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A library of novel bis -Schiff base derivatives based on thiobarbituric acid has been effectively synthesized by multi-step reactions as part of our ongoing pursuit of novel anti-diabetic agents. All these derivatives were subjected to in vitro α-glucosidase inhibitory potential testing after structural confirmation by modern spectroscopic techniques. Among them, compound 8 (IC 50  = 0.10 ± 0.05 µM), and 9 (IC 50  = 0.13 ± 0.03 µM) exhibited promising inhibitory activity better than the standard drug acarbose (IC 50  = 0.27 ± 0.04 µM). Similarly, derivatives ( 5 , 6 , 7 , 10 and 4 ) showed significant to good inhibitory activity in the range of IC 50 values from 0.32 ± 0.03 to 0.52 ± 0.02 µM. These derivatives were docked with the target protein to elucidate their binding affinities and key interactions, providing additional insights into their inhibitory mechanisms. The chemical nature of these compounds were reveal by performing the density functional theory (DFT) calculation using hybrid B3LYP functional with 6-311++G(d,p) basis set. The presence of intramolecular H-bonding was explored by DFT-d3 and reduced density gradient (RGD) analysis. Furthermore, various reactivity parameters were explored by performing TD-DFT at CAM-B3LYP/6-311++G(d,p) method.

α-Glucosidase inhibitors are described as the most effective in reducing post-prandial hyperglycaemia (PPHG) from all available anti-diabetic drugs used in the management of type 2 diabetes mellitus. As flavonoids are promising modulators of this enzyme’s activity, a panel of 44 flavonoids, organised in five groups, was screened for their inhibitory activity of α-glucosidase, based on in vitro structure–activity relationship studies. Inhibitory kinetic analysis and molecular docking calculations were also applied for selected compounds. A flavonoid with two catechol groups in A- and B-rings, together with a 3-OH group at C-ring, was the most active, presenting an IC50 much lower than the one found for the most widely prescribed α-glucosidase inhibitor, acarbose. The present work suggests that several of the studied flavonoids have the potential to be used as alternatives for the regulation of PPHG.

Societal Impact Statement Apples are affordable and accessible fruit with tremendous biodiversity. Among over 10,000 identified apple cultivars, only a few are commercially available. Habitual fruit consumption is correlated with the prevention of Type 2 diabetes and related complications. Particularly, (poly)phenols found in apples are major contributors to their antidiabetic properties. Here, we have screened (poly)phenol‐rich extracts of 476 apple accessions in Canada's Apple Biodiversity Collection for antidiabetic properties. The results of this work provide insights into the prevention and management of Type 2 diabetes by identifying high (poly)phenol‐containing specialty apples for use in fresh fruit form or value‐added functional food ingredients. Summary The recent trend in sedentary lifestyles and nutritionally‐imbalanced diets has elevated the prevalence of Type 2 diabetes in many parts of the world. Some pharmacological glycemic management can cause undesirable gastrointestinal side effects or hypoglycemia. Thus, there is a growing interest in safe glycemic management using dietary (poly)phenols. In this study, (poly)phenol‐rich extracts of 476 apple accessions from Canada's Apple Biodiversity Collection (ABC) and six major apple (poly)phenols were assessed for in vitro antidiabetic properties against the activities of α‐glucosidase, α‐amylase, and dipeptidyl peptidase‐4 (DPP‐4) and the formation of advanced glycation end products (AGE). Apple (poly)phenol extracts varied in their antidiabetic activities in a dose‐dependent manner. High (poly)phenol‐containing apples demonstrated that their total phenolic contents (TPC) were inversely correlated with the IC50 values of α‐glucosidase, α‐amylase, and AGE formation, but not DPP‐4. Concentrations of major (poly)phenol compounds such as procyanidin B2, phloridzin, and epicatechin in apples were significantly inversely correlated with IC50 values of α‐glucosidase in the high (poly)phenol‐containing apples. High TPC apples are not suitable for marketing for fresh fruit consumption due to bitterness and astringency; however, these apples show potential to use in the development of value‐added functional food ingredients or nutraceuticals for blood glucose management. The high TPC apple, “S23‐03‐749,” an advanced breeding line of dessert apple, presents a novel option as a specialty apple cultivar for the dietary management of glycemia. Summary Les pommes sont des fruits abordables et accessibles avec une formidable biodiversité. Parmi plus de 10,000 cultivars de pommiers identifiés, seuls quelques‐uns sont disponibles dans le commerce. La consommation habituelle de fruits est corrélée à la prévention du diabète de type 2 et des complications associées. En particulier, les (poly)phénols présents dans les pommes sont des contributeurs majeurs à leurs propriétés antidiabétiques. Ici, nous avons examiné des extraits riches en (poly)phénols de 476 pommes de la Collection Biodiversité des pommes du Canada pour leurs propriétés antidiabétiques. Les résultats de ces travaux donnent un aperçu de la prévention et de la gestion du diabète de type 2 en identifiant des pommes de spécialité à haute teneur en (poly)phénols à utiliser sous forme de fruits frais ou d'ingrédients alimentaires fonctionnels à valeur ajoutée. Apples are affordable and accessible fruit with tremendous biodiversity. Among over 10,000 identified apple cultivars, only a few are commercially available. Habitual fruit consumption is correlated with the prevention of Type 2 diabetes and related complications. Particularly, (poly)phenols found in apples are major contributors to their antidiabetic properties. Here, we have screened (poly)phenol‐rich extracts of 476 apple accessions in Canada's Apple Biodiversity Collection for antidiabetic properties. The results of this work provide insights into the prevention and management of Type 2 diabetes by identifying high (poly)phenol‐containing specialty apples for use in fresh fruit form or value‐added functional food ingredients.

