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Biomolecules Sep 2020Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to... (Review)
Review
Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to severe cardiac and skeletal muscle myopathy due to progressive accumulation of glycogen. The discovery that acid alpha-glucosidase resides in the lysosome gave rise to the concept of lysosomal storage diseases, and Pompe disease became the first among many monogenic diseases caused by loss of lysosomal enzyme activities. The only disease-specific treatment available for Pompe disease patients is enzyme replacement therapy (ERT) which aims to halt the natural course of the illness. Both the success and limitations of ERT provided novel insights in the pathophysiology of the disease and motivated the scientific community to develop the next generation of therapies that have already progressed to the clinic.
Topics: Autophagy; Enzyme Replacement Therapy; Genetic Therapy; Glycogen; Glycogen Storage Disease Type II; Humans; Lysosomal Storage Diseases; Lysosomes; Muscle, Skeletal; alpha-Glucosidases
PubMed: 32962155
DOI: 10.3390/biom10091339 -
Journal of Mother and Child Oct 2020Pompe disease is an autosomal recessive lysosomal glycogen storage disorder caused by the deficiency of acid alpha-glucosidase and subsequent progressive glycogen... (Review)
Review
Pompe disease is an autosomal recessive lysosomal glycogen storage disorder caused by the deficiency of acid alpha-glucosidase and subsequent progressive glycogen accumulation due to mutations in the GAA gene. Pompe disease manifests with a broad spectrum of disease severity, ranging from severe infantile-onset diseases such as hypotonia and hypertrophic cardiomyopathy to late-onset diseases such as myopathy and respiratory compromise. The diagnosis requires demonstration of deficiency of the lysosomal acid alpha-glucosidase enzyme, which can be assayed in dried blood spot or liquid blood samples, together with supportive biomarker tests, and confirmed with molecular genetic analysis. Targeted screening of at-risk populations and universal newborn screening can result in earlier diagnosis and enable earlier treatment initiation, which result in the potential improvement of clinical outcomes. Disease-modifying treatment with enzyme replacement therapy has partially altered the natural history of the disease, but more efficacious novel therapies are under evaluation including second-generation enzyme replacement therapies, molecular chaperones and gene therapy approaches. Long-term survivors with Pompe disease are now manifesting novel aspects of the disease including widespread vascular disease, smooth muscle and central nervous system involvement, and these emerging phenotypes will require additional specific therapeutic approaches.
Topics: Enzyme Replacement Therapy; Genetic Therapy; Glycogen Storage Disease Type II; Humans; alpha-Glucosidases
PubMed: 33554498
DOI: 10.34763/jmotherandchild.20202402si.2001.000002 -
Biomolecules Dec 2021Type-II diabetes mellitus (T2DM) results from a combination of genetic and lifestyle factors, and the prevalence of T2DM is increasing worldwide. Clinically, both... (Review)
Review
Type-II diabetes mellitus (T2DM) results from a combination of genetic and lifestyle factors, and the prevalence of T2DM is increasing worldwide. Clinically, both α-glucosidase and α-amylase enzymes inhibitors can suppress peaks of postprandial glucose with surplus adverse effects, leading to efforts devoted to urgently seeking new anti-diabetes drugs from natural sources for delayed starch digestion. This review attempts to explore 10 families e.g., , , , , , , , and as medicinal plants, and folk and herb medicines for lowering blood glucose level, or alternative anti-diabetic natural products. Many natural products have been studied in silico, in vitro, and in vivo assays to restrain hyperglycemia. In addition, natural products, and particularly polyphenols, possess diverse structures for exploring them as inhibitors of α-glucosidase and α-amylase. Interestingly, an in silico discovery approach using natural compounds via virtual screening could directly target α-glucosidase and α-amylase enzymes through molecular modeling. , , Studio, and have been used to discover new candidates as inhibitors or activators. While docking score, binding energy (Kcal/mol), the number of hydrogen bonds, or interactions with critical amino acid residues have been taken into concerning the reliability of software for validation of enzymatic analysis, in vitro cell assay and in vivo animal tests are required to obtain leads, hits, and candidates in drug discovery and development.
