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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.

Nanomaterials (NMs) are currently being used in agricultural soils as part of a new bioremediation (BR) process. In this study, we reviewed the biosynthesis of NMs, as well as their chemical composition and prospective strategies for helpful and sustainable agricultural soil bioremediation (BR). Different types of NMs, such as nanoparticles, nanocomposites, nanocrystals, nano-powders, and nanotubes, are used in agricultural soil reclamation, and they reflect the toxicity of NMs to microorganisms. Plants (Sargassum muticum, Dodonaea viscose, Aloe Vera, Rosemarinus officinalis, Azadirachta indica, Green tea, and so on) and microorganisms (Escherichia coli, Shewanella oneidensis, Pleurotus sp., Klebsiella oxytoca, Aspergillus clavatus, and so on) are the primary sources for the biosynthesis of NMs. By using the BR process, microorganisms, such as bacteria and plants, can immobilize metals and change both inorganic and organic contaminants in the soil. Combining NMs with bioremediation techniques for agricultural soil remediation will be a valuable long-term solution.

Over the years, great attention has been paid to coumarin derivatives, a set of versatile molecules that exhibit a wide variety of biological activities and have few toxic side effects. In this study, we investigated the antidiabetic potential of 6-formyl umbelliferone (6-FU), a novel furanocoumarin isolated from Angelica decursiva. Numerous pharmacological activities of 6-FU have been previously reported; however, the mechanism of its antidiabetic activity is unknown. Therefore, we examined the action of 6-FU on a few candidate-signaling molecules that may underlie its antidiabetic activity, including its inhibition of protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant aldose reductase (HRAR), and advanced glycation end-product (AGE) formation (IC50 = 1.13 ± 0.12, 58.36 ± 1.02, 5.11 ± 0.21, and 2.15 ± 0.13 μM, respectively). A kinetic study showed that 6-FU exhibited mixed-type inhibition against α-glucosidase and HRAR and competitive inhibition of PTP1B. Docking simulations of 6-FU demonstrated negative binding energies and close proximity to residues in the binding pockets of those enzymes. We also investigated the molecular mechanisms underlying 6-FU’s antidiabetic effects. 6-FU significantly increased glucose uptake and decreased PTP1B expression in insulin-resistant C2C12 skeletal muscle cells. Moreover, 6-FU (0.8–100 μM) remarkably inhibited the formation of fluorescent AGEs in glucose-fructose-induced human serum albumin glycation over the course of 4 weeks. The findings clearly indicate that 6-FU will be useful in the development of multiple target-oriented therapeutic modalities for the treatment of diabetes and diabetes-related complications.

In this study, we determined the effect of manure application on net nitrification rates (NNRs), heavy metal concentrations (HMCs), and abundance of ammonia-oxidizing archaea (AOA)/bacteria (AOB), and nitrite-oxidizing bacteria (NOB) in soil. HMCs were measured by atomic absorption spectroscopy. Abundance of AOA, AOB, and NOB was enumerated by q-PCR. NNRs ranged from 2.8 to 14.7 mg kg−1 h−1 and were significantly (p

Abstract Background: Infant and child mortality are indicators of population wellbeing. Although, Child mortality rates are declining in Egypt, national averages mask regional disparities. For that, identification and quantification of factors contributing to mortality, at the local level, through ecological correlation studies could provide a guide to more focused public health interventions for reducing mortality. The study aims to improve child health and decrease child mortality rate through recognizing ecological/environmental factors predicting child mortality among municipalities in Giza governorate. Methodology: Ecological, cross sectional study, adopting the municipalities (n=215) as unit of analysis, was conducted to examine associations between child mortality and some human development indicators. Results: High negative significant correlation between U5MR and access to water (r=-0.966) was found. Access to sanitation and access to electricity are negatively correlated with U5MR with r=-0.955 and - 0.905 respectively. The results with IMR were similar to that with U5MR. An increase in one percentage access of household to safe water predict 1.05and 0.78 fewer U5MR and IMR (R2=0.97 and 0.98; P≤0.001) respectively. U5MR and IMR decrease, significantly, by 0.82 and 0.61deaths, respectively, with increase access to sanitation by 1%. Conclusion: Access to safe water and sanitation are strong predictors of U5MR and IMR. Increase coverage of households by safe water has the largest impact in reduction of children mortality rate. For that, the study recommends advocacy to ensure coverage of household with safe water and sanitation system. Keywords: Child mortality; Ecological correlation; Safe water

