Antidiabetic potential of Lysiphyllum strychnifolium (Craib) A. Schmitz compounds in human intestinal epithelial Caco-2 cells and molecular docking-based approaches

Abstract

Background Lysiphyllum strychnifolium (Craib) A. Schmitz, a traditional Thai medicinal plant, is mainly composed of polyphenols and flavonoids and exhibits several pharmacological activities, including antioxidant, anticancer, antimicrobial, and antidiabetic activities. However, the mechanism by which pure compounds from L. strychnifolium inhibit glucose catalysis in the small intestine and their effect on the glucose transporter remain unknown. Methods The objectives of this research were to examine the effect of 3,5,7-trihydroxychromone-3-O-𝛼-L-rhamnopyranoside (compound 1) and 3,5,7,3’,5’-pentahydroxy-flavanonol-3-O-𝛼-L-rhamnopyranoside (compound 2) on the inhibition of α-amylase and α-glucosidase, as well as glucose transporters, such as sodium-glucose cotransporter 1 (SGLT1), glucose transporter 2 (GLUT2), and glucose transporter 5 (GLUT5), using Caco-2 cells as a model of human intestinal epithelial cells. Additionally, the binding affinity and interaction patterns of compounds against two receptor proteins (SGLT1 and GLUT2) were determined for the first time utilizing a molecular docking approach. Results In the α-amylase inhibition assay, a concentration-dependent inhibitory response was observed against the enzyme. The results indicated that compound 1 inhibited α-amylase activity in a manner similar to that of acarbose (which exhibit IC50 values of 3.32 ± 0.30 µg/mL and 2.86 ± 0.10 µg/mL, respectively) in addition to a moderate inhibitory effect for compound 2 (IC50 = 10.15 ± 0.53 µg/mL). Interestingly, compounds 1 and 2 significantly inhibited α-glucosidase and exhibited better inhibition than that of acarbose, with IC50 values of 5.35 ± 1.66 µg/mL, 510.15 ± 1.46 µg/mL, and 736.93 ± 7.02 µg/mL, respectively. Additionally, α-glucosidase activity in the supernatant of the Caco-2 cell monolayer was observed. In comparison to acarbose, compounds 1 and 2 inhibited α-glucosidase activity more effectively in Caco-2 cells without cytotoxicity at a concentration of 62.5 µg/mL. Furthermore, the glucose uptake pathways mediated by SGLT1, GLUT2, and GLUT5- were downregulated in Caco-2 cells treated with compounds 1 and 2. Additionally, molecular modeling studies revealed that compounds 1 and 2 presented high binding activity with SGLT1 and GLUT2. Conclusion In summary, our present study was the first to perform molecular docking with compounds present in L. strychnifolium extracts. Our findings indicated that compounds 1 and 2 reduced glucose uptake in Caco-2 cells by decreasing the expression of glucose transporter genes and inhibiting the binding sites of SGLT1 and GLUT2. Therefore, compounds 1 and 2 may be used as functional foods in dietary therapy for postprandial hyperglycemia modulation of type 2 diabetes.

Antihyperglycemic effects of Lysiphyllum strychnifolium leaf extract in vitro and in vivo

“…These results were corroborated by Noonong et al. ( 2022 ) who found that the isolated polyphenols from ethanol extract of LS stems exhibited more potent inhibitory effect towards α-glucosidase than that of α-amylase.…”

“…Moreover, these polyphenols also downregulated SGLT1 and GLUT2 mRNA expression in Caco-2 cells (Noonong et al. 2022 ). Therefore, trilobatin, gallic acid, and other polyphenols may contribute to the hypoglycemic effects of the LS leaf extract.…”

“…2019 ; Noonong et al. 2022 ). Moreover, evidence indicates that resveratrol, epicatechin, quercetin, and gallic acid isolated from LS stems inhibited α-glucosidase and DPP-IV enzymes, and quercetin promoted glucose storage in 3T3-L1 adipocyte cells (Praparatana et al.…”

Germinated and non-germinated cooked whole millet (Pennisetum glaucum (L.) R. Br.) flours show a promising effect on protein quality, biochemical profile and intestinal health in vivo

“…Other studies with caco-2 cells indicate that the phytochemicals, such as polyphenols and tannins, have the capacity to suppress glucose uptake in intestinal cells, by the inhibition of SGLT1. [75][76][77] In addition, reduced SGLT1 in the intestine increases the glucose available for metabolisation by the gut microbiota in the colon, where it reduces the colonic pH, thus increasing SCFA production and gut health. 74,78 In our study, plasma glucose was reduced by the consumption of cooked whole germinated millet flour.…”

Lysiphyllum strychnifolium (Craib) A. Schmitz Extracts Moderate the Expression of Drug-Metabolizing Enzymes: In Vivo Study to Clinical Propose

“…This plant is a popular folk medicine that has traditionally been used for a variety of medical purposes such as treating fever, cancer, allergy, and alcohol intoxication, as well as for detoxification, promoting health, and neutralizing pesticide poisoning in animals and humans [ 3 , 4 , 5 ]. The stem ethanol extract of LS has been used for anti-HIV-1 integrase and showed anti-allergy properties [ 6 ] and antidiabetic properties [ 7 ]. The dried powdered stems and leaves are applied as herbal tea, and hydroalcoholic extracts are widely prescribed by traditional doctors [ 4 ].…”