Diabetes is a common metabolic disease characterized by abnormally high plasma glucose levels, leading to major complications, such as diabetic neuropathy, retinopathy, and cardiovascular diseases. One of the effective managements of diabetes mellitus, in particular, non-insulin-dependent diabetes mellitus (NIDDM) to decrease postprandial hyperglycemia, is to retard the absorption of glucose by inhibition of carbohydrate hydrolyzing enzymes, such as α-glucosidase and α-amylase, in the digestive organs. α-Glucosidase is the key enzyme catalyzing the final step in the digestive process of carbohydrates. Hence, α-glucosidase inhibitors can retard the liberation of d-glucose from dietary complex carbohydrates and delay glucose absorption, resulting in reduced postprandial plasma glucose levels and suppression of postprandial hyperglycemia. In recent years, many efforts have been made to identify effective α-glucosidase inhibitors from natural sources in order to develop a physiologic functional food or lead compounds for use against diabetes. Many α-glucosidase inhibitors that are phytoconstituents, such as flavonoids, alkaloids, terpenoids,anthocyanins, glycosides, phenolic compounds, and so on, have been isolated from plants. In the present review, we focus on the constituents isolated from different plants having α-glucosidase inhibitory potency along with IC50 values.

The concept of functional foods is gaining more importance due to its role in maintaining a healthy status and preventing some metabolic diseases. The control of diabetes, in particular type-2 (T2DM), could be considered a big challenge since it involves other factors such as eating habits. From the pharmacological point of view, inhibiting digestive enzymes, such as α-amylase and α-glucosidase, is one of the mechanisms mainly used by synthetic drugs to control this disease; however, several side effects are described. For that reason, using bioactive compounds may appear as an alternative without presenting the complications synthetic drugs available on the market have. The winemaking industry generates tons of waste annually, and grape pomace (GP) is the most important. GP is recognized for its nutritional value and as a source of bioactive compounds that are helpful for human health. This review highlights the importance of GP as a possible source of α-amylase and α-glucosidase inhibitors. Also, it is emphasized the components involved in this bioactivity and the possible interactions among them. Especially, some phenolic compounds and fiber of GP are the main ones responsible for interfering with the human digestive enzymes. Preliminary studies in vitro confirmed this bioactivity; however, further information is required to allow the specific use of GP as a functional ingredient inside the market of products recommended for people with diabetes. Graphical abstract

Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphate-receptor targeting and enzyme uptake aimed at increased glycogen clearance, compared with the current approved standard of care, alglucosidase alfa, in patients with late-onset Pompe disease. We did a randomised, double-blind, phase 3 trial at 55 sites in 20 countries. We enrolled individuals (aged ≥3 years) with enzymatically confirmed late-onset Pompe disease who had never received treatment. We used a centralised treatment allocation system to randomly allocate participants to either avalglucosidase alfa or alglucosidase alfa. Participants and investigators were unaware of their treatment allocation. The primary outcome measure was change from baseline to week 49 in upright forced vital capacity percent (FVC%) predicted. We used a hierarchical fixed sequential testing strategy, whereby non-inferiority of avalglucosidase alfa compared with alglucosidase alfa was assessed first, with a non-inferiority margin of 1·1. If non-inferiority was seen, then superiority was tested with a 5% significance level. The key secondary objective was effect on functional endurance, measured by the 6-minute walk test (6MWT). Safety was assessed, including treatment-emergent adverse events and infusion-associated reactions. The modified intent-to-treat population was the primary analysis population for all efficacy analyses. The safety population was the analysis population for safety analyses. This trial is registered with ClinicalTrials.gov, NCT02782741. We report results of the 49-week primary analysis period. Between Nov 2, 2016, and March 29, 2019, 100 participants were randomly allocated avalglucosidase alfa (n=51) or alglucosidase alfa (n=49). Treatment with avalglucosidase alfa resulted in a least-squares mean improvement in upright FVC% predicted of 2·89% (SE 0·88) compared with 0·46% (0·93) with alglucosidase alfa at week 49 (difference 2·43% [95% CI −0·13 to 4·99]). Non-inferiority was shown because the lower bound of the 95% CI for the difference far exceeded the predefined non-inferiority margin but did not exclude 0 (p=0·0074). Superiority was not reached (p=0·063), so formal testing was stopped, as per the testing hierarchy. Improvements were also seen in the 6MWT with avalglucosidase alfa compared with alglucosidase alfa, with greater increases in distance covered (difference 30·01 m [95% CI 1·33 to 58·69]) and percent predicted (4·71% [0·25 to 9·17]). Treatment-emergent adverse events potentially related to treatment were reported in 23 (45%) of 51 participants in the avalglucosidase alfa group and in 24 (49%) of 49 in the alglucosidase alfa group, and infusion-associated reactions were reported in 13 (26%) participants in the avalglucosidase alfa group and 16 (33%) in the alglucosidase alfa group. Of the five trial withdrawals, all in the alglucosidase alfa group, four were due to adverse events, including two infusion-associated reactions. Serious treatment-emergent adverse events were reported in eight (16%) participants who received avalglucosidase alfa and in 12 (25%) who received alglucosidase alfa. One participant treated with alglucosidase alfa died because of acute myocardial infarction determined to be unrelated to treatment. Antidrug antibody responses were similar in both groups. High and persistent titres (≥12 800) and neutralising antibodies were more common with alglucosidase alfa (in 16 [33%] participants) than with avalglucosidase alfa (ten [20%]). We consider that this study provides evidence of clinically meaningful improvement with avalglucosidase alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported. An open-label extended-treatment period is ongoing to confirm the long-term safety and efficacy of avalglucosidase alfa, with the aim for this therapy to become the new standard treatment in late-onset Pompe disease. Sanofi Genzyme.

