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Ginseng (Panax ginseng C. A. Meyer) extract has been reported to inhibit the angiotensin converting enzyme (ACE); however, the possible inhibitory action of most of its constituents (ginsenosides) against ACE remains unknown. Thus, in this study, we investigated ginsenoside derivatives' inhibitory effect on ACE. We assessed the activities of 22 ginsenosides, most of which inhibited ACE significantly. Notably, protopanaxatriol, protopanaxadiol, and ginsenoside Rh2 exhibited the most potent ACE inhibitory potential, with IC50 values of 1.57, 2.22, and 5.60 μM, respectively. Further, a kinetic study revealed different modes of inhibition against ACE. Molecular docking studies have confirmed that ginsenosides inhibit ACE via many hydrogen bonds and hydrophobic interactions with catalytic residues and zinc ion of C- and N-domain ACE that block the catalytic activity of ACE. In addition, we found that the active ginsenosides stimulated glucose uptake in insulin-resistant C2C12 skeletal muscle cells in a dose-dependent manner. Moreover, the most active ginsenosides' reactive oxygen species (ROS) and peroxynitrite (ONOO-) scavenging properties were evaluated, in which IC50 values ranged from 1.44-43.83 to 2.36-39.56 μM in ONOO- and ROS, respectively. The results derived from these computational and in vitro experiments provide additional scientific support for the anecdotal use of ginseng in traditional medicine to treat cardiovascular diseases such as hypertension.

Pomegranate (Punica granatum L.) extract has been reported to inhibit cholinesterase and the β-site amyloid precursor protein cleaving enzyme 1 (BACE1); however, most of its constituents' potential inhibition of these enzymes remains unknown. Thus, we investigated the anti-Alzheimer's disease (anti-AD) potential of 16 ellagitannin and gallotannin, and nine anthocyanin derivatives' inhibition of BACE1, AChE, and BChE, and gallagic acid inhibited both the best. Further, a kinetic study identified different modes of inhibition, and a molecular docking simulation revealed that active compounds inhibited these three enzymes with low binding energy through hydrophilic and hydrophobic interactions in the active site cavities. Gallagic acid and castalagin decreased Aβ peptides secretion from neuroblastoma cells that overexpressed human β-amyloid precursor protein significantly by 10 μM. Further, treatment with gallagic acid and castalagin reduced BACE1 and APPsβ expression levels significantly without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Co-incubation of Aβ42 with gallagic acid reduced Aβ42-induced intracellular reactive oxygen species (ROS) production significantly. Our results suggest that pomegranate constituents, specifically gallagic acid, may be useful in developing therapeutic treatment modalities for AD.

Didymin is a naturally occurring orally active flavonoid glycoside (isosakuranetin 7-O-rutinoside) found in various citrus fruits, which has been previously reported to possess a wide variety of pharmacological activities including anticancer, antioxidant, antinociceptive, neuroprotective, hepatoprotective, inflammatory, and cardiovascular. However, there have not been any reports concerning its anti-diabetic potential until now. Therefore, we evaluated the anti-diabetic potential of didymin via inhibition of α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), rat lens aldose reductase (RLAR), human recombinant AR (HRAR), and advanced glycation end-product (AGE) formation inhibitory assays. Didymin strongly inhibited PTP1B, α-glucosidase, HRAR, RLAR, and AGE in the corresponding assays. Kinetic study revealed that didymin exhibited a mixed type inhibition against α-glucosidase and HRAR, while it competitively inhibited PTP1B and RLAR. Docking simulations of didymin demonstrated negative binding energies and close proximity to residues in the binding pocket of HRAR, RLAR, PTP1B and α-glucosidase, indicating that didymin have high affinity and tight binding capacity towards the active site of these enzymes. Furthermore, we also examined the molecular mechanisms underlying the anti-diabetic effects of didymin in insulin-resistant HepG2 cells which significantly increased glucose uptake and decreased the expression of PTP1B in insulin-resistant HepG2 cells. In addition, didymin activated insulin receptor substrate (IRS)-1 by increasing phosphorylation at tyrosine 895 and enhanced the phosphorylations of phosphoinositide 3-kinase (PI3K), Akt, and glycogen synthasekinase-3(GSK-3). Interestingly, didymin reduced the expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase, two key enzymes involved in the gluconeogenesis and leading to a diminished glucose production. The results of the present study clearly demonstrated that didymin will be useful for developing multiple target-oriented therapeutic modalities for treatment of diabetes, and diabetes-associated complications.