Cav3.2 calcium channels are important mediators of nociceptive signaling in the primary afferent pain pathway, and their expression is increased in various rodent models of chronic pain. Previous work from our laboratory has shown that this is in part mediated by an aberrant expression of deubiquitinase USP5, which associates with these channels and increases their stability. Here, we report on a novel bioactive rhodanine compound (II-1), which was identified in compound library screens. II-1 inhibits biochemical interactions between USP5 and the Cav3.2 domain III-IV linker in a dose-dependent manner, without affecting the enzymatic activity of USP5. Molecular docking analysis reveals two potential binding pockets at the USP5-Cav3.2 interface that are distinct from the binding site of the deubiquitinase inhibitor WP1130 (a.k.a. degrasyn). With an understanding of the ability of some rhodanines to produce false positives in high-throughput screening, we have conducted several orthogonal assays to confirm the validity of this hit, including in vivo experiments. Intrathecal delivery of II-1 inhibited both phases of formalin-induced nocifensive behaviors in mice, as well as abolished thermal hyperalgesia induced by the delivery of complete Freund's adjuvant (CFA) to the hind paw. The latter effects were abolished in Cav3.2 null mice, thus confirming that Cav3.2 is required for the action of II-1. II-1 also mediated a robust inhibition of mechanical allodynia induced by injury to the sciatic nerve. Altogether, our data uncover a novel class of analgesics─well suited to rapid structure-activity relationship studies─that target the Cav3.2/USP5 interface.

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.

Cassia obtusifolia L., of the Leguminosae family, is used as a diuretic, laxative, tonic, purgative, and natural remedy for treating headache, dizziness, constipation, tophobia, and lacrimation and for improving eyesight. It is commonly used in tea in Korea. Various anthraquinone derivatives make up its main chemical constituents: emodin, chrysophanol, physcion, obtusifolin, obtusin, au rantio-obtusin, chryso-obtusin, alaternin, questin, aloe-emodin, gluco-aurantio-obtusin, gluco-obtusifolin, naphthopyrone glycosides, toralactone-9-β-gentiobioside, toralactone gentiobioside, and cassiaside. C. obtusifolia L. possesses a wide range of pharmacological properties (e.g., antidiabetic, antimicrobial, anti-inflammatory, hepatoprotective, and neuroprotective properties) and may be used to treat Alzheimer’s disease, Parkinson’s disease, and cancer. In addition, C. obtusifolia L. contributes to histamine release and antiplatelet aggregation. This review summarizes the botanical, phytochemical, and pharmacological features of C. obtusifolia and its therapeutic uses.

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.

Nitrification increases soil fertility and a higher rate of grain production in cereal and leguminous crops. However, differential response of the nitrifying microbes and net nitrification rates (NNRs) of chemical fertilizers in cereals and leguminous crop soils of Bangladesh are unknown. Hence, the current research was undertaken to find out the differential response of the nitrifying microbes and NNRs of chemical fertilizers in some cereals (Triticum aestivum and Zea mays) and leguminous crops (Lins esculenta, Pisum sativum, and Cicer arietinum) soils. The NNRs and occurrence of ammonia-oxidizing archaea (AOA)/ammonia-oxidizing bacteria (AOB), and nitrite-oxidizing bacteria (NOB) were enumerated by mass spectrophotometer and q-PCR, respectively. The ranges of NNRs were 2.84±0.41 to 12.86±1.09 mg kg−1 h−1 and significantly higher (p

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.

