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Postprandial hyperglycemia, typical manifestation of Type 2 Diabetes Mellitus (T2DM), is associated with notable global morbidity and mortality. Preventing the advancement of this condition by delaying the rate of glucose absorption through inhibition of α-amylase and α-glucosidase enzymatic activities is of utmost importance. Finding a safe antidiabetic drug is essential since those that are currently on the market have drawbacks like unpleasant side effects. The current study utilized computer-aided drug design (CADD), as a quick and affordable method to find a substitute drug template that can be used to control postprandial hyperglycemia by modulating the activity of α-amylase and α-glucosidase enzymes. The Natural Products Activity and Species database (NPASS) (30,926 compounds) was screened in silico, with a focus on evaluating drug-likeness, toxicity profiles and ability to bind on a target protein. Two molecules NPC204580 (Chrotacumine C) and NPC137813 (1-O-(2-Methoxy-4-Acetylphenyl)-6-O-(E-Cinnamoyl)-Beta-D-Glucopyranoside) were identified as potential dual inhibitors for α-amylase and α-glucosidase with free binding energies of -14.46 kcal/mol and -12.58 kcal/mol for α-amylase, and -8.42 kcal/mol and -8.76 kcal/mol for α-glucosidase, respectively. The molecules showed ionic, H-bonding and hydrophobic interactions with critical amino acid residues of both enzymes. Moreover, 100 ns molecular dynamic simulations showed that both molecules are stable on the receptors' active sites based on root mean square deviation (RMSD), root mean square fluctuation (RMSF), and the Generalized Born surface area (GBSA) energy calculated. The two compounds are thus promising therapeutic agents for T2DM that merit further investigation due to their excellent binding energies, encouraging pharmacokinetics, toxicity profiles, and stability as demonstrated in simulated studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ndarawit et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

α-Glucosidase inhibitors are important in the treatment of type 2 diabetes by regulating blood glucose levels and reducing carbohydrate absorption. The present study focuses on identifying new inhibitors bearing imidazo[1,2-c]quinazoline backbone through multi-step synthesis. The inhibitory potencies of the novel derivatives were tested against Saccharomyces cerevisiae α-glucosidase, revealing IC 50 values ranging from 50.0 ± 0.12 µM to 268.25 ± 0.09 µM. Among them, 2-(4-(((2,3-diphenylimidazo[1,2-c]quinazolin-5-yl)thio)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-methoxyphenyl)acetamide (19e) and 2-(4-((benzo[4,5]imidazo[1,2-c]quinazolin-6-ylthio)methyl)-1H-1,2,3-triazol-1-yl)-N-(2-methoxyphenyl)acetamide (27e) emerged as the most potent inhibitors and were further investigated in various assessments. Finally, molecular docking studies were performed to reveal the crucial binding interactions and to confirm the results obtained from structure-activity relationship (SAR) analysis., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Six Schiff bases with general name 5-(diethylamino)-2-(((halophenyl)imino)methyl)phenol (where halo = 4-fluoro (H1), 2-fluoro (H2), 2-bromo (H3), 4-bromo (H4), 4-chloro (H5) and 3-chloro-4-fluoro (H6)) were prepared by the condensation reaction between 4-(diethylamino)salicylaldehyde and suitable halogenated aromatic amines. The six halogenated Schiff bases were elucidated using different spectroscopic techniques and the structure of H3 and H6 were confirmed using single-crystal X-ray crystallography. The bond lengths of C7-N1, C7-C8 and C8-C9 obtained from structural analysis for both compounds depicted their enol-tautomeric characteristic form. The Hirshfeld analysis revealed that H‧‧‧H intermolecular contacts contributed most towards the Hirshfeld surfaces of both H3 (47.6%) and H6 (39.9%). Quantum chemical calculation studies showed that H1 and H2 have the highest and lowest energy band gap (∆E = 3.80 eV for H1 and ∆E = 3.73 eV for H2), depicting H2 and H1 as the most and least chemically reactive respectively among all the compounds. α-Amylase and α-glucosidase assay were used to evaluate the antidiabetes prowess of the synthesized compounds. All the compounds exhibited lower IC 50 values than acarbose (reference drug) in α-amylase assay experiments and H5 with lowest IC 50 value of 63.54 μM could be suggested to have the highest α-amylase inhibitory potential among the test samples. For α-glucosidase assay, H1-H6 displayed good antidiabetic potential. However, none of the compounds outshined acarbose with H6 having highest α-glucosidase inhibitory potential when compared to others i.e., IC 50 of H6 = 60.89 μM and IC 50 of acarbose = 51.42 μM. We measured the antioxidant potential of H1-H6 exploring 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and ferric reducing ability power (FRAP) assays. The DPPH as well as NO radical scavenging assay showed that all the compounds exhibited excellent antioxidant results with some of the compounds surpassing catechin (reference drug). Compound H5 with IC 50 values of 30.32 mM and 31.73 mM outshined catechin with IC 50 values of 31.17 mM and 140.62 mM for DPPH and NO assays respectively. All the compounds fell within the threshold of Lipinski's Ro5 projecting them as orally bioavailable and less toxic future therapeutics., (© 2024. The Author(s).)