Topics: Computer Simulation; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Gene Expression Regulation, Enzymologic; Glycoside Hydrolase Inhibitors; Humans; Hydrogen Bonding; Hypoglycemic Agents; Molecular Docking Simulation; Plants, Medicinal; Polyphenols; alpha-Amylases; alpha-Glucosidases
PubMed: 34944521
DOI: 10.3390/biom11121877 -
Biomolecules Aug 2023Pompe disease (PD) is an autosomal recessive disorder caused by mutations in the gene that lead to a deficiency in the acid alpha-glucosidase enzyme. Two clinical... (Review)
Review
Pompe disease (PD) is an autosomal recessive disorder caused by mutations in the gene that lead to a deficiency in the acid alpha-glucosidase enzyme. Two clinical presentations are usually considered, named infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD), which differ in age of onset, organ involvement, and severity of disease. Assessment of acid alpha-glucosidase activity on a dried blood spot is the first-line screening test, which needs to be confirmed by genetic analysis in case of suspected deficiency. LOPD is a multi-system disease, thus requiring a multidisciplinary approach for efficacious management. Enzyme replacement therapy (ERT), which was introduced over 15 years ago, changes the natural progression of the disease. However, it has limitations, including a reduction in efficacy over time and heterogeneous therapeutic responses among patients. Novel therapeutic approaches, such as gene therapy, are currently under study. We provide a comprehensive review of diagnostic advances in LOPD and a critical discussion about the advantages and limitations of current and future treatments.
Topics: Humans; Glycogen Storage Disease Type II; alpha-Glucosidases; Mutation; Genetic Therapy; Enzyme Replacement Therapy
PubMed: 37759679
DOI: 10.3390/biom13091279 -
Food and Chemical Toxicology : An... Nov 2020Recently the use of bioactive α-glucosidase inhibitors for the treatment of diabetes have been proven to be the most efficient remedy for controlling postprandial... (Review)
Review
Recently the use of bioactive α-glucosidase inhibitors for the treatment of diabetes have been proven to be the most efficient remedy for controlling postprandial hyperglycemia and its detrimental physiological complications, especially in type 2 diabetes. The carbohydrate hydrolysing enzyme, α-glucosidase, is generally competitively inhibited by the α-glucosidase inhibitors and results in the delayed glucose absorption in small intestine, ultimately controlling the postprandial hyperglycemia. Here we have reviewed the most recent updates in the bioactive α-glucosidase inhibitors category. This review provides an overview of the α-glucosidase inhibitory potentials and efficiency of controlling postprandial hyperglycemia of various bioactive compounds such as flavonoids, phenolic compound, polysaccharide, betulinic acid, tannins, anthocyanins, steroids, polyol, polyphenols, galangin, procyanidins, hydroxyl-α-sanshool, hydroxyl-β-sanshool, erythritol, ganomycin, caffeoylquinic acid, resin glycosides, saponins, avicularin, oleanolic acids, urasolic acid, ethanolic extracts etc., from various dietary and non-dietary naturally occurring sources.
Topics: Animals; Diabetes Mellitus, Type 2; Glycoside Hydrolase Inhibitors; Humans; Molecular Structure; Plant Extracts; alpha-Glucosidases
PubMed: 32916220
DOI: 10.1016/j.fct.2020.111738 -
Molecules (Basel, Switzerland) May 2022Diabetes mellitus is a metabolic disorder and is a global challenge to the current medicinal chemists and pharmacologists. This research has been designed to isolate and...