In this study, we determined the effect of manure application on net nitrification rates (NNRs), heavy metal concentrations (HMCs), and abundance of ammonia-oxidizing archaea (AOA)/bacteria (AOB), and nitrite-oxidizing bacteria (NOB) in soil. HMCs were measured by atomic absorption spectroscopy. Abundance of AOA, AOB, and NOB was enumerated by q-PCR. NNRs ranged from 2.8 to 14.7 mg kg

This present work is designed to evaluate the anti-diabetic potential of 22 ginsenosides via the inhibition against rat lens aldose reductase (RLAR), and human recombinant aldose reductase (HRAR), using DL-glyceraldehyde as a substrate. Among the ginsenosides tested, ginsenoside Rh2, (20S) ginsenoside Rg3, (20R) ginsenoside Rg3, and ginsenoside Rh1 inhibited RLAR significantly, with IC50 values of 0.67, 1.25, 4.28, and 7.28 µM, respectively. Moreover, protopanaxadiol, protopanaxatriol, compound K, and ginsenoside Rh1 were potent inhibitors of HRAR, with IC50 values of 0.36, 1.43, 2.23, and 4.66 µM, respectively. The relationship of structure–activity exposed that the existence of hydroxyl groups, linkages, and their stereo-structure, as well as the sugar moieties of the ginsenoside skeleton, represented a significant role in the inhibition of HRAR and RLAR. Additional, various modes of ginsenoside inhibition and molecular docking simulation indicated negative binding energies. It was also indicated that it has a strong capacity and high affinity to bind the active sites of enzymes. Further, active ginsenosides suppressed sorbitol accumulation in rat lenses under high-glucose conditions, demonstrating their potential to prevent sorbitol accumulation ex vivo. The findings of the present study suggest the potential of ginsenoside derivatives for use in the development of therapeutic or preventive agents for diabetic complications.

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

Diabetes mellitus is one of the greatest global health issues and much research effort continues to be directed toward identifying novel therapeutic agents. Insulin resistance is a challenging integrally related topic and molecules capable of overcoming it are of considerable therapeutic interest in the context of type 2 diabetes mellitus (T2DM). Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling transduction and is regarded a novel therapeutic target in T2DM. Here, we investigated the inhibitory effect of α-methyl artoflavanocoumarin (MAFC), a natural flavanocoumarin isolated from Juniperus chinensis, on PTP1B in insulin-resistant HepG2 cells. MAFC was found to potently inhibit PTP1B with an IC50 of 25.27 ± 0.14 µM, and a kinetics study revealed MAFC is a mixed type PTP1B inhibitor with a K i value of 13.84 µM. Molecular docking simulations demonstrated MAFC can bind to catalytic and allosteric sites of PTP1B. Furthermore, MAFC significantly increased glucose uptake and decreased the expression of PTP1B in insulin-resistant HepG2 cells, down-regulated the phosphorylation of insulin receptor substrate (IRS)-1 (Ser307), and dose-dependently enhanced the protein levels of IRS-1, phosphorylated phosphoinositide 3-kinase (PI3K), Akt, and ERK1. These results suggest that MAFC from J. chinensis has therapeutic potential in T2DM by inhibiting PTP1B and activating insulin signaling pathways.

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.

Two new flavonoids, bismilachinone (11) and smilachinin (14), were isolated from the leaves of Smilax china L. together with 14 known compounds. Their structures were elucidated using spectroscopic methods. The PTP1B, α-glucosidase, and DPP-IV inhibitory activities of compounds 1-16 were evaluated at the molecular level. Among them, compounds 4, 7, and 10 showed moderate DPP-IV inhibitory activities with IC50 values of 20.81, 33.12, and 32.93 μM, respectively. Compounds 3, 4, 6, 11, 12, and 16 showed strong PTP1B inhibitory activities, with respective IC50 values of 7.62, 10.80, 0.92, 2.68, 9.77, and 24.17 μM compared with the IC50 value for the positive control (ursolic acid: IC50 = 1.21 μM). Compounds 2-7, 11, 12, 15, and 16 showed potent α-glucosidase inhibitory activities, with respective IC50 values of 8.70, 81.66, 35.11, 35.92, 7.99, 26.28, 11.28, 62.68, 44.32, and 70.12 μM. The positive control, acarbose, displayed an IC50 value of 175.84 μM. In the kinetic study for the PTP1B enzyme, compounds 6, 11, and 12 displayed competitive inhibition with Ki values of 3.20, 8.56, and 5.86 μM, respectively. Compounds 3, 4, and 16 showed noncompetitive inhibition with Ki values of 18.75, 5.95, and 22.86 μM, respectively. Molecular docking study for the competitive inhibitors (6, 11, and 12) radically corroborates the binding affinities and inhibition of PTP1B enzymes. These results indicated that the leaves of Smilax china L. may contain compounds with anti-diabetic activity.