In this study, the peptides of soy protein obtained by enzymatic digestion with proteases were analyzed for their antidiabetic, antihypertensive, and antioxidant activities. Peptides prepared with alkaline proteinase (AP) exhibited the highest α‐glucosidase inhibitory activity compared with those from papain and trypsin digestion. AP hydrolysates also exhibited dipeptidyl peptidase IV (DPP‐IV) inhibitory, angiotensin‐converting enzyme (ACE) inhibitory, and antioxidant activities. Gastrointestinal digestion of peptides enhanced α‐glucosidase, DPP‐IV, and ACE inhibitory activities compared with AP hydrolysates. AP peptides showing highest α‐glucosidase inhibitory activity were purified by anion‐exchange and size‐exclusion chromatography， and identified using tandem MS. We found three novel α‐glucosidase inhibitory peptides with sequences LLPLPVLK, SWLRL, and WLRL with IC50 of 237.43 ± 0.52, 182.05 ± 0.74, and 162.29 ± 0.74 μmol/L, respectively. Therefore, peptides hydrolyzed from soy protein are promising natural ingredients for nutraceutical applications assisting in the management of diabetes. Soy protein hydrolysates prepared by alkaline proteinase (AP) digestion exhibited the highest α‐glucosidase inhibitory activity compared to those from papain and trypsin digestion. Gastrointestinal digestion of peptides slightly enhanced α‐glucosidase, DPP‐IV, and ACE inhibitory activities compared to AP hydrolysate. We found three novel α‐glucosidase inhibitory peptides with sequences LLPLPVLK, SWLRL, and WLRL with IC50 of 237.43 ± 0.52, 182.05 ± 0.74, and 162.29 ± 0.74 μmol/L, respectively.

Six new DIKETOPIPERAZINE alkaloids aspergiamides A–F (1–6), together with ten known alkaloids (7–16), were isolated from the mangrove endophytic fungus Aspergillus sp. 16-5c. The structures of the new compounds were elucidated based on 1D/2D NMR spectroscopic and HR-ESIMS data analyses. The absolute configurations of aspergiamides A-F were established based on the experimental and calculated ECD data. All the compounds were evaluated for the antidiabetic activity against α-glucosidase and PTP1B enzyme. The bioassay results disclosed compounds 1 and 9 exhibited significant α-glucosidase inhibitory with IC50 values of 18.2 and 7.6 μM, respectively; compounds 3, 10, 11, and 15 exhibited moderate α-glucosidase inhibition with IC50 values ranging from 40.7 to 83.9 μM; while no compounds showed obvious PTP1B enzyme inhibition activity.

In this study, some biological activities including antioxidant activity (DPPH radical scavenging activity, ABTS radical scavenging activity, and CUPRAC assay), DPP-IV enzyme inhibitory activity, and α-glucosidase enzyme inhibitory activity of peptides released from in vitro gastrointestinal digested casein and the whey proteins of camel and donkey milk were evaluated. While the highest antioxidant activity was determined to be in the digested camel casein fraction using the ABTS and CUPRAC methods, the digested donkey casein fraction was determined to have the highest radical scavenging activity using the DPPH method. The highest DPP-IV inhibitory activity was detected in digested camel and donkey milk casein fractions. Digested whey fractions of camel and donkey milk had a lower DPP-IV inhibitory activity compared to the digested casein fractions. However, digested whey fractions of camel and donkey milk did not show α-glucosidase inhibitory activity, and digested donkey casein fraction showed the highest α-glucosidase inhibitory activity with a 12.5 µg/mL IC50 value. It was concluded that peptides released from digested casein fraction of camel and donkey milk have potent antioxidant and particularly antidiabetic properties.