and Technology (VAST). A voucher specimen (CKC-TN01) was deposited at the Institute of Natural Products Chemistry (INPC), VAST.

Extraction and Isolation

The roots of P. cuspidatum (1.2 kg) were dried and cut into small pieces and then extracted with methanol (MeOH) with sonication for 2 hours, at 45 °C. The extract was then filtered before being evaporated under reduced pressure to give a crude MeOH extract (250 g). This was dissolved in water and further partitioned with n-hexane and EtOAc to give a hexane fraction (20 g) an EtOAc fraction (120.8 g), and a water residue. These fractions were then tested for their 2-NBDG uptake effects on 3T3-L1 adipocyte cells. The detailed isolation and purification of the isolated compounds are presented in the Supplemental Material.

Biological Assay

The PTP1B inhibitory assays, determination of the inhibition mode of active compounds, the 2-NBDG uptake stimulatory, and cell viability assay were performed according to the methods described in Supplemental Material.

Statistical Analysis

Data are represented as mean ± SD of at least 3 independent experiments performed in triplicate assays and determined by regression analysis. Sigma Plot program version 11.0 was used for the analysis of the kinetic data.

Supplemental Material

Supplementary Material 1 - Supplemental material for Natural PTP1B Inhibitors From Polygonum cuspidatum and Their 2-NBDG Uptake Stimulation

Supplemental material, Supplementary Material 1, for Natural PTP1B Inhibitors From Polygonum cuspidatum and Their 2-NBDG Uptake Stimulation by Hong-Luyen Le, Dao-Cuong To, Manh-Hung Tran, Thi-Thuy Do and Phi-Hung Nguyen in Natural Product Communications

Supplemental Material

Supplementary Material 2 - Supplemental material for Natural PTP1B Inhibitors From Polygonum cuspidatum and Their 2-NBDG Uptake Stimulation

Supplemental material, Supplementary Material 2, for Natural PTP1B Inhibitors From Polygonum cuspidatum and Their 2-NBDG Uptake Stimulation by Hong-Luyen Le, Dao-Cuong To, Manh-Hung Tran, Thi-Thuy Do and Phi-Hung Nguyen in Natural Product Communications

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this work was supported by the Post-Doctoral Program of the Vietnam Academy of Science and Technology (The project code number: GUST.STS.ĐT2017-HH14).

ORCID iDs

Dao-Cuong To

Phi-Hung Nguyen

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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