As a traditional medicine, Angelica decursiva has been used for the treatment of many diseases. The goal of this study was to evaluate the potential of four natural major dihydroxanthyletin-type coumarins—(+)-trans-decursidinol, Pd-C-I, Pd-C-II, and Pd-C-III—to inhibit the enzymes, protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase. In the kinetic study of the PTP1B enzyme’s inhibition, we found that (+)-trans-decursidinol, Pd-C-I, and Pd-C-II led to competitive inhibition, while Pd-C-III displayed mixed-type inhibition. Moreover, (+)-trans-decursidinol exhibited competitive-type, and Pd-C-I and Pd-C-II mixed-type, while Pd-C-III showed non-competitive type inhibition of α-glucosidase. Docking simulations of these coumarins showed negative binding energies and a similar proximity to residues in the PTP1B and α-glucosidase binding pocket, which means they are closely connected and strongly binding with the active enzyme site. In addition, dihydroxanthyletin-type coumarins are up to 40 µM non-toxic in HepG2 cells and have substantially increased glucose uptake and decreased expression of PTP1B in insulin-resistant HepG2 cells. Further, coumarins inhibited ONOO−-mediated albumin nitration and scavenged peroxynitrite (ONOO−), and reactive oxygen species (ROS). Our overall findings showed that dihydroxanthyletin-type coumarins derived from A. decursiva is used as a dual inhibitor for enzymes, such as PTP1B and α-glucosidase, as well as for insulin susceptibility.

The formation of advanced glycation end-products (AGE) and aldose reductase activity have been implicated in the development of diabetic complications. The present study was aimed to evaluate human recombinant aldose reductase (HRAR) and AGE inhibitory activity of seven natural dihydroxanthyletin-type coumarins, 4-hydroxy Pd-C-III (1), 4'-methoxy Pd-C-I (2), Pd-C-I (3), Pd-C-II (4), Pd-C-III (5), decursidin (6), and (+)-trans-decursidinol (7) from Angelica decursiva. Coumarins 1-7 showed potent HRAR and AGE inhibitory activities with ranges of IC

Ginseng (Panax ginseng and red ginseng) extract has been reported to inhibit the formation of advanced glycation end-products (AGEs); however, the potential inhibitory activity of its major constituents (ginsenosides) against AGE formation is still unknown. In the present study, we investigated the inhibitory effect of ginsenoside derivatives on AGE formation. Herein, we assessed the activity of 22 ginsenosides, most of which significantly inhibited fluorescent AGE formation. Notably, ginsenoside Rh2, ginsenoside Rh1, and compound K exhibited the most potent AGE inhibitory potential with IC50 values of 3.38, 8.42, and 10.85 µM, respectively. The structure– activity relationship revealed that the presence of sugar moieties, hydroxyl groups, and their linkages, and the stereostructure of the ginsenoside skeleton played an important role in the inhibition of AGE formation. Furthermore, the inhibitory activity of the most active ginsenoside Rh2 on fructose-glucose-mediated protein glycation and oxidation of bovine serum albumin (BSA) was explored. Rh2 (0.1–12.5 µM) inhibited the formation of fluorescent AGE and non-fluorescent AGE, as well as the level of fructosamine and prevented protein oxidation by decreasing protein carbonyl formation and protein thiol group modification. Rh2 also suppressed the formation of the β-cross amyloid structure of BSA. Ginsenosides might be promising new anti-glycation agents for the prevention of diabetic complications via inhibition of AGE formation and oxidation-dependent protein damage.

The aim of this study was to investigate the protective effects of juice powders from sweet orange [Citrus sinensis (L.) Osbeck], unshiu mikan (Citrus unshiu Marcow), and mini tomato (Solanum lycopersicum L.), and their major flavonoids, hesperidin, narirutin, and rutin in tert-butyl hydroperoxide (t-BHP)-induced oxidative stress in HepG2 cells. The increased reactive oxygen species and decreased glutathione levels observed in t-BHP-treated HepG2 cells were ameliorated by pretreatment with juice powders, indicating that the hepatoprotective effects of juice powders and their major flavonoids are mediated by induction of cellular defense against oxidative stress. Moreover, pretreatment with juice powders up-regulated phase-II genes such as heme oxygenase-1 (HO-1), thereby preventing cellular damage and the resultant increase in HO-1 expression. The high-performance liquid chromatography profiles of the juice powders confirmed that hesperidin, narirutin, and rutin were the key flavonoids present. Our results suggest that these fruit juice powders and their major flavonoids provide a significant cytoprotective effect against oxidative stress, which is most likely due to the flavonoid-related bioactive compounds present, leading to the normal redox status of cells. Therefore, these fruit juice powders could be advantageous as bioactive sources for the prevention of oxidative injury in hepatoma cells.

