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Peroxynitrite (ONOO - ) is a reactive oxidant formed from superoxide (•O 2 - ) and nitric oxide (•NO), that can oxidize several cellular components, including essential protein, non-protein thiols, DNA, low-density lipoproteins (LDL), and membrane phospholipids. ONOO - has contributed to the pathogenesis of diseases such as stroke, heart disease, Alzheimer's disease, and atherosclerosis. Because of the lack of endogenous enzymes to thwart ONOO - activation, developing a specific ONOO - scavenger is remarkably important. In this study, the ability of hesperetin (3′,5,7-trihydroxy-4-methoxyflavanone) to scavenge ONOO - and to protect cells against ONOO - and ROS was investigated. The data gained show that hesperetin can efficiently scavenge authentic ONOO - . In spectrophotometric analysis, the data revealed that hesperetin led to declined ONOO - -mediated nitration of tyrosine through electron donation. Hesperetin exhibited significant inhibition on the nitration of bovine serum albumin (BSA) by ONOO - in a dose-dependent manner. Hesperetin also manifested cytoprotection from cell damage induced by ONOO - and ROS. The present study suggests that hesperetin is a powerful ONOO - scavenger and promotes cellular defense activity in the protection against ONOO - involved diseases. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the inhibitory action of protocatechuic aldehyde (PCA) on tyrosinase activity. PCA is one of the compounds found in the root of Salvia miltiorrhiza. Our study documented that PCA has a potent inhibitory effect on tyrosinase, which catalyzes the rate-limiting step of melanin biosynthesis. Although melanin biosynthesis has an essential function normally in human skin for defense against ultraviolet light of the sun, its abnormal activity as seen in pigmentation disorder could lead to serious medical problems. Our data showed that PCA, with concentrations ranging from 1×10-5M to 8×10-5M, exhibited dose-dependent inhibition of the enzyme activity with 50% of inhibition at 19.92×10-6M. A further kinetic analysis on PCA inactivation of tyrosinase activity revealed a competitive inhibition of the enzyme at the L-tyrosine binding site. The findings of our present study merit further research on the applicability of PCA as a potential agent for treatment of pigmentation disorder. [ABSTRACT FROM AUTHOR]

Peroxynitrite (ONOO-) is one of cytotoxic species produced by the reaction between superoxide (•O2-) and nitric oxide (NO). The main aim of this study was to identify ONOO- scavenging constituents from herbs. Methanolic extracts derived from one hundred thirty eight herbs were screened out for their ONOO- scavenging activities. Twenty herbs showed excellent ONOO- scavenging activity in a dose dependent manner. Of them, Artemisia iwayomogi, which showed the highest activity, was fractioned with several solvents. The ONOO- scavenging activity of fractions was in order of ethyl acetate (EtOAc) > n-butanol (BuOH) > dichloromethane (CH2Cl2) > water (H2O) fraction. The EtOAc and the n-BuOH fractions were further purified to isolate active principles by column chromatography. Apigenin 7-methylether (genkwanin), apigenin 7,4'-di-O methylether, jaceosidin, and scopoletin from the EtOAc fraction and chlorogenic acid, 2,4-dihydroxy 6-methoxy acetophenone 4-O-β-D-glucoside, quebrachitol, and scopolin from the n-BuOH fraction were identified. The scavenging activities of chlorogenic acid (IC50 = 0.52 ± 0.04 µM), genkwanin (IC50 = 1.01 ± 0.10 µM), and scopoletin (IC50 = 1.03 ± 0.15 µM) were higher than or comparable to a well-known ONOO- scavenger, penicillamine (IC50 = 1.76 ± 0.18 µM), suggesting that those compounds might be developed as effective ONOO- scavengers for, prevention of the ONOO--involved diseases. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Antioxidant activity of Pinus densiflora Sieb. et Zucc. (Pinaceae) was evaluated for potential to inhibit hydroxyl radicals, inhibit total reactive oxygen species generation in kidney homogenates using 2',7'-dichlorodihydrofluorescein diacetate (DCHF-DA) and scavenge authentic peroxynitrites. The methanolic extract of P. densiflora showed strong antioxidant activity in the tested model systems and thus fractionated with several solvents. The antioxidant activity potential of the individual fraction was in the order of ethyl acetate > n-butanol > water > dichloromethane fraction. The ethyl acetate soluble fraction exhibiting strong antioxidant activity was further purified by repeated silica gel and Sephadex LH-20 column chromatographies. An active lignan (+)-isolarisiresinol xylopyranoside, as well as two active flavonoids [kaempferol 3-O-β-galactopyranoside and its 6"-acetyl derivative], were isolated. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Investigates the effect of methanol extract and protocatechuic acid from the leaves of Zanthoxylum piperitum on lipid peroxidation and drug metabolizing enzymes in the liver of bromobenzene-treated rats. Reduction of the level of peroxide induced by bromobenzene; Restoration of the activity of epoxide hydrolase which had been decreased by bromobenzene.