Pompe disease, a rare genetic neuromuscular disorder, is caused by a deficiency of acid alpha-glucosidase (GAA), leading to an accumulation of glycogen in lysosomes, and resulting in the progressive development of muscle weakness. The current standard treatment, enzyme replacement therapy (ERT), is not curative and has limitations such as poor penetration into skeletal muscle and both the central and peripheral nervous systems, a risk of immune responses against the recombinant enzyme, and the requirement for high doses and frequent infusions. To overcome these limitations, lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy has been proposed as a next-generation approach for treating Pompe disease. This study demonstrates the potential of lentiviral HSPC gene therapy to reverse the pathological effects of Pompe disease in a preclinical mouse model. It includes a comprehensive safety assessment via integration site analysis, along with single-cell RNA sequencing analysis of central nervous tissue samples to gain insights into the underlying mechanisms of phenotype correction., Competing Interests: Declaration of interests All authors were former employees of AVROBIO, Inc., Cambridge, MA, USA during the conception and writing of the manuscript, except V.M., M.R., and A.S. N.P.v.T. and C.M. are inventors on patents in the field of HSC gene therapy. AVROBIO, Inc., has a preclinical gene therapy program for Pompe disease (AVR-RD-03) based on a genetically modified HSPC platform using lentiviral vectors. Collection of data and analysis was performed as part of the program. This research received no external funding and was sponsored by AVROBIO, Inc., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to compare the concentration of phenolic compounds, glucosinolates, proteins, sugars and vitamin C between kohlrabi ( Brassica oleracea var. acephala gongylodes ), Savoy cabbage ( B. oleracea sabauda ), Brussels sprouts ( B. oleracea gemmifera ), cauliflower ( B. oleracea botrytis ), radish ( Raphanus sativus ) and garden cress ( Lepidium sativum ) microgreens for their antioxidant and hypoglycemic potential. In addition, we applied an in vitro-simulated system of human digestion in order to track the bioaccessibility of the selected phenolic representatives, and the stability of the microgreens' antioxidant and hypoglycemic potential in terms of α-amylase and α-glucosidase inhibition after each digestion phase. Using spectrophotometric and RP-HPLC methods with statistical analyses, we found that garden cress had the lowest soluble sugar content, while Savoy cabbage and Brussels sprouts had the highest glucosinolate levels (76.21 ± 4.17 mg SinE/g dm and 77.73 ± 3.33 mg SinE/g dm, respectively). Brussels sprouts were the most effective at inhibiting protein glycation (37.98 ± 2.30% inhibition). A very high positive correlation ( r = 0.830) between antiglycation potential and conjugated sinapic acid was recorded. For the first time, the antidiabetic potential of microgreens after in vitro digestion was studied. Kohlrabi microgreens best inhibited α-amylase in both initial and intestinal digestion (60.51 ± 3.65% inhibition and 62.96 ± 3.39% inhibition, respectively), and also showed the strongest inhibition of α-glucosidase post-digestion (19.22 ± 0.08% inhibition). Brussels sprouts, cauliflower, and radish had less stable α-glucosidase than α-amylase inhibitors during digestion. Kohlrabi, Savoy cabbage, and garden cress retained inhibition of both enzymes after digestion. Kohlrabi antioxidant capacity remained unchanged after digestion. The greatest variability was seen in the original samples, while the intestinal phase resulted in the most convergence, indicating that digestion reduced differences between the samples. In conclusion, this study highlights the potential of various microgreens as sources of bioactive compounds with antidiabetic and antiglycation properties. Notably, kohlrabi microgreens demonstrated significant enzyme inhibition after digestion, suggesting their promise in managing carbohydrate metabolism and supporting metabolic health.

Acanthopanax senticosus belongs to Araliaceae family and is traditionally used as a tonic. The roots and stems are mainly used as treatments for hypodynamia, rheumatism, and hypertension, but their frequent use may lead to extinction. However, comprehensive and simultaneous analysis of the remaining parts were still limited. There is a need to reorganize them for standardization of functional foods. In this study, 50 phenolic compounds and 82 triterpenoid saponins from the shoots, leaves, fruits, and stems of were characterized using UPLC-QTOF-MS and UPLC-QTRAP-MS/MS. Among them, 52 compounds were newly determined as the cis and malonyl-bound phenolic acids and were found to be structural isomers of Acanthopanax flavonoids and saponins. All compounds were absolutely/relatively quantified, and shoots had the highest content. Peroxynitrite and α-glucosidase inhibitory activities were performed, followed by evaluation of structure-activity relationships. Particularly, hederasaponin B and ciwujianoside B showed remarkable efficacy, which were affected by the C-23 hydroxylation, the C-20(29) double bond, and the presence of rhamnose. These detailed profiling can be used as fundamental data for increasing the utilization of A. senticosus and developing them into functional foods., (© 2024. The Author(s).)

