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Concept: Pancreatic lipase

170

Pancreatic triacylglycerol lipase (PNLIP) are primary lipases that are critical for triacylglyceride digestion in human. Since reduced metabolism of triacylglyceride might be a plausible concept for weight loss, we screened for potential PNLIP inhibitors from traditional Chinese medicine (TCM) with the aim to identify weight loss candidate compounds. TCM candidates Aurantiamide, Cnidiadin, and 2-hexadecenoic acid exhibited higher Dock Scores than the commercial drug Orlistat, and were also predicted to have inhibitory characteristics against PNLIP using constructed MLR (R(2) = 0.8664) and SVM (R(2) = 0.9030) models. Molecular dynamics indicated that the TCM-PNLIP complexes formed were stable. We identified that the PNLIP binding site has several residues that can serve as anchors, and a hydrophobic corridor that provides additional stability to the complex. Aurantiamide, Cnidiadin, and 2-hexadecenoic acid all have features that correspond to these binding site features, indicating their potential as candidates for PNLIP inhibitors. The information presented in this study may provide helpful insights to designing novel weight-control drugs.

Concepts: Protein, Health, Enzyme, Triglyceride, Lipid, Lipase, Traditional Chinese characters, Pancreatic lipase

163

Activity-guided isolation of a methanolic extract of Galla Rhois using pancreatic lipase and 3T3-L1 adipocytes led to the isolation of seven phenolic compounds: protoaphin-fb (1), 2-O-digalloyl-1,3,4,6-tetra-O-galloyl-b-D-glucose (2), 1,2,3,4,6-penta-O-galloyl-b-D-glucose (3), 1,2,4,6-tetra-O-galloyl-b-D-glucose (4), 3-hydroxy-5-methoxy-phenol 1-O-b-D-glucoside (5), methylgallate (6), and gallic acid (7). Their structures were established on the basis of NMR and MS spectroscopic data interpretation. All isolates were evaluated for their inhibitory effects on pancreatic lipase, and compounds 1-5 exhibited potent inhibitory effects on this enzyme, with IC50 values ranging from 30.6 ± 2.4 to 3.5 ± 0.5 mM. In addition, the highly galloylated compound 2 was also found to induce potent inhibition of adipocyte differentiation in 3T3-L1 cells.

Concepts: Enzyme, Pancreas, Cytoplasm, Fat, Adipocyte, Lipase, Gallic acid, Pancreatic lipase

28

Pancreatic lipase is a potential therapeutic target for the treatment of diet-induced obesity in humans. In an ongoing search for new pancreatic lipase inhibitors from natural sources, a methanolic extract of marine brown algae, Eisenia bicyclis, showed a significant inhibitory effect against pancreatic lipase. Bioassay-guided isolation of this methanolic extract using a pancreatic lipase inhibitory assay led to the isolation and identification of six known phlorotannins: eckol (1), fucofuroeckol A (2), 7-phloroeckol (3), dioxindehydroeckol (4), phlorofucofuroeckol A (5), and dieckol (6). The structures were established on the basis of nuclear magnetic resonance and mass spectrometry spectroscopic data interpretation. Among the isolated phloroglucinol polymers, compounds 2 and 3 showed potent inhibitory effects on pancreatic lipase with IC(50) values ranging from 37.2 ± 2.3 to 12.7 ± 1.0 μM, respectively. Copyright © 2012 John Wiley & Sons, Ltd.

Concepts: Spectroscopy, Effect, Nuclear magnetic resonance, John Wiley & Sons, Isotope, Lipase, Astronomical spectroscopy, Pancreatic lipase

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Cassia auriculata (Caesalpiniaceae) is a common Asian beverage and medicinal plant widely used in tradition medicine for diabetes, hyperlipidemia and various other disease conditions. Previous studies on crude extracts of C. auriculata have documented the scientific basis for some of its traditional medicinal uses. The present study investigates the antilipase activity of the ethanol extract of the aerial parts along with the previously isolated compounds (kaempferol-3-O-rutinoside, rutin, kaempferol, quercetin and luteolin). The crude extract displayed inhibitory activity against pancreatic lipase with IC(50) of 6.0 ± 1.0 µg/mL. The most active antilipase compound was kaempferol-3-O-rutinoside with IC(50) value (2.9 ± 0.50 μM) only about twice weaker than the standard antilipase drug, orlistat (IC(50)  = 1.45 ± 0.26 μM). Luteolin, quercetin and rutin were found to be weak pancreatic lipase inhibitors (IC(50) over 100 μM), whereas kaempferol showed no activity up to 250 μM. The antihyperlipidemic effect of C. auriculata could be attributed to direct lipase inhibitory effect of the plant constituents. Copyright © 2012 John Wiley & Sons, Ltd.