Peroxynitrite is a cytotoxic intermediate produced by the reaction between the superoxide anion (O2) and nitric oxide (NO). The aim of this study was to investigate the scavenging effects of Curcuma longa L. on authentic peroxynitrite, and further studies are planned that will attempt to identify the active principles from the active fractions. The methanolic extract of C. longa showed 50% scavenging activity (IC50) at concentration of 1.7 ± 0.08 µg/ml, and was thus fractionated with several solvents. The peroxynitrite scavenging activity potential of the individual fraction was in the order of ethyl acetate > dichloromethane > water fraction. The ethyl acetate soluble fraction exhibiting strong scavenging activity was further purified by repeated silica gel column chromatography. Peroxynitrite scavenging diarylheptanoids, curcumin I (1), curcumin II (2), and curcumin III (3) were isolated as active principles. Compounds 1–3 showed the peroxynitrite scavenging activities with IC50 values of 4.0 ± 0.04, 6.4 ± 0.30, and 29.7 ± 1.29 µM, respectively. Penicillamine as positive control exhibited IC50 value of 2.38 ± 0.34 µM. The structure-activity relationship of diarylheptanoids on peroxynitrite was also discussed. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

To investigate the antioxidant activity of mustard leaf (Brassica juncea), we prepared four fractions (CH2Cl2, EtOAc, BuOH and H2O fractions) and examined their radical scavenging activities in vitro and in vivo. Based on the in vitro results of spin trapping and 1,1-diphenyl-2-picrylhydrazyl radical, we carried out an in vivo study with the BuOH fraction to investigate its effect on oxidative stress in rats with streptozotocin-induced diabetes. We found that in comparison with untreated diabetic control rats, oral administration of the BuOH fraction (100 or 200 mg/kg body weight/day for 10 days) induced a significant decrease in serum glucose and glycosylated protein, which is glycosylated with hemoglobin as an indicator of oxidative stress. Moreover, administration of the BuOH fraction also effectively reduced the serum superoxide and nitrite/nitrate levels. Furthermore, the levels of thiobarbituric acid-reactive substances in serum and liver were also significantly lower than in the control group. These results indicate that the BuOH fraction of mustard leaf controls glucose metabolism and reduces lipid peroxidation as well as the level of oxygen radicals, ameliorating the damage caused by oxidative stress in diabetes. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Cholecystokinin (CCK) is one of the most abundant peptides in the central nervous system and is believed to function as a neurotransmitter as well as a gut hormone with an inverse correlation of its level to anxiety and depression. Therefore, CCK receptors (CCKRs) could be a relevant target for novel antidepressant therapy. Methods: In silico target prediction was first employed to predict the probability of the bromophenols interacting with key protein targets based on a model trained on known bioactivity data and chemical similarity considerations. Next, we tested the functional effect of natural bromophenols from Symphyocladia latiuscula on the CCK2 receptor followed by a molecular docking simulation to predict interactions between a compound and the binding site of the target protein. Results: Results of cell-based functional G-protein coupled receptor (GPCR) assays demonstrate that bromophenols 2,3,6-tribromo-4,5- dihydroxybenzyl alcohol (1), 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (2), and bis-(2,3,6-tribromo-4,5-dihydroxybenzyl) ether (3) are full CCK2 antagonists. Molecular docking simulation of 1-3 with CCK2 demonstrated strong binding by means of interaction with prime interacting residues: Arg356, Asn353, Val349, His376, Phe227, and Pro210. Simulation results predicted good binding scores and interactions with prime residues, such as the reference antagonist YM022. Conclusions: The results of this study suggest bromophenols 1--3 are CCK2R antagonists that could be novel therapeutic agents for CCK2R-related diseases, especially anxiety and depression. [ABSTRACT FROM AUTHOR]