The effects of anthocyanins on in vitro and in vivo digestibility of potato starch were evaluated in this study. Then the influence of anthocyanins on physicochemical property of potato starch and the activity of starch digestive enzymes (α-amylase and α-glucosidase) were also investigated to understand the mechanism of anthocyanins on starch digestibility. Results have shown that dietary anthocyanins could effectively inhibit the biological activities of α-amylase and α-glucosidase to delay the peak of postprandial blood glucose. Characterization of physicochemical properties of potato starch indicates a structural change due to the presence of anthocyanins, hindering its access to starch digestive enzymes. Among all anthocyanins, lingonberry anthocyanin significantly promoted the retrogradation of potato starch (7.153 % to 25.913 %) and exert promising inhibition on α-amylase and α-glucosidase. Lingonberry anthocyanins mainly interacted with potato starch through hydrogen bonds, which reduce the amount of amylose molecules leached from potato starch and loosen the three-dimensional (3D) network structure of starch gel. This study could provide theoretical evidence for utilization of anthocyanins in diabetic-management function food., Competing Interests: Declaration of competing interest All authors have reviewed the manuscript and approved to submit to your journal. The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Type 2 diabetes mellitus (T2D) causes complications due to metabolic disorders besides increasing blood glucose. Sweet corn cob selenium polysaccharide (SeSCP) is a complex of Se with Sweet corn cob polysaccharide that has good hypoglycemic efficacy, but its effect on T2D metabolism has not been determined. In this study, the hypoglycemic effect of SeSCP was investigated by in vitro and in vivo experiments, and the levels of metabolites in feces were analyzed in a high-fat diet and STZ-induced T2D mouse model by Liquid chromatography-mass spectrometry (LC-MS). The results indicated that SeSCP regulates α-amylase and α-glucosidase through competitive reversible inhibition, and the reaction is spontaneous, driven by van der Waals forces and hydrogen bonding. In vivo, SeSCP modulates glucose transport decreasing glucose entry into the bloodstream. The metabolites mainly affected by SeSCP-MC were adenine, LysoPA (0:0/18:2(9Z, 12Z)), cysteine-S-sulfate, and demeclocycline (hydrochloride) metabolites. SeSCP interfered with β-alanine metabolism, starch and sucrose metabolism, ether lipid metabolism, glycerophospholipid metabolism, glyoxylate and dicarboxylate metabolism, pantothenate and CoA biosynthesis, etc. Additionally, SeSCP exhibited more effective metabolic interventions than metformin and SCP. Therefore, SeSCP can reduce complications while improving T2D blood glucose., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The co-contamination of heavy metal ions and organic pollutants has posed a threat to human health. Herein, this study investigated the intermolecular interactions of bisphenol S (BPS) and hexavalent chromium (Cr(VI)) under both individual and coexisting conditions, with alpha-glucosidase (AG), a key enzyme in carbohydrate metabolism, and the corresponding effects on the structure and function of AG. Multiple spectroscopic and molecular docking methods were employed to conduct the investigation in vitro and in silico. The results indicated that both BPS and Cr(VI) quenched the fluorescence of AG via a combined static and dynamic quenching processes. At 310 K, the binding constants of AG with BPS in the AG-BPS and (AG-Cr(VI))-BPS systems were 1.84 × 10 4 and 2.03 × 10 4  L mol -1 , and the binding constants of AG with Cr(VI) in the AG-Cr(VI) and (AG-BPS)-Cr(VI) systems were 6.14 × 10 3 and 4.35 × 10 3  L mol -1 . Cr(VI) could significantly affect the binding site of BPS in AG, while BPS had a minimal impact on the binding site of Cr(VI) in AG. BPS and Cr(VI) caused varied structural alterations of AG, and the impact of their coexistence on the structure of AG was related to the order in which they were added. Both BPS and Cr(VI) had a concentration-related effect on AG activity. This study provides valuable insights into the molecular mechanisms underlying the combined toxic effects of BPS and Cr(VI) on AG, highlighting the potential health risks associated with their environmental co-exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, sixteen compounds were isolated from the branches of Mitragyna diversifolia, including twelve triterpenes (1-12), a phenolic compound (13), and three flavonoids (14-16). Among them, compounds 1-7, and 10-16 were reported for the first time from this plant. Compounds 7, 14, and 15 exhibited significant inhibitory activities against α-glucosidase, with IC 50 values of 18.48 ± 2.74, 12.14 ± 1.58 and 35.77 ± 4.52 µM, respectively. Furthermore, the inhibitory kinetics of α-glucosidase revealed that all fractions, active compounds 7, 14, and 15 belong to the mix inhibition type. In molecular docking, the analysis showed that compounds 13, 14, 15, and 16 possessed superior binding capacities with α-glucosidase (-8.3, -9.6, -9.9, and -9.2 kcal/mol, respectively). The results of the glucose uptake experiment indicated that only compound 14 showed a significant promotion effect on the glucose uptake rate of 3T3-L1 adipocytes (P < 0.05). Meanwhile, compounds 13, 14, 15, and 16 possessed potent antioxidant abilities with DPPH, ABTS, and FRAP. In DNA and protein oxidative damage assays, compound 15 had a stronger effect than the positive control Vc. The network-based pharmacological analysis platform was used to predict the diabetes-related target proteins of active compounds 7, 13, 14, 15, and 16, and two candidate targets (ALB and PPARG) related to their therapeutic effects on diabetes were identified., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Diabetes mellitus characterized by abnormal glucose concentration is a metabolic disease. α-Glu inhibitors from natural sources are a good choice for searching for high-efficiency and low-toxicity hypoglycemic drugs. In this study, a naturally effective α-Glu inhibitor aspergillus triazolate A (ATA) with a peculiar structure was first found in Oxalis corniculate L., then its activity and mechanism were first elucidated through various methods. These mechanisms included enzyme kinetics, circular dichroism spectra, fluorescence spectra, synchronous fluorescence spectrum, 3D fluorescence spectrum, and molecular docking. Meanwhile, the ability to reduce postprandial blood glucose was further investigated in vivo. Research results revealed that ATA was a mixed type α-Glu inhibitor with an IC 50 value of 66.87 ± 1.50 μM, which bound to the enzyme from a single site through hydrogen bonding and hydrophobic forces causing the looser secondary structure of α-Glu. It was also found that the binding site of α-Glu was closer to the Trp residue, and the endogenous fluorescence of α-Glu was quenched in a static quenching form. Moreover, the sucrose loading test in vivo revealed that the ATA of 20 mg/kg could effectively reduce the postprandial blood glucose level. Hence, ATA could be used as lead compound to develop novel α-Glu inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Elevated blood sugar levels caused by starch digestion was a target for controlling diabetes mellitus. The in vitro and in vivo digestibility of wheat starch was evaluated to find that adding 15 % persimmon leaf extract (PLE) to starch reduced its digestibility by 69.50 % and the peak postprandial blood glucose by 23.63 %. Subsequently, we observed under scanning electron microscopy and atomic force microscopy that the presence of PLE led to the destruction of starch structure and the aggregation of α-glucosidase so as to decrease starch digestion and hinder the binding of starch to α-glucosidase. Through multi-spectral analysis, PLE hindered the clathrate of iodine and starch, and also increased the crystallinity of starch by 48.58 %. For α-glucosidase inhibitory activity (IC 50  = 72.49 μg/mL), PLE preferentially occupied the active center of α-glucosidase, changed its fluorescence characteristics and secondary structure through hydrogen bonding and hydrophobic interaction. Moreover, among the 23 potential α-glucosidase inhibitors screened from PLE, combined with molecular simulation, Procyanidin B2 had the strongest inhibitory effect (IC 50  = 33.22 μg/mL) and binding energy (-7.09 kcal/mol), which was most effectively inhibitory on digestion. These results indicated the potential of PLE in hypoglycemia targeting both starch and α-glucosidase., Competing Interests: Declaration of competing interest The authors declared that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