Skipjack tuna, Katsuwonus pelamis, are distributed throughout the Pacific Ocean in the tropical and subtropical areas, including South Korea, Japan and Indonesia. The antidiabetic and antioxidant potential of 70% ethanol (EtOH) extract of skipjack tuna heart were investigated via protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant aldose reductase (HRAR), 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, peroxynitrite (ONOO−), 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical, and total reactive oxygen species (ROS). The 70% EtOH tuna heart extract exhibited potent inhibitory activity against PTP1B, α-glucosidase and HRAR with inhibition percentages of 85.42, 82.70 and 51.1%, respectively, at a concentration range of 1–2 mg/mL. In addition, it was a potent inhibitor against DPPH, ABTS, ONOO−, and ROS with inhibition percentages of 69.45, 58.31, 96.20 and 34.02%, respectively, at a concentration of 1 mg/mL. The total phenolic content present in tuna extract was 15.80 mg/g GAE. The results demonstrate the potential antidiabetic and antioxidant activities of tuna heart extract. Practical Application Tuna has been consumed as a healthy protein source for hundreds of years. As a food, skipjack is a very good source of protein, vitamins, minerals and omega-3 fatty acids and can lower blood pressure and cholesterol. Generally, the meat of skipjack tuna is used as food and other parts such as the heart are used as fertilizer. Recent studies have identified a number of bioactive components from fish muscle protein, collagen, peptides, gelatin, oil, bone and internal organs that remain after processing. These fish components showed antioxidant, antihypertensive, antiproliferative, antimicrobial and antianemic activities. The findings demonstrated antidiabetic and antioxidant potential of tuna heart extract.

Objective To use structure-activity analysis to study the anti-Alzheimer's disease (anti-AD) activity of natural coumarins isolated from Angelica decursiva and Artemisia capillaris , along with one purchased coumarin (daphnetin). Methods Umbelliferone, umbelliferone 6-carboxylic acid, scopoletin, isoscopoletin, 7-methoxy coumarin, scoparone, scopolin, and esculetin have been previously isolated; however 2′-isopropyl psoralene was isolated from Angelica decursiva for the first time to evaluate their inhibitory effects against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) enzyme activity. We scrutinized the potentials of coumarins as cholinesterase and BACE1 inhibitors via enzyme kinetics and molecular docking simulation. Results Among the test compounds, umbelliferone 6-carboxylic acid, esculetin and daphnetin exhibited potent inhibitory activity against AChE, BChE and BACE1. Both esculetin and daphnetin have a catechol group and exhibit significant anti-AD activity against AChE and BChE. In contrast, presence of a sugar moiety and methoxylation markedly reduced the anti-AD activity of the coumarins investigated in this study. With respect to BACE1 inhibition, umbelliferone 6-carboxylic acid, esculetin and daphnetin contained carboxyl or catechol groups, which significantly contributed to their anti-AD activities. To further investigate these results, we generated a 3D structure of BACE1 using Autodock 4.2 and simulated binding of umbelliferone 6-carboxylic acid, esculetin and daphnetin. Docking simulations showed that different residues of BACE1 interacted with hydroxyl and carboxylic groups, and the binding energies of umbelliferone 6-carboxylic acid, esculetin and daphnetin were negative (−4.58, −6.25 and −6.37 kcal/mol respectively). Conclusions Taken together, our results suggest that umbelliferone 6-carboxylic acid, esculetin and daphnetin have anti-AD effects by inhibiting AChE, BChE and BACE1, which might be useful against AD.