Concepts: Pharmacology, Neurology, In vitro, Quercetin, Flavonoid, Flavonols, Tincture, Pancreatic lipase

28

Abstract The present research work explores an innovative technological solution to constraints in efficient oral delivery of poorly water-soluble anti-obesity drug orlistat. Nanoemulsion of orlistat and its subsequent transformation into multi-unit pellet system (MUPS) for improved oral delivery was developed. Orlistat nanoemulsion was developed with capryol PGMC as an oil phase and cremophor RH40 as an emulsifier using high-pressure homogenization. Influence of critical processing parameters on globule size distribution, polydispersity index and physical stability of nanoemulsion was evaluated. The optimized nanoemulsion was transformed into MUPS using an extrusion spheronization technique. Optimized formulation was characterized at nanoemulsion as well as MUPS stage. DLS and nanoparticle tracking analysis studies of orlistat nanoemulsion exhibited unimodal size distribution with polydispersity value <0.1. Confocal laser scanning microscopy (CLSM) studies confirmed the presence of uniform spherical nanosized oil droplets of nanoemulsified orlistat. DSC and PXRD studies of MUPS confirmed amorphization of embedded nanoemulsified orlistat. In-vitro dissolution studies in surfactant-reduced media demonstrated remarkable improvement in dissolution compared to pure orlistat and marketed formulation (Xenical Capsules 120 mg, Hoffman-La Roche, Basle, Switzerland). Comparative in-vitro bovine porcine pancreatic lipase inhibition studies of pure orlistat, marketed product and developed MUPS showed 13.57- and 2.41-fold higher lipase inhibition with developed MUPS compared to pure orlistat and marketed products, respectively.

Concepts: Obesity, Liquid, Phase, Emulsion, Hoffmann–La Roche, Pancreatic lipase, Orlistat, Basel

28

Context: During the last few decades, the prevalence of obesity in the western world has dramatically increased with epidemic proportions. Hand in hand with this statistic, the incidences of obesity-linked diseases such as diabetes are increasing with pandemic rate. The search for novel drugs and nutritional intervention approaches for obesity is now of significant importance. Objective: The anti-obesity potential of eriodictyol (ERD) and its close structural analogue, sigmoidin A (SGN), were evaluated. SGN was isolated from Erythrina abyssinica Lam. ex DC. (Fabaceae). Materials and methods: Concentrations between 300 and 0.1 µM of test samples and reference drugs made in three-fold dilutions were tested for enzyme inhibitory effects. The major obesity target, pancreatic lipase, was used to test the anti-obesity potential while the selective effects of the compounds were determined through assessments of effects on α-glucosidase. Results: The inhibitory effect of SGN on pancreatic lipase (IC(50), 4.5 ± 0.87 µM) was 30-times greater than that of ERD (IC(50), 134 ± 19.39 µM) while their effect on α-glucosidase enzyme was comparable (IC(50) value of 62.5 ± 9.47 and 57.5 ± 13.15 µM). The anti-obesity drug, orlistat, inhibited pancreatic lipase with an IC(50) value of 0.3 ± 0.04 µM, while the anti-diabetic drug, acarbose, inhibited α-glucosidase with an IC(50) value of 190.6 ± 16.05 µM. Discussion: Although less active than the standard anti-obesity drug, orlistat, the observed activity indicated that prenylation of the flavonoid skeleton potently enhances anti-lipase activity. Conclusion: Such groups of flavonoids need to be further investigated for their therapeutic and nutritional benefit in combating obesity problems.