To find potential α-glucosidase inhibitors, a series of 2β-acetoxyferuginol derivatives containing cinnamic acid (WXC-1 ∼ 25) were synthesized and investigated their biological activity. All derivatives (WXC-1 ∼ 25) displayed better inhibitory activity (IC 50 values: 7.56 ± 1.35 ∼ 25.63 ± 1.72 μM) compared to acarbose (IC 50 vaule: 564.28 ± 48.68 μM). In particularly, WXC-25 with 4-hydroxycinnamic acid section showed the best inhibitory activity (IC 50 vaule: 2.02 ± 0.14 μM), ∼75-fold stronger than acarbose. Kinetics results suggested WXC-25 being one reversible non-competition inhibitors. Fluorescence quenching results indicated that WXC-25 quenched the fluorescence of α-glucosidase in a static manner. 3D fluorescence spectra results indicated that WXC-25 treatment could cause the conformation changes of α-glucosidase. Moreover, molecular docking simulated the detailed interaction of WXC25 with α-glucosidase., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A novel series of thiazole derivatives with pyrazole scaffold 16a-l as hybrid rosiglitazone/celecoxib analogs was designed, synthesized and tested for its PPAR-γ activation, α-glucosidase, α-amylase and COX-2 inhibitory activities. Regarding the anti-diabetic activity, all compounds were assessed in vitro against PPAR-γ activation, α-glucosidase and α-amylase inhibition in addition to in vivo hypoglycemic activity (one day and 15 days studies). Compounds 16b, 16c, 16e and 16 k showed good PPAR-γ activation (activation % ≈ 72-79 %) compared to that of the reference drug rosiglitazone (74 %). In addition, the same derivatives 16b, 16c, 16e and 16 k showed the highest inhibitory activities against α-glucosidase (IC 50  = 0.158, 0.314, 0.305, 0.128 μM, respectively) and against α-amylase (IC 50  = 32.46, 23.21, 7.74, 35.85 μM, respectively) compared to the reference drug acarbose (IC 50  = 0.161 and 31.46 μM for α-glucosidase and α-amylase, respectively). The most active derivatives 16b, 16c, 16e and 16 k also revealed good in vivo hypoglycemic effect comparable to that of rosiglitazone. In addition, compounds 16b and 16c had the best COX-2 selectivity index (S.I. = 18.7, 31.7, respectively) compared to celecoxib (S.I. = 10.3). In vivo anti-inflammatory activity of the target derivatives 16b, 16c, 16e and 16 k supported the results of in vitro screening as the derivatives 16b and 16c (ED 50  = 8.2 and 24 mg/kg, respectively) were more potent than celecoxib (ED 50  = 30 mg/kg). In silico docking, ADME, toxicity, and molecular dynamic studies were carried out to explain the interactions of the most active anti-diabetic and anti-inflammatory compounds 16b, 16c, 16e and 16 k with the target enzymes in addition to their physiochemical parameters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The different parts of Sorbus torminalis (L.) Crantz are used in traditional medicine for various conditions such as cardiac diseases, cough, and diabetes, indicating its significant medicinal potential. Therefore, the current investigation aimed to reveal the phenolic composition of the poorly studied S. torminalis methanol extract of the bark, as well as its capacity to inhibit enzymes relevant to cardiovascular, neurodegenerative, and metabolic diseases. A total of 28 phenolic components, including 20 procyanidins aglycones (A- and B-type), four procyanidin glycosides, catechin and its glycoside, and two (epi)catechin derivatives, were detected using LC-MS. The contents of total polyphenols (6.22 %), total tannins (3.04 %), condensed tannins (0.70 %), and total flavonoids (0.24 %) were determined spectrophotometrically, highlighting the considerable phenolic richness of the examined plant material. The concentration-dependent ability to inhibit α-amylase (IC 50 =130 μg /mL), α-glucosidase (IC 50 =312.13 μg /mL), acetylcholinesterase (IC 50 =156.46 μg /mL), butyrylcholinesterase (IC 50 =217.68 μg /mL), and angiotensin-converting enzyme (IC 50 =36.77 μg /mL) was demonstrated in vitro. The in silico approach showed that catechin, procyanidin B2 and C1, S. torminalis bark constituents, can form stable complexes with the target enzymes but with different binding affinity. The results supported the medicinal potential of S. torminalis bark and significantly expanded our knowledge of its chemistry, justifying further research., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The current work investigates the chemodiversity, in vitro antioxidant, α-amylase and α-glucosidase inhibitory potential of Cinnamomum tamala (CT) leaf essential oil (EO) collected from different localities of East Khasi Hills District of Meghalaya, India. Gas chromatography-mass spectrometry (GC-MS) analysis of all the extracted leaf essential oils facilitated the identification of several compounds in a variable range along with eugenol as the major component (74.79-95.12 %). CT8 exhibited the highest antioxidant activity (IC 50 =11.23±0.27 μg/mL for 2,2-diphenyl-1-picrylhydrazyl (DPPH) and IC 50 =21.54±0.37 μg/mL for 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) among all EO evaluated. The results showed that the ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) values for CT8 were 83.26±1.92 μM trolox/g oil and 70.29±1.90 ascorbic acid equivalents (AAE)/g of oil. α-amylase and α-glucosidase inhibition were highest in sample CT8 with IC 50 values of 3.62±0.42 μg/mL and 16.29±0.32 μg/mL respectively. Caryophyllene, cyclohexene, 1, 5, 5-trimethyl-6-(2-propenylidene), germacrene D and eugenol showed strong binding potential toward α-amylase and α-glucosidase. It concluded that the chemodiversity and antidiabetic potential of C. tamla oil from Khasi Hills have never been studied. It can be taken as a dietary supplement as an antioxidant and antidiabetic to control blood glucose., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Ultrasound-assisted extraction of Cissus repens polysaccharides (CRPs) was optimized through response surface methodology (RSM) based on Box-Behnken design (BBD). The maximum CRPs yield (16.18 %) was achieved under the optimum extraction conditions: extraction time 72 min, extraction temperature 74 °C, extraction power 240 W. Then three-phase partitioning (TPP) method combined with gradient alcohol precipitation was used to obtained CRP20, CRP40, CRP60 and CRP80 from CRPs, and CRP80 has a higher purity than others. The primary chemical and structural characteristics of CRP80 were investigated by UV, FT-IR, high-performance liquid chromatography (HPLC) and high-performance gel-permeation chromatography (HPGPC). CRP80 is mainly composed of glucose, galactose, arabinose and mannose, with a molecular weights of approximately 2.95 kDa. Furthermore, the antioxidant activity and hypoglyceamic activity of CRP80 in vitro were evaluated. The results showed that CRP80 had strong scavenging activities on ABTS, hydroxyl and DPPH radicals, as well as high scavenging activities on α-glucosidase and α-amylase. Our research provided an efficient method for the extraction of polysaccharides from C. repens and CRP80 has potential as a promising source of natural antioxidants and hypoglycemic agent for the functional food and medicinal industries., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