Various types of chemical fertilizers are used in agricultural production in Bangladesh. However, plants and microbes' responses to the nitrification activity of chemical fertilizers are unknown. The goal of this study was to determine the responses of plants and nitrifying archaea/bacteria and comammox amoA Nitrospira inopinata bacteria to the net nitrification rates (NNRs) of chemical fertilizers in four vegetable soils. The abundance of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB), nitrite-oxidizing bacteria (NOB), and comammox amoA N. inopinata was determined by q-PCR. The NNRs ranged from 2.96 ± 0.39 to 10 ± 1.19 mg kg−1 h−1 and were significantly higher (p

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.

Phytochemical study on the corks of Euonymus alatus resulted in the isolation of a novel 3-hydroxycoumarinflavanol (23), along with ten triterpenoids (1-10), ten phenolic derivatives (11-20), and two flavonoid glycosides (21 and 22). Their structures were determined by extensive 1D and 2D-nuclear magnetic resonance spectroscopic and mass spectrometry data analysis. Furthermore, their inhibitory effects against the protein tyrosine phosphatases 1B (PTP1B) and α-glucosidase enzyme activity were evaluated. Compounds 6, 7, 9, 15, 19, and 23 were non-competitive inhibitors, exhibiting most potency with IC50 values ranging from 5.6 ± 0.9 to 18.4 ± 0.3 µm, against PTP1B. Compound 3 (competitive), compounds 5 and 15 (mixed-competitive) displayed potent inhibition with IC50 values of 15.1 ± 0.7, 23.6 ± 0.6 and 14.8 ± 0.9 µm, respectively. Moreover, compounds 15, 20, and 23 exhibited potent inhibition on α-glucosidase with IC50 values of 10.5 ± 0.8, 9.5 ± 0.6, and 9.1 ± 0.5 µm, respectively. Thus, these active ingredients may have value as new lead compounds for the development of new antidiabetic agents.

Three new serratene-type triterpenoids (1–3) and a new hydroxy unsaturated fatty acid (13) together with nine known compounds (4–12) were isolated from Lycopodiella cernua. The chemical structures were established using NMR, MS, and Mosher’s method. Compound 13 showed the most potent inhibitory activity against acetylcholinesterase (AChE) with an IC50 value of 0.22 μM. For butyrylcholinesterase (BChE) inhibitory activity, 5 showed the most potent activity with an IC50 value of 0.42 μM. Compound 2 showed the most potent activity with an IC50 of 0.23 μM for BACE-1 inhibitory activity. The kinetic activities were investigated to determine the type of enzyme inhibition involved. The types of AChE inhibition shown by compounds 4, 5, and 13 were mixed; BChE inhibition by 5 was competitive, while 2 and 6 showed mixed-types. In addition, molecular docking studies were performed to investigate the interaction of these compounds with the pocket sites of AChE. The docking results revealed that the tested inhibitors 3, 4, and 13 were stably present in several pocket domains of the AChE residue.

Inhibitors of protein tyrosine phosphatase 1B (PTP1B) are promising agents for the treatment of type 2 diabetes and obesity. The bioactivity-guided isolation led to the separation of two new compounds, (±)-tradescantin (13) and tradescantoside (16), along with fourteen known compounds (1-12, 14, and 15) from the aerial parts of Tradescantia spathacea Sw. (Commelinaceae). Their chemical structures were elucidated by spectroscopic methods as well as by comparing with those reported in the literature. The isolated compounds (1-16) were then examined for their inhibitory activity toward PTP1B. The results indicated that compounds 2, 6, 8, and 12 possessed potent inhibition with IC50 values of 7.82±0.79, 6.80±0.89, 4.55±0.92, and 6.38±0.14 μM, respectively. Kinetic study of compounds 2, 6, 8, 12, 13, and 16 was conducted and the structure-activity relationships of the isolated compounds (1-16) were also discussed herein. To the best of our knowledge, all the isolates were separated for the first time from this plant.

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.

