Promising Inhibitory Effects of Anthraquinones, Naphthopyrone, and Naphthalene Glycosides, from Cassia obtusifolia on α-Glucosidase and Human Protein Tyrosine Phosphatases 1B

Abstract

The present work aims to evaluate the anti-diabetic potentials of 16 anthraquinones, two naphthopyrone glycosides, and one naphthalene glycoside from Cassia obtusifolia via inhibition against the protein tyrosine phosphatases 1B (PTP1B) and α-glucosidase. Among them, anthraquinones emodin and alaternin exhibited the highest inhibitory activities on PTP1B and α-glucosidase, respectively. Moreover, we examined the effects of alaternin and emodin on stimulation of glucose uptake by insulin-resistant human HepG2 cells. The results showed that alaternin and emodin significantly increased the insulin-provoked glucose uptake. In addition, our kinetic study revealed that alaternin competitively inhibited PTP1B, and showed mixed-type inhibition against α-glucosidase. In order to confirm enzyme inhibition, we predicted the 3D structure of PTP1B using Autodock 4.2 to simulate the binding of alaternin. The docking simulation results demonstrated that four residues of PTP1B (Gly183, Arg221, Ile219, Gly220) interact with three hydroxyl groups of alaternin and that the binding energy was negative (−6.30 kcal/mol), indicating that the four hydrogen bonds stabilize the open form of the enzyme and potentiate tight binding of the active site of PTP1B, resulting in more effective PTP1B inhibition. The results of the present study clearly demonstrate that C. obtusifolia and its constituents have potential anti-diabetic activity and can be used as a functional food for the treatment of diabetes and associated complications.

Antidiabetic potential of anthraquinones: A review

“…In contrast, administration of emodin for 7 days at same dose and via the same route reduced FBG by 77.2% in C57BL/6J mice (Feng et al, ). This partly supports the in vitro study, which showed the potential of emodin in improving insulin resistance (Jung et al, ). In KKAy diabetic mice, oral administration of emodin for 2 weeks showed antihyperglycemia (40%) and upregulate the calcium channel expression in the pancreas and heart in diabetic rats model (Liu et al, ; Zhao et al, ).…”

“…Obtusin, chryso‐obtusin, and chryso‐obtusin‐2‐O‐β‐D‐glucoside from S. obtusifolia inhibited PTP 1B (IC 50 obtusin: 6.44 μM; chryso‐obtusin: 14.88 μM; chryso‐obtusin‐2‐O‐β‐D‐glucoside: 39.34 μM; Jung et al, ). The authors further highlighted that aurantio‐obtusin showed higher PTP 1B (IC 50 : 27.19 μM) inhibition compared with gluco‐aurantio obtusin (IC 50 : 31.3 μM) at the same concentration.…”

“…Emodin and its derivatives, aloe‐emodin, alaternin, and questin isolated from S. obtusifolia L. and R. emodi Wall. have shown potent α‐glucosidase inhibitory activity (IC 50 emodin: 1.02 μM; aloe‐emodin: 1.40 μM alaternin: 0.99 μM; questin: 136.19 μM; Jung, Ali, & Choi, ; Arvindekar et al, ). This corroborates the previous studies that reported the potential of S. obtusifolia and R. emodi extracts to inhibit α‐amylase and α‐glucosidase activities (Babu et al, ; Vadivel, Kunyanga, & Biesalski, ).…”

“…Emodin, aloe‐emodin, 2‐hydroxyemodin‐1 methylether, alaternin, and questin isolated from S. obtusifolia inhibited PTP 1B activity with IC 50 values of 3.51, 56.01, 5.22, 1.22, and 5.69 μM, respectively (Jung et al, ). The data further showed that except for aloe‐emodin, the compounds have higher PTP 1B inhibition compared with the S. obtusifolia crude extract (IC 50 : 14.79 μM).…”

“…Chrysophanol isolated from S. obtusifolia and rhubarb rhizome inhibited PTP 1B activity (IC 50 : 5.8 μM) and stimulated glucose transport in insulin‐stimulated myotubes (Babu et al, ; Jung et al, ; Lee & Sohn, ; Lee, Yoon, Hwang, Kim, & Kim, ). Chrysophanol glucosides, chrysophanol‐8‐O‐β‐D‐glucopyranoside, chrysophanol triglucoside, and chrysophanol tetraglucoside from S. obtusifolia inhibited PTP 1B activity with IC 50 values of 8.8, 80.17, and 103.89 μM, respectively (Jung et al, ). Similarly, Onoda et al () have reported that chrysophanol isolated from Masiningan extract, a traditional herbal medicine consisting of Cannabis sativa Linne, Paeonia lactiflora Pallas, Citrus aurantium Linne, Magnolia officinalis Rehd.…”