Concepts: Nutrition, Enzyme, Diabetes mellitus, Obesity, Anti-diabetic drug, Flavonoid, Lipase, Pancreatic lipase

27

Abstract Bioassay-guided isolation of an aqueous methanolic extract of Vitis vinifera using pancreatic lipase inhibitory activity led to isolation of seven stilbenoids, wilsonol C (1), heyneanol A (2), ampelopsin A (3), pallidol A (4), cis-piceid (5), trans-piceid (6) and trans-resveratrol (7). The structures were established on the basis of NMR and MS spectroscopic data interpretation. All isolates were evaluated for their inhibitory effects on pancreatic lipase, and stilbenoid 1 exhibited potent inhibitory effect on pancreatic lipase with IC50 values of 6.7 ± 0.7 µM.

Concepts: Effect, Resveratrol, The Roots, Pancreatic lipase, Stilbenoid, Piceid, Stilbenoids

27

Abstract Twenty-three phenolic compounds were isolated from Dioscorea opposita by bioactivity-guided method and their inhibitory effect against pancreatic lipase was evaluated. A total of 15 isolates reduced lipase activity at IC(50) values of less than 50 µM and 3,3',5-trihydroxy-2'-methoxybibenzyl showed the highest inhibition with an IC(50) value of 8.8 µM. This study is a first to reveal the pancreatic lipase inhibitory activity by both D. opposita and its isolated compounds.

Concepts: Enzyme, Tropical agriculture, Value, Lipase, Pancreatic lipase, Yam, Dioscorea, Dioscorea opposita

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  The pancreatic lipase inhibitory (PLI) activity of leaf extracts (aqueous, 60 and 99.8 (v/v)% EtOH) of Salacia reticulata Wight, referred to “Kothala himbutu” (KT) in Singhalese, was compared with that of KT stem extracts. Evaporated residue contents and PLI activity of each leaf extract were higher than those of each stem extract, respectively. Among the extracts, the 60% EtOH leaf extract showed the most potent PLI activity. The 60% EtOH leaf extract was separated by a Diaion HP20/water-acetone system and furthermore the most potent fraction by a Sephadex LH20/water-ethanol-acetone system. The 60% acetone fraction from the LH20/water-ethanol-acetone system had the most potent PLI activity (IC(50) value; 15 ppm). The active compounds in the active fraction of KT leaves were most likely a polyphenol, as assessed by the Folin-Ciocalteu method. Based on these spectroscopic and chemical examinations, the active fraction was shown to be proanthocyanidin oligomers composed of epigallocatechin, epicathechin, and epiafzelechin as main constituents. The degree of polymerization was estimated to be about 5 from the ratio of the peak area of the thio ethers/flavan-3-ols at 230 nm. This was consistent with the results of matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) MS, which showed the [M+Na](+) peaks corresponding to trimers-octamers. From the average molecular weight and IC(50) value of the active compounds estimated on these results, the active compounds from the KT leaf extract were one of the stronger effective lipid-lowering therapeutic agent, of which PLI activity (μM/L) was almost the same as epigallocatechin gallate. Practical Application:  Proanthocyanidin oligomers isolated from Salacia reticulata, referred to “Kothala himbutu” (KT) in Singhalese, leaves was proved to potently inhibit pancreatic lipase activity. After confirming in vivo examination, healthy foods, teas, and liquors containing the extracts of KT leaves are expected to be on market.

Concepts: Mass spectrometry, Ratio, Catechin, Lipase, Matrix-assisted laser desorption/ionization, Epigallocatechin gallate, Leaf vegetable, Pancreatic lipase

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Abstract Pancreatic lipase (PL) is considered as one of the safest target for diet-induced anti-obesity drug development. Orlistat is the only PL inhibitor approved for anti-obesity treatment till date. In the process of exploration of new PL inhibitors, we have screened culture filtrates of 70 endophytic fungi of medicinal plants using qualitative as well as quantitative in-vitro PL assays. The qualitative assays indicated potential PL inhibition in only three isolates, namely #57 TBBALM, #33 TBBALM and #1 CSSTOT. Only ethyl acetate extracts of the culture filtrates of these isolates exhibited the PL inhibition. #57 TBBLAM ethyl acetate extract of culture filtrate exhibited potential PL inhibition with an IC50 of 3.69 µg/ml which was comparable to the positive control, i.e. Orlistat exhibiting IC50 value of 2.73 µg/ml. Further molecular phylogenetic tools and morphological studies were used to identify the isolate #57 TBBALM as Penicillium species.

Concepts: Pharmacology, Plant, Fungus, Enzyme inhibitor, Inhibitor, Xanthine oxidase inhibitor, Penicillium, Pancreatic lipase