A focused chemical investigation into the polar fractions of a well-known traditional Chinese medicine called Sang-Bai-Pi (the root bark of Morus alba) yielded a panel of prenylated flavanones. The new compounds were identified as four pairs of enantiomers (1a/1b-4a/4b) featuring the same constitution structure, on the basis of HRMS, NMR and ECD analyses. Several previously reported known racemic co-metabolites were also analyzed and separated by HPLC on chiral columns, and the absolute configurations of pure enantiomers were established via ECD technique for the first time. The inhibition of these isolates against the antidiabetic target α-glycosidase was further tested, with most of them showing decent inhibitory activity compared with the positive control acarbose. The interaction mechanism of two selected compounds (3a & 4b) was explored by kinetics experiment, which revealed a mixed type of inhibition pattern toward the enzyme., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Type 2 diabetes mellitus (T2DM), a disease that threatens public health worldwide and can cause a series of irreversible complications, has been a major concern. Although the treatment based on hypoglycemic drugs is effective, its side effects should not be ignored, which has led to an urgent need for developing new hypoglycemic drugs. Bioactive peptides with antidiabetic effects obtained from food proteins have become a research hotspot as they are safer and with higher specificity than traditional hypoglycemic drugs. Here, we reviewed antidiabetic peptides that have the ability to inhibit key enzymes (α-glucosidase, α-amylase, and DPP-IV) in T2DM, the hypoglycemic mechanisms and structure-activity relationships were summarized, some antidiabetic peptides that improve insulin resistance and reverse gut microbiota and their metabolites were overviewed, the bitterness of antidiabetic peptides was predicted in silico, proposed solutions to the current challenges encountered in the development of antidiabetic peptide drugs, and provided an outlook on the future focus of commercial production. It provides a reference for the application of food-derived antidiabetic peptides., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

α-Glucosidase (α-Glu) is implicated in the progression and pathogenesis of type II diabetes (T2D). In this study, we developed a rapid colorimetric technique using platinum nanoparticles stabilized by chitosan (Ch-PtNPs) to detect α-Glu activity and its inhibitor. The Ch-PtNPs facilitate the conversion of 3,3',5,5'-tetramethylbenzidine (TMB) into oxidized TMB (oxTMB) in the presence of dissolved O 2 . The catalytic hydrolysis of 2-O-α-D-glucopyranosyl-L-ascorbic acid (AA-2G) by α-Glu produces ascorbic acid (AA), which reduces oxTMB to TMB, leading to the fading of the blue color. However, the presence of α-Glu inhibitors (AGIs) hinders the generation of AA, allowing Ch-PtNPs to re-oxidize colorless TMB back to blue oxTMB. This unique phenomenon enables the colorimetric detection of α-Glu activity and AGIs. The linear range for α-Glu was found to be 0.1-1.0 U mL -1 and the detection limit was 0.026 U mL -1 . Additionally, the half-maximal inhibition value (IC 50 ) for acarbose, an α-Glu inhibitor, was calculated to be 0.4769 mM. Excitingly, this sensing platform successfully detected α-Glu activity in human serum samples and effectively screened AGIs. These promising findings highlight the potential application of the proposed strategy in clinical diabetes diagnosis and drug discovery., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Bacillus stercoris PSSR12 (B. stercoris PE), an isolate from rice field soils, was identified via 16s rRNA sequencing. The synthesis of the inulin and inulin producing enzyme (IPE) in B. stercoris PE was verified using SDS-PAGE and FTIR. This study aimed to assess the impact of B. stercoris PE treatment on in vitro inhibition of α-amylase and α-glucosidase from traditional and commercial rice varieties of South India. Additionally, the study investigated enzymatic inhibition and mRNA expression of starch synthesis genes (RAmy1a, GBSSIa, SBEIIa, and SBEIIb). Glucose transporter gene expression (GLUT1 and GLUT4) patterns were analyzed in 3T3-L1 adipocytes to evaluate glucose uptake in B. stercoris PE treated rice varieties. The application of B. stercoris PE enhanced grain quality by imparting starch ultra-structural rigidity, inhibiting starch metabolizing enzymes, and inducing molecular changes in starch synthesis genes. This approach holds promise for managing type II diabetes mellitus and potentially reducing insulin dependence., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This study explored the potential of ultrasonic-assisted three-phase partitioning (UTPP) to simultaneously extract lipids, proteins, and polysaccharides from Idesia polycarpa Maxim (IPM) cake meal, a significant byproduct of oil extraction. The impact of variables such as inorganic salt type, solid-liquid ratio, salt concentration, pH, ultrasonic time, temperature, and volume of dimethyl carbonate was examined. Based on the single-factor tests and response surface methodology (RSM), optimal conditions were identified as 30 % ammonium citrate, a 1:26 solid-liquid ratio, pH 3, 31 min of ultrasonic time, 30 °C temperature, and 15 mL of dimethyl carbonate. These conditions achieved extraction rates of 8.10 % for lipids, 5.03 % for proteins, and 10.03 % for polysaccharides, with recovery rates of 91.62 %, 83.08 %, and 93.95 % respectively. Chemical analysis showed the lipid fraction rich in linoleic acid, and the protein fraction high in glutamic acid, aspartate, and serine. The polysaccharide fraction, mainly RG-I pectin with a molecular weight of 226.58 kDa, exhibited strong thermal stability and inhibitory effects on α-glucosidase and glycation, suggesting potential for functional food and dietary supplement applications. This highlights UTPP as a sustainable method for effectively utilizing valuable compounds from IPM cake meal, outperforming traditional extraction techniques., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The Hippophae rhamnoides L. pomace was generated in the production process for juice, wine of food industry. To expand the application of pomace, the extraction process optimization, enrichment and identification of triterpene acids were performed in this study. The extraction yield was 14.87% under optimal ultrasound-assisted extraction techniques performed via response surface methodology. The extract was subsequently purified to obtain the triterpenoid acid enrichment fraction (TPF) with the content of 75.23% ± 1.45%. 13 triterpenoid acids were identified via UPLC-Triple-TOF MS/MS and further semi-quantified through comparison with triterpenoid acid standards. TPF exhibited a strong inhibitory effect on α-glucosidase with IC 50 value of 5.027 ± 0.375 μg/mL, as determined via enzyme inhibition experiment and molecular docking. Additionally, the TPF significantly reduced postprandial glucose levels, as revealed via carbohydrate tolerance tests, as well as ameliorate serum lipid profiles. Therefore, pomace may be a promising resource of functional food components with therapeutic and commercial values., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