Poncirin, a natural flavanone glycoside present abundantly in many citrus fruits, contains an extensive range of biological activities. However, the antidiabetic mechanism of poncirin is unexplored yet. In this study, we examined the anti-diabetic prospective of poncirin by evaluating its ability to inhibit protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant AR (HRAR), rat lens aldose reductase (RLAR), and advanced glycation end-product (AGE) formation (IC50 = 7.76 ± 0.21, 21.31 ± 1.26, 3.56 ± 0.33, 11.91 ± 0.21, and 3.23 ± 0.09 µM, respectively). Kinetics data and docking studies showed the lowest binding energy and highest affinity for the mixed and competitive type of inhibitors of poncirin. Moreover, the molecular mechanisms underlying the antidiabetic outcomes of poncirin in insulin resistant C2C12 skeletal muscle cells were explored, which significantly increased glucose uptake and decreased the expression of PTP1B in C2C12 cells. Consequently, poncirin increased GLUT-4 expression level by activating the IRS-1/PI3K/Akt/GSK-3 signaling pathway. Moreover, poncirin (0.5–50 µM) remarkably inhibited the formation of fluorescent AGE, nonfluorescent CML, fructosamine, and β-cross amyloid structures in glucose-fructose-induced BSA glycation during 4 weeks of study. Poncirin also notably prevented protein oxidation demonstrated with decreasing the protein carbonyl and the consumption of protein thiol in the dose-dependent manner. The results clearly expressed the promising activity of poncirin for the therapy of diabetes and its related complications.

In the present study, we investigated the anti-Alzheimer's disease (AD) potential of six dihydroxanthyletin-type coumarins, 4'-hydroxy Pd-C-III (1), decursidin (2), Pd-C-I (3), 4'-methoxy Pd-C-I (4), Pd-C-II (5), and Pd-C-III (6) from Angelica decursiva by evaluating their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Coumarins 1-6 exhibited dose-dependent inhibition of AChE, BChE, and BACE1. IC50 values were 1.0-4.01 µM for AChE, 5.78-13.91 µM for BChE, and 1.99-17.34 µM for BACE1. Kinetic studies revealed that 1 was noncompetitive inhibitor for AChE, while 2-6 were mixed-type inhibitors of AChE. Compounds 1, 5 and 6 had mixed-type inhibitory effects against BChE; 2 was a competitive inhibitor; and 3 and 4 were noncompetitive inhibitors. Against BACE1, compounds 1, 2, 3, 5 showed mixed-type inhibition and 4, 6 were noncompetitive inhibitors. Molecular docking simulation of the compounds demonstrated negative-binding energies indicating high proximity to the active site and tight binding to the enzyme. These data suggested that the compounds inhibited AChE, BChE, and BACE1, providing a preventive and therapeutic strategy for AD treatment.

The author would like to include conflict of interest statement of the online published article. The correct conflict of interest statement should read as: Conflict of interest The authors declare no conflict of interest.

Angelica decursiva Fr. et Sav. (Umbelliferae) has traditionally been used to treat different diseases due to its antitussive, analgesic, and antipyretic activities. It is also a remedy for thick phlegm, asthma, and upper respiratory infections. Recently, the leaf of A. decursiva has been consumed as salad without showing any toxicity. This plant is a rich in different types of coumarin derivatives, including dihydroxanthyletin, psoralen, dihydropsoralen, hydroxycoumarin, and dihydropyran. Its crude extracts and pure constituents possess antiinflammatory, anti-diabetic, anti-Alzheimer disease, anti-hypertension, anti-cancer, antioxidant, anthelmintic, preventing cerebral stroke, and neuroprotective activities. This valuable herb needs to be further studied and developed not only to treat these human diseases, but also to improve human health. This review provides an overview of current knowledge of A. decursiva metabolites and their biological activities to prioritize future studies.

In the present study, we investigated the anti-diabetic potential of six natural coumarins, 4-hydroxy Pd-C-III ( 1 ), 4′-methoxy Pd-C-I ( 2 ), decursinol ( 3 ), decursidin ( 4 ), umbelliferone 6-carboxylic acid ( 5 ), and 2′-isopropyl psoralene ( 6 ) isolated from Angelica decursiva and evaluated their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, and ONOO − -mediated protein tyrosine nitration. Coumarins 1–6 showed potent PTP1B and α-glucosidase inhibitory activities with ranges of IC 50 values of 5.39–58.90 μM and 65.29–172.10 μM, respectively. In the kinetic study for PTP1B enzyme inhibition, compounds 1 , 5 , and 6 were competitive, whereas 2 and 4 showed mixed type, and 3 displayed noncompetitive type inhibition. For α-glucosidase enzyme inhibition, compounds 1 and 3 exhibited good mixed-type, while 2 , 5 , and 6 showed noncompetitive and 4 displayed competitive type inhibition. Furthermore, these coumarins also effectively suppressed ONOO − -mediated tyrosine nitration in a dose-dependent manner. To further investigate PTP1B inhibition, we generated a 3D structure of PTP1B using Autodock 4.2 and simulated the binding of compounds 1 – 6 . Docking simulations showed that different residues of PTP1B interacted with different functional groups of compounds 1–6 through hydrogen and hydrophobic interactions. In addition, the binding energies of compounds 1 – 6 were negative, suggesting that hydrogen bonding may stabilize the open form of the enzyme and potentiate tight binding of the active site of PTP1B, thereby resulting in more effective PTP1B inhibition. These results demonstrate that the whole plant of A. decursiva and its coumarins are useful as potential functional food ingredients for the prevention and treatment of type 2 diabetes.