Morus bombycis has a long history of usage as a treatment for metabolic diseases, especially, diabetes mellitus (DM). Thus, we aimed to isolate and evaluate bioactive constituents derived from M. bombycis leaves for the treatment of DM. According to bioassay-guided isolation by column chromatography, eight compounds were obtained from M. bombycis leaves: two phenolic compounds, p-coumaric acid (1) and chlorogenic acid methyl ester (2), one stilbene, oxyresveratrol (3), two stilbene dimers, macrourin B (4) and austrafuran C (6), one 2-arylbenzofuran, moracin M (5), and two Diels–Alder type adducts, mulberrofuran F (7) and chalcomoracin (8). Among the eight isolated compounds, the anti-DM activity of 3–8 (which possess chemotaxonomic significance in Morus species) was evaluated by inhibition of α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), human recombinant aldose reductase (HRAR), and advanced glycation end-product (AGE) formation as well as by scavenging peroxynitrite (ONOO−), which are crucial therapeutic targets of DM and its complications. Compounds 4 and 6–8 significantly inhibited α-glucosidase, PTP1B, and HRAR enzymes with mixed-type and non-competitive-type inhibition modes. Furthermore, the four compounds had low negative binding energies in both enzymes according to molecular docking simulation, and compounds 3–8 exhibited strong antioxidant capacity by inhibiting AGE formation and ONOO− scavenging. Overall results suggested that the most active stilbene-dimer-type compounds (4 and 6) along with Diels–Alder type adducts (7 and 8) could be promising therapeutic and preventive resources against DM and have the potential to be used as antioxidants, anti-diabetic agents, and anti-diabetic complication agents.

Previously, we reported the anti-diabetic effect of Morus alba root bark and the compounds therein. In our continuous study of other parts of this plant, the ability of the branch of Morus alba to inhibit α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), and advanced glycation end products (AGEs) formation was evaluated. Moreover, there are no previous studies that have performed enzyme kinetics and molecular docking analyses, along with assessments of peroxynitrite (ONOO−) inhibitory activities. Since the Morus alba branch exhibited favorable inhibitory effects, repeated column chromatography was performed to obtain eight compounds, including four flavonoids (1, 3, 6, 8), one arylbenzofuran (2), one stilbene (5), one Diels–Alder-type adduct (7), and one sterol (4). Among them, compounds 1–3 and 5–7 were mixed-type inhibitors of α-glucosidase, sharing the same catalytic residues with acarbose and the same allosteric sites with (Z)-3-bytylidenephthalide. On the other hand, kuwanon C (1) and oxyresveratrol (5) interacted with residues of the allosteric site (α3 and α6 helices) of PTP1B, indicating their use as non-competitive inhibitors. Interestingly, kuwanon G (7) directly bound the catalytic site, or interrupted the binding between the substrate and the active site, as a mixed-type inhibitor. Moreover, most of the compounds exhibited greater activity against AGE formation and ONOO− than positive controls. The IC50 values required to inhibit ONOO− using compounds 1, 3, 5, 6, and 7 were reported for the first time, and range from 1.08 to 12.92 μM. Based on the structure–activity relationship, the presence of hydroxyl, resorcinol, and prenyl moieties was important in the prevention of diabetes’ pathological mechanisms, and these findings have been further supported by molecular docking analysis. These computational and experimental results will be useful in the development of therapeutic candidates to prevent/treat diabetes and its complications.