Sargassum serratifolium C. Agardh (Phaeophyceae, Fucales) is a marine brown alga that belongs to the family Sargassaceae. It is widely distributed throughout coastal areas of Korea and Japan. S. serratifolium has been found to contain high concentrations of plastoquinones, which have strong anti-cancer, anti-inflammatory, antioxidant, and neuroprotective activity. This study aims to investigate the anti-diabetic activity of S. serratifolium and its major constituents through inhibition of protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, and ONOO−-mediated albumin nitration. S. serratifolium ethanolic extract and fractions exhibited broad PTP1B and α-glucosidase inhibitory activity (IC50, 1.83~7.04 and 3.16~24.16 µg/mL for PTP1B and α-glucosidase, respectively). In an attempt to identify bioactive compounds, three plastoquinones (sargahydroquinoic acid, sargachromenol and sargaquinoic acid) were isolated from the active n-hexane fraction of S. serratifolium. All three plastoquinones exhibited dose-dependent inhibitory activity against PTP1B in the IC50 range of 5.14–14.15 µM, while sargachromenol and sargaquinoic acid showed dose-dependent inhibitory activity against α-glucosidase (IC50 42.41 ± 3.09 and 96.17 ± 3.48 µM, respectively). In the kinetic study of PTP1B enzyme inhibition, sargahydroquinoic acid and sargaquinoic acid led to mixed-type inhibition, whereas sargachromenol displayed noncompetitive-type inhibition. Moreover, plastoquinones dose-dependently inhibited ONOO−-mediated albumin nitration. Docking simulations of these plastoquinones demonstrated negative binding energies and close proximity to residues in the binding pocket of PTP1B and α-glucosidase, indicating that these plastoquinones have high affinity and tight binding capacity towards the active site of the enzymes. These results demonstrate that S. serratifolium and its major plastoquinones may have the potential as functional food ingredients for the prevention and treatment of type 2 diabetes.

Coumarins, which have low toxicity, are present in some natural foods, and are used in various herbal remedies, have attracted interest in recent years because of their potential medicinal properties. In this study, we report the isolation of two natural coumarins, namely umbelliferone (1) and 6-formyl umbelliferone (2), from Angelica decursiva, and the synthesis of 8-formyl umbelliferone (3) from 1. We investigated the anti-Alzheimer disease (anti-AD) potential of these coumarins by assessing their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1). Among these coumarins, 2 exhibited poor inhibitory activity against AChE and BChE, and modest activity against BACE1. Structure–activity relationship analysis showed that 2 has an aldehyde group at the C-6 position, and exhibited strong anti-AD activity, whereas the presence or absence of an aldehyde group at the C-8 position reduced the anti-AD activity of 3 and 1, respectively. In addition, 2 exhibited concentration-dependent inhibition of peroxynitrite-mediated protein tyrosine nitration. A kinetic study revealed that 2 and 3 non-competitively inhibited BACE1. To confirm enzyme inhibition, we predicted the 3D structures of AChE and BACE1, and used AutoDock 4.2 to simulate binding of coumarins to these enzymes. The blind docking studies demonstrated that these molecules could interact with both the catalytic active sites and peripheral anionic sites of AChE and BACE1. Together, our results indicate that 2 has an interesting inhibitory activity in vitro, and can be used in further studies to develop therapeutic modalities for the treatment of AD.

Obesity is a complex, multifactorial, and chronic disease that increases the risk for type 2 diabetes, coronary heart disease and hypertension, and has become a major worldwide health problem. Developing novel anti-obesity drugs from natural products is a promising solution to the global health problem of obesity. While screening anti-obesity potentials of natural products, the methanol extract of the rhizome of Coptis chinensis (Coptidis Rhizoma) was found to significantly inhibit adipocyte differentiation and lipid contents in 3T3-L1 cells, as assessed by Oil-Red O staining. Five known alkaloids, berberine, epiberberine, coptisine, palmatine, and magnoflorine, were isolated from the n-BuOH fraction of the methanol extract of Coptidis Rhizoma. We determined the chemical structure of these alkaloids through comparisons of published nuclear magnetic resonance (NMR) spectral data. Furthermore, we screened these alkaloids for their ability to inhibit adipogenesis over a range of concentrations (12.5-50 μM). All five Coptidis Rhizoma alkaloids significantly inhibited lipid accumulation in 3T3-L1 cells without affecting cell viability in a concentration dependent manner. In addition, the five alkaloids significantly reduced the expression levels of several adipocyte marker genes including proliferator activated receptor-γ (PPAR-γ) and CCAAT/enhancer-binding protein-α (C/EBP-α). In the present study, we found that the isolated alkaloids inhibited adipogenesis in a dose-dependent manner in 3T3-L1 cells; this inhibition was attributed to their abilities to downregulate the protein levels of the adipocyte marker proteins PPAR-γ and C/EBP-α. Thus, these results suggest that Coptidis Rhizoma extract and its isolated alkaloids may be of therapeutic interest with respect to the treatment of obesity.