The aim of the present study was to investigate the hepatoprotective effects of different soluble fractions of methanolic derived Cassia obtusifolia seeds extract (COE) and its active components in tert-butyl hydroperoxide (t-BHP)-induced oxidative stress in HepG2 cells. Among the tested fractions, the ethyl acetate (EtOAc) fraction was the most active hepatoprotective fraction. From the active EtOAc fraction, six anthraquinones (alaternin, emodin, aloe emodin, 2-hydroxyemodin 1-methyl ether, chryso-obtusin-2-O-β-d-glucoside, and questin) and one naphthopyrone glycoside (cassiaside) were isolated. The cytotoxic effect in 200 µM t-BHP-induced HepG2 cells was inhibited by COE and their bioactive compounds. The protective effect of COE in 200 µM t-BHP-induced HepG2 cells may be associated with positive regulation of glutathione (GSH) and decreased in reactive oxygen species (ROS) formation of their bioactive compounds. The increased ROS and decreased GSH levels observed in t-BHP-treated HepG2 cells were ameliorated by pretreatment with cassiaside, alaternin, and aloe emodin, indicating that the hepatoprotective effects of these major constituents are mediated by induction of cellular defense against oxidative stress. Overall, COE displayed a significant cytoprotective effect against oxidative stress, which may most likely be because of active compounds like cassiaside, alaternin, and aloe emodin in COE, which leads to maintenance of the normal redox status of cells. Practical applications The dried and roasted seeds of Cassia obtusifolia are commonly consumed as brew tea and medicinal foods in Korea. The seeds have multiple therapeutic actions related to the treatment of liver disease, dementia, diabetes, eye inflammation, photophobia and lacrimation, dysentery, headache, as well as dizziness. The present study demonstrates the hepatoprotective effect through prevention of oxidative stress, suggesting that C. obtusifolia and its constituents may have beneficial effects in preventing hepatic diseases.

The aim of the present study was to evaluate the ability of raw mini tomato (Solanum lycopersicum L.) juice powder to attenuate cytotoxicity in combination with juice powders from two orange species [Citrus sinensis (L.) Osbeck and Citrus unshiu Marcow]. To this end, the hepatoprotective activities of these combinations against tert-butyl hydroperoxide (t-BHP)-induced oxidative stress in HepG2 cells were evaluated, and the most suitable ratios for optimal flavonoid availability were identified. The levels of intracellular reactive oxygen species (ROS) and glutathione (GSH) and the extent of upregulation of phase-ІІ proteins such as heme oxygenase-1 (HO-1) were quantified to assess the hepatoprotective effects of four different ratios of these powders. Three main compounds–hesperidin, narirutin, and rutin were analyzed by simultaneous high-performance liquid chromatography. The total phenolic and flavonoid contents of the 2:1:3 powder mixture were 8.69 mg/g GAE and 2.56 mg/g QE, respectively. The levels of these contents were correlated with the decrease in ROS, increase in GSH level, and restoration of HO-1. Furthermore, the hepatoprotective efficacy of each of the four ratios was attributed to its flavonoid content. These results indicate that combinations of juice powders, particularly at a ratio of 2:1:3, are a potentially useful therapeutic source of phenolic compounds for the treatment of oxidative stress-related hepatotoxicity. Practical applications Sweet orange (Citrus sinensis (L.), Unshiu mikan (Citrus unshiu Marcow) and mini tomato (Solanum lycopersicum L.) are rich sources of phenolic compounds which are consumed frequently in Korea. This research provides proper understanding of the consumption of these fruits in combination to deliver effective amount of phenolic compounds to promote human health and fight against oxidative stress related diseases. The present study demonstrates the hepatoprotective effect through prevention of oxidative stress, suggesting that combinations of juice powders may have beneficial effects in preventing hepatic diseases.