In the present study, we investigated the structure-activity relationship of naturally occurring hesperetin derivatives, as well as the effects of their glycosylation on the inhibition of diabetes-related enzyme systems, protein tyrosine phosphatase 1B (PTP1B) and α-glycosidase. Among the tested hesperetin derivatives, hesperetin 5-O-glucoside, a single-glucose-containing flavanone glycoside, significantly inhibited PTP1B with an IC50 value of 37.14 ± 0.07 µM. Hesperetin, which lacks a sugar molecule, was the weakest inhibitor compared to the reference compound, ursolic acid (IC50 = 9.65 ± 0.01 µM). The most active flavanone hesperetin 5-O-glucoside suggested that the position of a sugar moiety at the C-5-position influences the PTP1B inhibition. It was observed that the ability to inhibit PTP1B is dependent on the nature, position, and number of sugar moieties in the flavonoid structure, as well as conjugation. In the kinetic study of PTP1B enzyme inhibition, hesperetin 5-O-glucoside led to mixed-type inhibition. Molecular docking studies revealed that hesperetin 5-O-glucoside had a higher binding affinity with key amino residues, suggesting that this molecule best fits the PTP1B allosteric site cavity. The data reported here support hesperetin 5-O-glucoside as a hit for the design of more potent and selective inhibitors against PTP1B in the search for a new anti-diabetic treatment.

Traditional Chinese and Japanese medicines have become prime sources of drug discovery and there is a pressing need to investigate the effectiveness of these traditional medicines for modern drug discovery. Recently, among various traditional formulations, studies on Kangen-karyu (Guan- Yuan-Ke-Li), a mixture of six medicinal herbs (Salviae Miltiorrhizae Radix, Cnidii Rhizoma, Paeoniae Radix, Carthami Flos, Aucklandiae Radix, and Cyperi Rhizoma), have been growing to assess its neuroprotective role. This prompted us to undertake a thorough review of various targets of Kangen-karyu regarding its effectiveness against Alzheimer's disease, particularly focusing on cholinesterases, beta-site amyloid precursor protein cleaving enzyme 1, and glycogen synthase kinase 3ß. This review provides new insights into Kangen-karyu medication as a prospective anti- Alzheimer's medication and indicates the need for in-depth in vivo investigation in the future. [ABSTRACT FROM AUTHOR]

Metabolic syndrome is a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus. The risk factors include hypertension, dyslipidemia, hyperglycemia, and central obesity. Various diagnostic criteria have been proposed by different organizations over the past decade. The utilization of traditional Chinese medicine to treat metabolic syndrome has received increasing attention due to its wide availability. In this paper, we report the case of a 68-year-old patient with hypertension, hypercholesterolemia, borderline diabetes, and obesity, who showed an improvement in metabolic syndrome on the administration of 7.5 g of Kangen-karyu extract per day. After 6 months, the levels of serum total cholesterol, low-density lipoprotein-cholesterol, triglycerides, hemoglobin A1c were decreased. The abdominal circumference and body weight were decreased following administration. At that time, the somatic and subjective symptoms had partially disappeared. Herein, we present and discuss the evidence supporting the use of Kangen-karyu extract against metabolic syndrome. [ABSTRACT FROM AUTHOR]

Oligonol is a phenolic product derived from lychee fruit extract containing catechin-type monomers and oligomers of proanthocyanidins, produced by a manufacturing process which converts polyphenol polymers into oligomers. These proanthocyanidins have been reported to exhibit beneficial bioactivities in many studies, and so oligonol, a rich source of polyphenol, is expected to show favorable effects on various chronic diseases. This article summarizes recent work whether oligonol has an ameliorative effect on diabetic indices and renal disorders associated with gluco-lipotoxicity-mediated oxidative stress, inflammation, and apoptosis in db/db mice with diabetes. Oligonol was able to improve diabetic indices, prevent the development of diabetic renal disease, and preserve renal cells and the renal morphological structure via the attenuation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-induced oxidative stress, inhibition of advanced glycation endproduct (AGE) generation, and prevention of apoptosis-induced cell death in db/db mice, being independent of changes in the body weight or serum glucose levels. The present study provides important evidence that oligonol exhibits a pleiotropic effect, representing renoprotective effects against the development of diabetic complications in type 2 diabetic db/db mice. [ABSTRACT FROM AUTHOR]