Umbelliferone has been demonstrated to have a wide range of biological activities. However, the effect of incorporating a formyl moiety in the umbelliferone scaffold has not been investigated. In this paper, we investigated the inhibitory activity of six coumarins, namely umbelliferone (1), 6-formyl umbelliferone (2), 8-formyl umbelliferone (3), umbelliferone-6-carboxylic acid (4), esculetin (5), and scopoletin (6) against human monoamine oxidases (hMAOs), self-amyloid β (Aβ) aggregation, and lipid peroxidation. We found that all compounds had high selectivity for hMAO-A in comparison with hMAO-B. Among the compounds, 2 exhibited the highest hMAO inhibitory activity with an IC50 value of 3.23 µM for hMAO-A and 15.31 µM for hMAO-B. Enzyme kinetic analysis showed that 2 and 3 were competitive hMAO inhibitors. In silico hydrated molecular docking simulations revealed that the coumarins interacted with substrate-binding site residues of the enzymes and the isoalloxazine ring of FAD. In addition, formyl coumarins 2 and 3 significantly inhibited lipid peroxidation in rat brain homogenates and self-Aβ25-35 aggregation compared to other derivatives. These represent the first experimental and modelling data for hMAO-A/B inhibition by umbelliferone derivatives. Together, the data suggest that introduction of a formyl moiety in the 7-hydroxycoumarin scaffold, especially at the 6 position, plays an important role in the inhibition of hMAOs, Aβ self-aggregation, and lipid peroxidation. Umbelliferone derivative 2 is a promising therapeutic lead scaffold for developing anti-neuropsychiatric disorder drugs that function via selective hMAO-A inhibition.

To investigate the effect of C-glycosylation at different positions of luteolin, the structure-activity relationships of luteolin and a pair of isomeric C-glycosylated derivatives orientin and isoorientin, were evaluated. We investigated the effects of C-glycosylation on the antioxidant, anti-Alzheimer's disease (AD), anti-diabetic and anti-inflammatory effects of luteolin and its two C-glycosides via in vitro assays of peroxynitrite (ONOO(-)), total reactive oxygen species (ROS), nitric oxide (NO), 1,1-diphenyl-2-picrylhydraxyl (DPPH), aldose reductase, protein tyrosine phosphatase 1B (PTP1B), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor cleaving enzyme 1 (BACE1), and cellular assays of NO production and inducible nitric oxide synthase (iNOS)/cyclooxygenase-2 expression in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Of the three compounds, isoorientin showed the highest scavenging activity against DPPH, NO, and ONOO(-), while luteolin was the most potent inhibitor of ROS generation. In addition, luteolin showed the most potent anti-AD activity as determined by its inhibition of AChE, BChE, and BACE1. With respect to anti-diabetic effects, luteolin exerted the strongest inhibitory activity against PTP1B and rat lens aldose reductase. Luteolin also inhibited NO production and iNOS protein expression in LPS-stimulated macrophages, while orientin and isoorientin were inactive at the same concentrations. The effects of C-glycosylation at different positions of luteolin may be closely linked to the intensity and modulation of antioxidant, anti-AD, anti-diabetic, and anti-inflammatory effects of luteolin and its C-glycosylated derivatives.