Diabetes mellitus is a metabolic disorder and is a global challenge to the current medicinal chemists and pharmacologists. This research has been designed to isolate and evaluate antidiabetic bioactives from . The crude extracts, semi-purified and pure bioactives have been used in all in vitro assays. The in vitro α-glucosidase, α-amylase and DPPH free radical activities have been performed on all plant samples. The initial activities showed that ethyl acetate () was the potent fraction in all the assays. This fraction was initially semi-purified to obtain -. Among the semi-purified fractions, was dominant, exhibiting potent IC values in all the in vitro assays. Based on the potency and availability of materials, was subjected to further purification to obtain compounds (2,4-dichloro-6-hydroxy-3,5-dimethoxytoluene) and (2-methyl-6-(4-methylphenyl)-2-hepten-4-one). The two isolated compounds were characterized by mass and NMR analyses. The compounds and showed excellent inhibitions against α-glucosidase (21.45 for and 15.03 for μg/mL), α-amylase (17.65 and 16.56 μg/mL) and DPPH free radicals (7.62 and 14.30 μg/mL). Our study provides baseline research for the antidiabetic bioactives exploration from . The bioactive compounds can be evaluated in animals-based antidiabetic activity in future.
Topics: Animals; Antioxidants; Fragaria; Hypoglycemic Agents; Plant Extracts; alpha-Amylases; alpha-Glucosidases
PubMed: 35684382
DOI: 10.3390/molecules27113444 -
Molecules (Basel, Switzerland) Jul 2023To find potential α-glucosidase inhibitors, indolo[1,2-b]isoquinoline derivatives (-) were screened for their α-glucosidase inhibitory effects. All derivatives...
To find potential α-glucosidase inhibitors, indolo[1,2-b]isoquinoline derivatives (-) were screened for their α-glucosidase inhibitory effects. All derivatives presented potential α-glucosidase inhibitory effects with IC values of 3.44 ± 0.36~41.24 ± 0.26 μM compared to the positive control acarbose (IC value: 640.57 ± 5.13 μM). In particular, compound displayed the strongest anti-α-glucosidase activity, being ~186 times stronger than acarbose. Kinetic studies found that compounds , , , , and were all reversible mix-type inhibitors. The 3D fluorescence spectra and CD spectra results revealed that the interaction between compounds , , , , and and α-glucosidase changed the conformational changes of α-glucosidase. Molecular docking and molecular dynamics simulation results indicated the interaction between compounds and α-glucosidase. In addition, cell cytotoxicity and drug-like properties of compound were also investigated.
Topics: Molecular Structure; Structure-Activity Relationship; Acarbose; Molecular Docking Simulation; alpha-Glucosidases; Kinetics; Glycoside Hydrolase Inhibitors; Isoquinolines
PubMed: 37446942
DOI: 10.3390/molecules28135282 -
Molecules (Basel, Switzerland) Dec 2022The transformation of sesame lignans is interesting because the derived products possess enhanced bioactivity and a wide range of potential applications. In this study,...
The transformation of sesame lignans is interesting because the derived products possess enhanced bioactivity and a wide range of potential applications. In this study, the semisynthesis of 28 furofuran lignans using samin () as the starting material is described. Our methodology involved the protonation of samin () to generate an oxocarbenium ion followed by the attack from two different nucleophiles, namely, thiols (RSH) and alcohols (ROH). The highly diastereoselective thioether and ether furofuran lignans were obtained, and their configurations were confirmed by 2D NMR and X-ray crystallography. The mechanism underlying the reaction was studied by monitoring H NMR and computational calculations, that is, the diastereomeric α- and β-products were equally formed through the S1-like mechanism, while the β-product was gradually transformed via an S2-like mechanism to the α-congener in the late step. Upon evaluation of the inhibitory effect of the synthesized lignans against α-glucosidases and free radicals, the lignans and of the phenolic hydroxyl group were the most potent inhibitors. Additionally, the mechanisms underlying the α-glucosidase inhibition of and were verified to be of a mixed manner and noncompetitive inhibition, respectively. The results indicated that both and possessed promising antidiabetic activity, while simultaneously inhibiting α-glucosidases and free radicals.
