This study synthesized a series of hydroxyl-functionalized 2-arylbenzobfurans based on the structure of tournefolic acid A and evaluated them for antioxidant and α-glucosidase inhibitory activities. ...Compounds 5a, 5e, and 5n showed remarkable inhibition of α-glucosidase (IC50 values of 1.9–3.0 μM), and they appear to be even more potent than quercetin. A kinetic binding study indicated that compounds 5a and 5n used a mechanism of mixed-competition to inhibit α-glucosidase. This study also revealed that compounds 5a and 5n bind to either the α-glucosidase or α-glucosidase-4-NPGP complex. Using the crystal structure of the Saccharomyces cerevisiae α-glucosidase, the molecular docking study has predicted the binding of compounds 5a and 5n to the active site of α-glucosidase through both hydrophobic and hydrogen interactions. A DPPH radical scavenging assay further showed that most hydroxyl-functionalized 2-arylbenzobfurans possess antioxidant activity. The exception was compound 5p, which has only one hydroxyl group on the 2-phenyl ring of 2-arylbenzobfuran. Our results indicate that hydroxyl-functionalized 2-arylbenzobfurans possess both antidiabetic as well as antioxidant properties.
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•A series of new hydroxyl-functionalized 2-arylbenzobfurans has synthesized.•Antioxidant and α-glucosidase inhibition activities.•Inhibition kinetics of new compounds were determined.•Molecular docking study predicted the binding of compounds to α-glucosidase.
Introduction: Pompe disease is a rare, autosomal recessive disorder caused by deficiency of the glycogen‐degrading lysosomal enzyme acid alpha‐glucosidase. Late‐onset Pompe disease is a multisystem ...condition, with a heterogeneous clinical presentation that mimics other neuromuscular disorders. Methods: Objective is to propose consensus‐based treatment and management recommendations for late‐onset Pompe disease. Methods: A systematic review of the literature by a panel of specialists with expertise in Pompe disease was undertaken. Conclusions: A multidisciplinary team should be involved to properly treat the pulmonary, neuromuscular, orthopedic, and gastrointestinal elements of late‐onset Pompe disease. Presymptomatic patients with subtle objective signs of Pompe disease (and patients symptomatic at diagnosis) should begin treatment with enzyme replacement therapy (ERT) immediately; presymptomatic patients without symptoms or signs should be observed without use of ERT. After 1 year of ERT, patients' condition should be reevaluated to determine whether ERT should be continued. Muscle Nerve, 2012
Colored grains including red, purple, and black rice, purple corn, black barley, and black soybean contain anthocyanins. The present study was designed to (i) identify and quantify the individual ...anthocyanins and measure the total phenolic content (TPC), (ii) evaluate the antioxidant and α-glucosidase inhibitory activity, and (iii) correlate the TPC with total antioxidant activity and α-glucosidase inhibitory potency in these colored grains. The TPC was measured using a Folin−Ciocalteu assay, while the total antioxidant activity was determined by a method based on the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity. Among all of the studied colored grains, black rice possessed the highest TPC, which was 86 times greater than that of red rice. In addition, black rice had the highest total anthocyanin contents and α-glucosidase inhibitory activity. A significant positive correlation of the antioxidant activity and α-glucosidase inhibitory activity with total anthocyanin content and TPC was observed in this study. It is concluded that black rice possesses the highest antioxidant activity and α-glucosidase inhibitory among all of the colored grains tested and can be further explored as a functional food.
The Lantern Project is an ongoing complimentary diagnostic program for patients in the United States sponsored by Sanofi and implemented by PerkinElmer Genomics. It combines specific enzymatic, ...biomarker, and genetic testing to facilitate rapid, accurate laboratory diagnosis of Pompe disease and several other lysosomal storage diseases, and a multigene next-generation sequencing panel including Pompe disease, LGMD, and other neuromuscular disorders. This article reports data for Pompe disease collected from October 2018 through December 2021, including acid α-glucosidase (GAA) enzyme assay and GAA sequencing (standard or expedited for positive newborn screening NBS to rule out infantile-onset Pompe disease IOPD) and the Focused Neuromuscular Panel, which includes GAA. One hundred forty patients (12 received only GAA enzyme testing, 128 had GAA sequencing alone or in addition to enzyme assay) have been confirmed with Pompe disease in this project. Eight of the 140 had a variant of unknown significance, but GAA activity ≤2.10 μmol/L/h, thus were confirmed with Pompe disease. Three diagnosed patients 0–2 years old had cross-reactive immunologic material (CRIM)-negative GAA variants and thus IOPD. One additional infant with presumptive IOPD had a homozygous frameshift c.1846del, likely CRIM-negative; symptoms were not provided. Among the 128 patients with molecular results, the c.-32-13T>G splice variant was homozygous in 11, compound-heterozygous in 98, and absent in 19. Proximal muscle weakness (58 patients) was the most common sign reported at testing; elevated creatine kinase (29 patients) was the most common laboratory result. The most common symptom categories were muscular (73 patients), musculoskeletal (13 patients), and respiratory (23 patients). Clinical information was not available for 42 samples, and 17 infants had only “abnormal NBS” or “low GAA” reported. Cardiac symptoms in 7 included potentially age-related conditions in five c.-32-13T>G-compound-heterozygous adults (myocardial infarction, heart murmur/palpitations, congestive heart failure: 1 each; 2 with atrial fibrillation) and hypertrophic cardiomyopathy in 2 children (1 and 2 years old) with presumptive IOPD. One novel GAA variant was observed in a patient with enzyme activity 0.31 μmol/L/h: c.1853_1854ins49, a frameshift pathogenic variant. The Lantern Project demonstrates the combinatorial utility of enzyme assay, targeted single-gene testing, and a focused neuromuscular next-generation sequencing panel in diagnosing Pompe disease.