The dramatic increase in obesity-related diseases emphasizes the need to elucidate the cellular and molecular mechanisms underlying fat metabolism. Inhibition of adipocyte differentiation has been suggested to be an important strategy for preventing or treating obesity. In our previous study, we characterized an Ecklonia stolonifera extract and non-polar fractions thereof, including dichloromethane and ethyl acetate fractions. We showed that these fractions inhibited adipocyte differentiation and lipid formation/accumulation in 3T3-L1 preadipocytes, as assessed by Oil Red O staining. As part of our ongoing search for anti-obesity agents derived from E. stolonifera, in this work, we characterized five known phlorotannins, including phloroglucinol, eckol, dieckol, dioxinodehydroeckol, and phlorofucofuroeckol A, all of which were isolated from the active ethyl acetate fraction of E. stolonifera. We determined the chemical structures of these phlorotannins through comparisons of published nuclear magnetic resonance (NMR) spectral data. Furthermore, we screened these phlorotannins for their abilities to inhibit adipogenesis over a range of concentrations (12.5-100 μM). Of these five phlorotannins, phloroglucinol, eckol, and phlorofucofuroeckol A significantly concentration-dependently inhibited lipid accumulation in 3T3-L1 cells without affecting cell viability. In addition, the five isolated phlorotannins also significantly reduced the expression levels of several adipocyte marker genes, including proliferator activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), although they did so to different extents. These results suggest that the molecular weight of a phlorotannin is an important factor affecting its ability to inhibit adipocyte differentiation and modulate the expression levels of adipocyte marker genes.

A wide range of pharmacological properties of Sargassum spp. extracts and isolated components have been recognized. Although individual meroterpenoids of Sargassum species have been reported to possess strong activity against Alzheimer's disease (AD), the active compounds of Sargassum serratifolium have not been fully explored. Therefore, we evaluated the anti-AD activity of S. serratifolium extract through enzyme inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1). Three meroterpenoids (sargahydroquinoic acid (1), sargachromenol (2) and sargaquinoic acid (3)) were isolated from S. serratifolium. These compounds showed moderate AChE inhibitory activity, but exhibited potent inhibitory activity against BChE and BACE1 (15.1, 9.4, and 10.4µM for BChE; 4.3, 6.9, and 12.5µM for BACE1, respectively). Kinetic study and molecular docking simulation of these compounds demonstrated that 1 and 3 interacted with both catalytic aspartyl residues and allosteric sites of BACE1, whereas 2 interacted with the allosteric site of BACE1. The results of the present study demonstrate that meroterpenoids from S. serratifolium might be beneficial in the treatment of AD.

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.

Ethnopharmacological relevance Semen Cassiae has been traditionally used as an herbal remedy for liver, eye, and acute inflammatory diseases. Recent pharmacological reports have indicated that Cassiae semen has neuroprotective effects, attributable to its anti-inflammatory actions, in ischemic stroke and Alzheimer's disease (AD) models. Aim of the study The basic goal of this study was to evaluate the anti-AD activities of C. obtusifolia and its major constituents. Previously, the extract of C. obtusifolia seeds, was reported to have memory enhancing properties and anti-AD activity to ameliorate amyloid β-induced synaptic dysfunction. However, the responsible components of C. obtusifolia seeds in an AD are currently still unknown. In this study, we investigated the inhibitory effects of C. obtusifolia and its constituents against acetylcholinesterase (AChE), butyrylcholinesterase ( BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) enzyme activity. Materials and methods In vitro cholinesterase enzyme assays by using AChE, BChE, and BACE1 were performed. We also scrutinized the potentials of Cassiae semen active component as BACE1 inhibitors via enzyme kinetics and molecular docking simulation. Results In vitro enzyme assays demonstrated that C. obtusifolia and its major constituents have promising inhibitory potential against AChE, BChE, and BACE1. All Cassiae semen constituents exhibited potent inhibitory activities against AChE and BACE1 with IC 50 values of 6.29–109 µg/mL and 0.94–190 µg/mL, whereas alaternin, questin, and toralactone gentiobioside exhibited significant inhibitory activities against BChE with IC 50 values of 113.10–137.74 µg/mL. Kinetic study revealed that alaternin noncompetitively inhibited, whereas cassiaside and emodin showed mixed-type inhibition against BACE1. Furthermore, molecular docking simulation results demonstrated that hydroxyl group of alaternin and emodin tightly interacted with the active site residues of BACE1 and their relevant binding energies (−6.62 and −6.89 kcal/mol), indicating a higher affinity and tighter binding capacity of these compounds for the active site of BACE1. Conclusion The findings of the present study suggest the potential of C. obtusifolia and its major constituents for use in the development of therapeutic or preventive agents for AD, especially through inhibition of AChE, BChE and BACE1 activities.