Topics: Lignans; alpha-Glucosidases; Ether; Free Radicals; Ethyl Ethers; Ethers; Molecular Structure
PubMed: 36558136
DOI: 10.3390/molecules27249001 -
Journal of Enzyme Inhibition and... Dec 2020Embelin is a naturally occurring -benzoquinone isolated from (Burm. f.) of the Myrsinaceae family. It was first discovered to have potent inhibitory activity (IC =...
Embelin is a naturally occurring -benzoquinone isolated from (Burm. f.) of the Myrsinaceae family. It was first discovered to have potent inhibitory activity (IC = 4.2 μM) against α-glucosidase in this study. Then, four series of novel embelin derivatives were designed, prepared and evaluated in α-glucosidase inhibition assays. The results show that most of the embelin derivatives synthesised are effective α-glucosidase inhibitors, with IC values at the micromolar level, especially , , and , the IC values of which are 1.8, 3.3, and 3.6 μM, respectively. Structure-activity relationship (SAR) studies suggest that hydroxyl groups in the 2/5-position of -benzoquinone are very important, and long-chain substituents in the 3-position are highly preferred. Moreover, the inhibition mechanism and kinetics studies reveal that all of , , , and embelin are reversible and mixed-type inhibitors. Furthermore, docking experiments were carried out to study the interactions between and with α-glucosidase.
Topics: Benzoquinones; Dose-Response Relationship, Drug; Drug Design; Embelia; Glycoside Hydrolase Inhibitors; Humans; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship; alpha-Glucosidases
PubMed: 31969031
DOI: 10.1080/14756366.2020.1715386 -
PloS One 2022α-glucosidase inhibitors represent an important class of type 2 antidiabetic drugs and they act by lowering postprandial hyperglycemia. Today, only three synthetic...
α-glucosidase inhibitors represent an important class of type 2 antidiabetic drugs and they act by lowering postprandial hyperglycemia. Today, only three synthetic inhibitors exist on the market, and there is a need for novel, natural and more efficient molecules exhibiting this activity. In this study, we investigated the ability of Tamarix nilotica ethanolic and aqueous shoot extracts, as well as methanolic fractions prepared from aqueous crude extracts to inhibit α-glucosidase. Both, 50% ethanol and aqueous extracts inhibited α-glucosidase in a concentration-dependent manner, with IC50 values of 12.5 μg/mL and 24.8 μg/mL, respectively. Importantly, α-glucosidase inhibitory activity observed in the T. nilotica crude extracts was considerably higher than pure acarbose (IC50 = 151.1 μg/mL), the most highly prescribed α-glucosidase inhibitor on the market. When T. nilotica crude extracts were fractionated using methanol, enhanced α-glucosidase inhibitory activity was observed in general, with the highest observed α-glucosidase inhibitory activity in the 30% methanol fraction (IC50 = 5.21 μg/mL). Kinetic studies further revealed a competitive reversible mechanism of inhibition by the plant extract. The phytochemical profiles of 50% ethanol extracts, aqueous extracts, and the methanolic fractions were investigated and compared using a metabolomics approach. Statistical analysis revealed significant differences in the contents of the crude extracts and fractions and potentially identified the molecules that were most responsible for these observed variations. Higher α-glucosidase inhibitory activity was associated with an enrichment of terpenoids, fatty acids, and flavonoids. Among the identified molecules, active compounds with known α-glucosidase inhibitory activity were detected, including unsaturated fatty acids, triterpenoids, and flavonoid glycosides. These results put forward T. nilotica as a therapeutic plant for type 2 diabetes and a source of α-glucosidase inhibitors.
Topics: Diabetes Mellitus, Type 2; Ethanol; Flavonoids; Glycoside Hydrolase Inhibitors; Kinetics; Methanol; Plant Extracts; Tamaricaceae; alpha-Glucosidases
PubMed: 35286313
DOI: 10.1371/journal.pone.0264969