•Lantern Project provides enzyme, molecular, and NGS panel options for Pompe disease.•In 2018–21, 6473 panel tests and 1339 targeted tests have been conducted.•140 patients received a laboratory diagnosis of Pompe disease.•Enzyme activity informed several VUS alleles; one novel frameshift allele reported.•One patient each had an DMD or ANO5 variant along with GAA pathogenic/VUS alleles.
For digestion of starch in humans, α-amylase first hydrolyzes starch molecules to produce α-limit dextrins, followed by complete hydrolysis to glucose by the mucosal α-glucosidases in the small ...intestine. It is known that α-1,6 linkages in starch are hydrolyzed at a lower rate than are α-1,4 linkages. Here, to create designed slowly digestible carbohydrates, the structure of waxy corn starch (WCS) was modified using a known branching enzyme alone (BE) and an in combination with β-amylase (BA) to increase further the α-1,6 branching ratio. The digestibility of the enzymatically synthesized products was investigated using α-amylase and four recombinant mammalian mucosal α-glucosidases. Enzyme-modified products (BE-WCS and BEBA-WCS) had increased percentage of α-1,6 linkages (WCS: 5.3%, BE-WCS: 7.1%, and BEBA-WCS: 12.9%), decreased weight-average molecular weight (WCS: 1.73×10 8 Da, BE-WCS: 2.76×10 5 Da, and BEBA-WCS 1.62×10 5 Da), and changes in linear chain distributions (WCS: 21.6, BE-WCS: 16.9, BEBA-WCS: 12.2 DP w). Hydrolysis by human pancreatic α-amylase resulted in an increase in the amount of branched α-limit dextrin from 26.8% (WCS) to 56.8% (BEBA-WCS). The α-amylolyzed samples were hydrolyzed by the individual α-glucosidases (100 U) and glucogenesis decreased with all as the branching ratio increased. This is the first report showing that hydrolysis rate of the mammalian mucosal α-glucosidases is limited by the amount of branched α-limit dextrin. When enzyme-treated materials were gavaged to rats, the level of postprandial blood glucose at 60 min from BEBA-WCS was significantly higher than for WCS or BE-WCS. Thus, highly branched glucan structures modified by BE and BA had a comparably slow digesting property both in vitro and in vivo . Such highly branched α-glucans show promise as a food ingredient to control postprandial glucose levels and to attain extended glucose release.
The bromophenols, 2,4,6-tribromophenol and 2,4-dibromophenol, purified from
Grateloupia elliptica effectively inhibited
Saccharomyces cerevisiae and
Bacillus
stearothermophilus α-glucosidases, and ...moderately inhibited rat-intestinal sucrase and maltase as well. Both bromophenols exhibited mixed inhibition against
S. cerevisiae α-glucosidase.
Diabetes mellitus is a most serious and chronic disease whose incidence rates are increasing with incidences of obesity and aging of the general population over the world. One therapeutic approach for decreasing postprandial hyperglycemia is to retard absorption of glucose by inhibition of α-glucosidase. Two bromophenols, 2,4,6-tribromophenol and 2,4-dibromophenol, were purified from the red alga
Grateloupia elliptica. IC
50 values of 2,4,6-tribromophenol and 2,4-dibromophenol were 60.3 and 110.4
μM against
Saccharomyces cerevisiae α-glucosidase, and 130.3 and 230.3
μM against
Bacillus stearothermophilus α-glucosidase, respectively. In addition, both mildly inhibited rat-intestinal sucrase (IC
50 of 4.2 and 3.6
mM) and rat-intestinal maltase (IC
50 of 5.0 and 4.8
mM). Therefore, bromophenols of
G. elliptica have potential as natural nutraceuticals to prevent diabetes mellitus because of their high α-glucosidase inhibitory activity.