One new prenyl flavanone ( 1 ), (2 S )-8-prenyl-5,6-dihydroxy-7-methoxyflavanone, and one new diarylbutanol ( 2 ), (7' S )-3'-hydroxy-linderagatin-A, were isolated from the stem bark of Uvaria siamensis (Annonaceae), along with five known compounds, eriodictyol ( 3 ), quercetin ( 4 ), paprazine ( 5 ), N - trans -caffeoyltyramine ( 6 ), and N - trans -feruloyltyramine ( 7 ). Their structures were determined through extensive spectroscopic analyses and comparison with the literature. The α -glucosidase inhibitory potential of 1-7 was evaluated. Compound 6 showed the highest inhibitory activity against α -glucosidase and exhibited superior potency compared to the positive control, with an IC 50 value of 0.12  μ M.

Astragalus membranaceus is a traditional Chinese medicine with multiple pharmacological activities. Modern pharmacological research has found that Astragalus membranaceus extract has an inhibitory effect on α-glucosidase, however, which component can inhibit the activity of α-glucosidase and its degree of inhibition are unknown. To address this issue, this study used affinity ultrafiltration screening combined with UPLC-ESI-Orbitrap-MS technology to screen α-glucosidase inhibitors in Astragalus membranaceus . Using affinity ultrafiltration technology, we obtained the active components, and using UPLC-ESI-Orbitrap-MS technology, we quickly analyzed and identified them. As a result, a total of 8 ingredients were selected as α-glucosidase inhibitors.

A study was conducted to investigate the anti-diabetic and anti-urease potential of Osbeckia nutans leaves (ONL). Six compounds, i.e. quercetin-3-O-glucoside, myricetin, shikimic acid, catechin, trans-ferulic acid and luteolin were identified from the butanol sub-fraction, BE2 and the ethyl acetate sub-fraction, EA5 of ONL. BE2 inhibited α-glucosidase and Jack bean urease with IC 50 values of 0.036 μg/mL (437.46 μg/mL for acarbose) and 0.327 mg/mL (0.039 mg/mL for thiourea), respectively. In the glucose uptake experiment, BE2 (0.05 mg/mL) treatment resulted in a substantial increase in glucose uptake in free fatty acid (FFA)-treated cells at a concentration 10 times lower than that seen in EA5 (0.5 mg/mL) treated cells. The binding energies of quercetin-3-O-glucoside with α-glucosidase, glucose transporter GLUT4 and H. pylori urease were found to be -94.2585, -219.8271 and -254.391 kcal/mol, respectively. This study revealed that ONL has anti-diabetic and anti-urease abilities and further in-depth research may unveil its full potential.

Context: Alpha-glucosidase enzyme is considered an important therapeutic target for controlling hyperglycemia associated with type 2 diabetes. Novel scaffolds identified as potential alpha-glucosidase inhibitors from the Maybridge library utilizing pharmacophore modeling, molecular docking and biological evaluation are reported in this manuscript., Method: A total of 51 xanthone series scaffolds previously reported as alpha-glucosidase inhibitors were collected and used as training and test sets. These sets were employed to develop and validate a pharmacophore-based 3D-QSAR model with statistically meaningful results using Schrodinger software. The model showed a high F value (F, 80.1) at five component partial least square factors, a high cross-validation coefficient (Q 2 , 0.66) and a good correlation coefficient (R 2 , 0.95). Pearson correlation coefficient (r) of 0.8400 indicated a greater degree of confidence in the model. Subsequently, virtual screening was performed with PHASE module of Schrodinger software using the above model to identify novel alpha-glucosidase inhibitors, and mapped compounds were evaluated for their interactions with the protein. The X-ray co-crystallised structure of the alpha-glucosidase protein in complex with acarbose (PDB Code: 5NN8) was used for molecular docking analysis using GLIDE module and a total of eight compounds were further selected for biological evaluation. Molecular dynamics analysis using GROMACS software was performed in the active site of alpha-glucosidase protein to gain insights into binding mechanism of the four active compounds which were finally found to exhibit inhibitory activity in the biological assay., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The effect of inhibiting retrogradation and changes in chain length distribution by AG and BE, which are texture-modifying enzymes, has been clarified. To ascertain in which part of the rice grain retrogradation occurs and which enzymes is most effective, the degree of retrogradation in each part of the rice grain was measured from the surface to the core of the same rice grain using a synchrotron radiation X-ray beam with a beam size of 100 μm. Retrogradation was effectively suppressed at all measurement sites by enzyme addition, although the effect of enzymes was greater at the surface. Rice grain sections were stained with iodine and eosin. A starch layer that does not easily form a complex with iodine was observed inside the protein layer at the surface of cooked rice. A starch layer with a long molecular chain that forms complexes with iodine was observed inside the rice grain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

1-deoxynojirimycin (DNJ) is a well-known α-glucosidase inhibitor. A series of phenyltriazole-deoxynojirimycin hybrids containing C 4 and C 6 (4 and 6 methylenes, respectively) linkers were synthesized. These novel compounds were assessed for preliminary glucosidase inhibition and cytotoxicity tests in vitro. Among them, compounds 12 - 14 and 16 - 20 (IC 50 : 105 ± 9-11 ± 1 μM) were more active than deoxynojirimycin (DNJ, IC 50 = 155 ± 15 μM). The kinetics of enzyme inhibition measured by using Lineweaver-Burk plots indicated that compounds 18 and 19 were competitive inhibitors. In addition, a molecular docking study of α-glucosidase revealed that the interaction modes and the orientations of compound 18 and DNJ were clearly different. Furthermore, in tissue culture, HL60 cell compounds showed no cytotoxicity at low concentrations. When the concentration reached 50 µM, only compound 20 exhibited cytotoxicity. The structure-activity relationships exhibit that the length of the linker and the nature of 4-position substituents on the phenyl have a significant effect on the inhibitory potency of glucosidases and cytotoxicity.