Aims: The multifunctional potential of neferine derived from the embryo of Nelumbo nucifera seeds for the age-related neurodegenerative disorders, in vivo anti-amnesic activities and in vitro cholinesterases (ChEs)- and β-site APP cleaving enzyme 1 (BACE1)-inhibitory activities, as well as anti-inflammatory and antioxidant activities were investigated. Main methods: In vivo anti-amnesic activities were performed via the passive avoidance, Y-maze, and Morris water maze tasks in a scopolamine-induced amnesia model. The cell-free antioxidant capacities were evaluated by in vitro scavenging activities against 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radicals, and peroxynitrite (ONOO−), as well as inhibitory activities against nitric oxide (NO·), superoxide anion (·O2−), lipid peroxidation, and ONOO−-mediated tyrosine nitration. The intracellular antioxidant capacities were also determined via inhibitory activities of lipopolysaccharide (LPS)-induced NO· generation and NF-κB activation in RAW 264.7 cells. Key findings: Neferine showed significant improvement in cognitive impairment in scopolamine-induced amnesia animal models and moderate inhibitory activities in ChEs and BACE1 assays. In addition, it exhibited notable scavenging activities against DPPH, ABTS, NO·, and ·O2− radicals, as well as ONOO−. Neferine also demonstrated remarkable inhibitory activity against lipid peroxidation and protein nitration in cell-free antioxidant assays and moderate inhibitory activity of NO· generation with exceptional suppression of NF-κB activation in cell-based assays. Significance: The results demonstrate that the anti-amnesic effect of neferine may be mediated via antioxidant and anti-inflammatory capacities, as well as inhibition of ChEs and BACE1. [ABSTRACT FROM AUTHOR]

Presents a study which focused on the inhibition of NFKB by methyl chlorogenate from Eriobotrya japonica. Materials and methods; Results; Discussion.

Prophenoloxidase (pro-PO), a precursor of phenol oxidase (PO), was purified from the hemolymph of coleopteran Holotrichia diomphalia larvae. The enzyme was purified to apparent homogeneity, in six steps of chromatography, using Sephadex G-100, CM-52, Dextran- sulfate Sepharose CL-6B, Phenyl Sepharose CL-4B, Sephacryl S-200, and a Mono-Q column. The preparation exhibited a single band on SDS-PAGE. The proenzyme had a molecular weight of 158 kDa, as estimated by gel filtration. On SDS-PAGE under reducing conditions, it gave a 79 kDa band, indicating that it forms a dimer of the 79 kDa protein. On the other hand, the purified pro-PO gave two well-separated peaks, named pro- PO-1 and pro-PO-2, on reverse-phase HPLC. Amino acid compositions of both proteins were indistinguishable, thereby suggesting the presence of an allelic variant or an isoprotein. On dextran-sulfate Sepharose CL-6B chromatography, a fraction containing prophenoloxidase activating enzyme(s) (PPAE fraction), free from pro-PO, was also separated. In reconstitution experiments, the activation of purified pro-PO by PPAE fraction was observed in the presence of 5 mM Ca2+, with a specific limited proteolysis. The NH2-terminal sequence of generated PO was determined to be NH2-Phe-Gly-Glu-Asp-Asp-. The activated PO oxidized o-diphenols but did not oxidize mono-phenol and p-diphenol substrates. The purified pro-PO was not activated by trypsin, a-chymotrypsin, and SDS. [ABSTRACT FROM AUTHOR]