Glycogenosis type II (GSDII) is a rare autosomal disorder that is caused by the deficiency of alpha-glucosidase, a lysosomal enzyme that hydrolyzes glycogen to glucose. Autophagy dysregulation plays ...a critical role. Importantly, since 2006, both patients with infantile (classic Pompe disease) and adult GSDII (late-onset Pompe disease or LOPD) have been treated with enzyme replacement therapy (ERT). To support this use, several double-blind and observational studies including large cohorts of GSDII patients have been undertaken and have shown ERT to be effective in modifying the natural course of disease. Indeed, most LOPD cases improve in the first 20 months of treatment in a six-minute walk test (6MWT), while those who are untreated do not; instead, their response declines over time.
The author reviews avalglucosidase alpha, a therapy approved by both the FDA and European regulatory agencies. Herein, the author considers the pathophysiological approaches such as the role of enzyme entry, autophagy, and the response to ERT treatment of motor and respiratory components.
There has been a notable drive toward the research of various aspects of this disease regarding the role of new enzyme penetration and immune adverse events. Consequently, avalglucosidase alpha might be a further step forward.
Garcinia livingstonei is a traditional herbal medicine that showed beneficial health effects and bioactivities. Four compounds have been isolated from the plant leaves and were elucidated as lupeol, ...betulin, podocarpusflavone A, and amentoflavone. The inhibitory activities of G. livingstonei extract and isolated metabolites against fatty acid synthase (FAS), α-glucosidase, and xanthine oxidase (XO) were investigated in vitro. The affinity of the compounds toward the studied enzymes was investigated in silico. The plant extract inhibited FAS, α-glucosidase, and XO with IC50 values of 26.34, 67.88, and 33.05 µg/mL, respectively. Among the isolated metabolites, betulin exhibited the most inhibitory activity against α-glucosidase and XO with IC50 values of 38.96 and 30.94 µg/mL, respectively. Podocarpusflavone A and betulin were the most potent inhibitors of FAS with IC50 values of 24.08 and 27.96 µg/mL, respectively. Computational studies corroborated these results highlighting the interactions between metabolites and the enzymes. In conclusion, G. livingstonei and its constituents possess the potential to modulate enzymes involved in metabolism and oxidative stress.
In this study, we investigated the effects of microencapsulation conditions on product quality of pomegranate peel phenolics. Our results indicate an optimum air inlet temperature of 160 °C and 1/1 ...(w/w) or 1/3 (w/w) for phenolics/maltodextrin ratio. No differences were observed amongst the maltodextrins used for coatings. There were also no statistically significant differences in phenolic content of microcapsules for the storage periods of 90 days at 4 °C (p > 0.05). We also evaluated the resultant microencapsulated phenolics for enrichment of the functional properties of regular ice cream used as model food in our studies. Addition of pomegranate peel phenolics at 0.5 and 1.0% (w/w) showed significant improvement of the antioxidant and α-glucosidase inhibitory activities of the enriched ice creams compared with control sample. Antioxidant activity as EC50 and α-glucosidase inhibitory as IC50 of 1.0% phenolic enriched ice creams were 133.3 and 22.9 μg/mL, respectively. More than 75% of the panellists accepted the phenolic enriched ice creams in sensory evaluation, which lends supports to such products for commercial introduction to the general public with the potential as functional foods.
•Phenolics of pomegranate peels were microencapsulated.•Microencapsulation process improved storage stability of phenolics.•Phenolic enriched ice creams showed high acceptance by consumers.•Incorporation of pomegranate phenolics improved in vitro bioactivity of ice cream.
α-Glucosidase (AGS) inhibitors have been regarded as an ideal target for the management of type 2 diabetes mellitus (T2DM) since they can maintain an acceptable blood glucose level by delaying the ...digestion of carbohydrates and diminishing the absorption of monosaccharides. In the process of our endeavor in mining AGS inhibitors from natural sources, the culture broth of two mangrove-derived actinomycetes
sp. WHUA03267 and
sp. WHUA03072 exhibited an apparent inhibitory activity against AGS. A subsequent chemical investigation into the two extracts furnished 28 secondary metabolites that were identified by spectroscopic methods as two previously undescribed linear polyketides
-
, four benzenoid ansamycins
-
, fourteen cyclodipeptides
-
, one prenylated indole derivative
, two fusicoccane-type diterpenoids
-
, two hydroxamate siderophore
-
, and five others
-
. Among all of the isolates,
and
were obtained from actinomycetes for the first time, while
-
had never been reported to occur in a marine-derived microorganism previously. In the in vitro AGS inhibitory assay, compounds
,
,
,
,
,
, and
exhibited potent to moderate activity with IC
values ranging from 35.76 ± 0.40 to 164.5 ± 15.5 μM, as compared with acarbose (IC
= 422.3 ± 8.4 μM). The AGS inhibitory activity of
,
,
,
, and
was reported for the first time. In particular, autolytimycin (
) represented the first ansamycin derivative reported to possess the AGS inhibitory activity. Kinetics analysis and molecular docking were performed to determine the inhibition types and binding modes of these inhibitors, respectively. In the MTT assay,
,
,
,
,
,
, and
exhibited no apparent cytotoxicity to the human normal hepatocyte (LO2) cells, suggesting satisfactory safety of these AGS inhibitors.
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