Type 2 diabetes (T2D), characterized by insulin resistance and β-cell dysfunction, requires continuous advancements in management strategies, particularly in controlling postprandial hyperglycemia to prevent complications. Current antidiabetics, which have α-amylase and α-glucosidase inhibitory activities, have side effects, prompting the search for better alternatives. In addition, diabetes patients are particularly vulnerable to yeast infections because an unusual sugar concentration promotes the growth of Candida spp. in areas like the mouth and genitalia. Asphodelus microcarpus contains bioactive flavonoids with potential enzyme inhibitory properties. This study investigates α-amylase and α-glucosidase inhibitory activities and antioxidant and antimycotic capacity of ethanolic extracts from different parts of A. microcarpus . Results show that extracts significantly inhibit α-glucosidase, with the IC 50 value being up to 25 times higher than for acarbose, while exerting low α-amylase activity. The extracts also demonstrated strong antioxidant properties and low cytotoxicity. The presence of phenolic compounds is likely responsible for the observed biological activities. Molecular docking analysis of 11 selected compounds identified emodin and luteolin as significant inhibitors of α-glucosidase. Additionally, the extracts demonstrated significant antibiofilm action against an MDR strain of Candida albicans . These findings suggest that A. microcarpus is a promising source of natural compounds for T2D management.

The complex of oat β-glucan (OBG) and flavonoids hampered the digestion of starch-based food and retarded the blood glucose response; however, its effect on gastric emptying and its relative mechanism have not been thoroughly investigated. By using Fourier transform infrared (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), antioxidant ability, and enzymic inhibitory tests for the characterization and in vitro semi-dynamic digestion of complexes of OBG (high and low molecular weights) and sea buckthorn flavonoids, we found that the higher molecular weight complex (FU) exhibited stronger ABTS and DPPH radical scavenging abilities and higher α-glucosidase and α-amylase inhibition rates. Mice fed with rice flour with FU addition exhibited the slowest gastric emptying and intestinal propulsion rates and blood glucose rise and had the lowest activity of digestive enzymes and levels of insulin, ghrelin, motilin (MTL), and relevant gene (ghrelin and GHSR mRNA) expression than those in the control and low-molecular-weight groups. This study provided scientific data for the development of foods with delayed gastric rate and hypoglycemic index for specific populations.

Diabetes is a metabolic condition defined by abnormal blood sugar levels. Targeting starch-hydrolyzing enzymes and Dipeptidyl Peptidase 4 (DPP-4) expressed on the surface of numerous cells is one of the key strategies to lower the risk of Type-2 diabetes mellitus (T2DM). Dalbergia sissoo Roxb. bark (DSB) extracts have been reported to have anti-diabetic properties. This study intended to scientifically validate use of alcoholic and hydro-alcoholic extracts of DSB for T2DM by conducting preliminary phytochemical investigations, characterising potential phytochemicals using Fourier transform infrared (FT-IR) spectroscopy and Gas chromatography-mass spectrometry (GC-MS) analysis followed by comprehensive in-silico analysis. A qualitative phytochemical evaluation indicated the presence of alkaloids, phenolics, glycosides, conjugated acids and flavonoids. Ethanolic extracts showed highest total phenolic content (TPC) (127.072 ± 14.08031 μg GAE/g dry extract) and total flavonoid content (106.911 ± 5.84516 μg QE /g dry extract). Further FT-IR spectroscopy also revealed typical band values associated with phenol, alcohol, alkene, alkane and conjugated acid functional groups. The GC-MS analysis identified 139 compounds, 18 of which had anti-diabetic potential. In-silico ADMET analysis of potential compounds revealed 15 compounds that followed Lipinski's rule and demonstrated drug-like properties, as well as good oral bioavailability. Molecular docking was utilised to analyse their potential to interact with three targets: α-amylase, α-glucosidase, and DPP-4, which are crucial in managing diabetes-related problems. Molecular Docking analysis and membrane permeability test utilising the PerMM platform revealed that compounds in the extracts, such as Soyasapogenol B and Corydine, had better interactions and permeability across the plasma membrane than standard drugs in use. Molecular dynamics simulations also showed that selected compounds remained stable upon interaction with α-amylase. Overall, using the in-silico approaches it was predicted that DSB extracts contain potential phytochemicals with diverse anti-diabetic properties. It further needs to be investigated for possible development as formulation or drug of choice for treating T2DM., (© 2024. The Author(s).)

Compounds of natural origin found in varying quantities in plant-based products constitute a highly significant category, possessing structural significance as well as the capacity to regulate oxidative processes. The activity of these compounds may be modulated by the composition of the biological environment in which they operate, the pH of the environment, or the presence of metal cations in plants or plant extracts. A successful complexation reaction was mainly confirmed by FT-IR, observing the shift from the original transmittance of catechin bonds, especially O-H ones. This work shows the synthetic methodology and the optimization process that took place to synthesize a catechin-copper complex, which demonstrated antioxidant activity. It was tested for iron chelation ability, hydroxyl radicals, and the inhibition of lipoxygenase (15-LOX). An antidiabetic assay was performed by determining the inhibition of alpha-amylase and alpha-glucosidase, finding that the synthesized complex had similar inhibitory potential as pure catechin. The antibacterial tests showed results against Staphylococcus aureus and the antifungal properties of the complex against Candida albicans .

Dendrobium officinale Kimura & Migo (D. officinale) has been widely used as Chinese medicine and functional food. In present study, the structural characteristics of anthocyanins in D. officinale were investigated by ultra-performance liquid chromatography with diode array detector (UPLC-DAD) and ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-Q-TOF-MS/MS). Totally, 14 anthocyanins were detected and identified, and 13 of them were first reported in D. officinale. Results showed that the vast majority of anthocyanins had multi-glycosylated cyanidin core, with variable acylation pattern mainly comprising phenolic acids. The composition and content of anthocyanins in D. officinale stems with different cultivation modes and years have been compared. The anthocyanins showed potent antioxidant activity in terms of radicals scavenging capacity and reducing power, as well as superior α-amylase and α-glucosidase inhibitory activity. The results provided a complete profile of anthocyanins in D. officinale and laid a foundation for further utilizing them as functional foods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Camellia flavida var. flavida, commonly known as "Jinhua Tea", has its flowers and leaves traditionally utilized as tea and functional food sources. However, there is limited knowledge about its bioactive components and their biological activities. This study isolated ten previously unidentified glycoside compounds from the flowers of Camellia flavida , including three oleanane-type triterpenoid saponins (compounds 1 - 3 ) and seven flavonoid glycosides (compounds 4 - 10 ), collectively named flavidosides A-J. This study assessed the cytotoxicity of these compounds against a panel of human cancer cell lines and their α-glucosidase inhibitory activities. Notably, flavidoside C showed significant cytotoxicity against BEL-7402 and MCF-7 cell lines, with IC 50 values of 4.94 ± 0.41 and 1.65 ± 0.39 μM, respectively. Flavidoside H exhibited potent α-glucosidase inhibitory activity, with an IC 50 value of 1.17 ± 0.30 mM. These findings underscore the potential of Camellia flavida in the development of functional foods.

Cyanobacteria, especially Arthrospira, are valuable resources of nutrients and natural pigments with many beneficial health-related properties. This study optimized the extraction conditions of Arthrospira to achieve high phenolic contents and antioxidant activities. Under optimized extraction conditions, the bioactive compounds (phenolics and pigment components), antioxidant activities, and inhibitions of the key enzymes relevant to some non-communicable diseases were compared between Arthrospira platensis and Arthrospira maxima. Optimized extraction conditions were determined as 2 h shaking time, 50 °C extraction temperature, and 1% (w/v) solid-to-liquid ratio, giving effective phenolic and phycocyanin contents using aqueous extraction, while 80% (v/v) aqueous ethanolic extraction provided high total chlorophyll content. Most antioxidant activities were higher using 80% (v/v) aqueous ethanolic extracts. Both Arthrospira species inhibited the key enzymes involved in controlling non-communicable diseases including hyperlipidemia (lipase), diabetes (α-amylase, α-glucosidase, and dipeptidyl peptidase-IV), Alzheimer's disease (acetylcholinesterase, butyrylcholinesterase and β-secretase), and hypertension (angiotensin-converting enzyme). High inhibitory activities were detected against β-secretase (BACE-1), the enzyme responsible for β-amyloid plaque formation in the brain that acts as a significant hallmark of Alzheimer's disease. Arthrospira extract and donepezil (Alzheimer's disease drug) synergistically inhibited BACE-1, suggesting the potential of Arthrospira extracts as effective BACE-1 inhibitors. Interestingly, A. maxima exhibited higher bioactive compound contents, antioxidant activities, and key enzyme inhibitions than A. platensis, indicating high potential for future food and medicinal applications., (© 2024. The Author(s).)

The cloud forest (CF), a hugely biodiverse ecosystem, is a hotspot of unexplored plants with potential for discovering pharmacologically active compounds. Without sufficient ethnopharmacological information, developing strategies for rationally selecting plants for experimental studies is crucial. With this goal, a CF metabolites library was created, and a ligand-based virtual screening was conducted to identify molecules with potential hypoglycemic activity. From the most promising botanical families, plants were collected, methanolic extracts were prepared, and hypoglycemic activity was evaluated through in vitro enzyme inhibition assays on α-amylase, α-glucosidase, and dipeptidyl peptidase IV (DPP-IV). Metabolomic analyses were performed to identify the dominant metabolites in the species with the best inhibitory activity profile, and their affinity for the molecular targets was evaluated using ensemble molecular docking. This strategy led to the identification of twelve plants (in four botanical families) with hypoglycemic activity. Sida rhombifolia (Malvaceae) stood out for its DPP-IV selective inhibition versus S. glabra . A comparison of chemical profiles led to the annotation of twenty-seven metabolites over-accumulated in S. rhombifolia compared to S. glabra , among which acanthoside D and cis -tiliroside were noteworthy for their potential selective inhibition due to their specific intermolecular interactions with relevant amino acids of DPP-IV. The workflow used in this study presents a novel targeting strategy for identifying novel bioactive natural sources, which can complement the conventional selection criteria used in Natural Product Chemistry.

The health-promoting properties of blueberries are widely recognized and are mainly attributed to anthocyanins. However, fruit's chemical composition includes also other components and strongly depends on varieties and climatic conditions. Here, 1 H NMR metabolite profiling and biological activity of four blueberry cultivars (Spartan, Jewels, Misty, Camelia) grown in Central Italy over two years were reported. Untargeted and targeted NMR analyses allowed the quantification of sugars, organic acids, amino acids, anthocyanins, lipids, and other compounds. Spectrophotometric assays evaluated total phenolic and flavonoid content, antioxidant activity, and enzyme inhibitory activity toward cholinesterase, α -amylase, α -glucosidase, and tyrosinase. Statistical analysis showed a correlation between chemical composition and biological activity, revealing markers specific to blueberry cultivars (quinic acid, quercitrin, myo -inositol, myrtillin, and petunidin-3- O -glucoside). Almost all antioxidant assays were correlated with the chlorogenic acid levels. A strong effect of harvesting on chemical composition and biological activities was observed, with Misty cultivar having the highest antioxidant activity.

The four recently described isoflavones, derrisrobustones A-D, and eight known isoflavones extracted from Derris robusta (DC.) Benth. (Leguminosae) were identified as potential isoflavones for α-glucosidase inhibitory activity. However, the inhibitory ability of each isoflavone was quite different and the structural and dynamical properties of the isoflavones in the binding with α-glucosidase have not been studied. In this study, the molecular dynamics (MD) simulation and the molecular mechanics generalized Born surface area (MM/GBSA) methods were applied to gain insight into isoflavones bound with the α-glucosidase active site. The results found that the isoflavones with a hydroxy substituent could be stabilized in the α-glucosidase active site with low values of the binding free energy, especially derrisrobustone D and derrubone. The isoflavones, except for derrubone, were bound with α-glucosidase by means of electrostatic force effectively.

The formation of atroposelective biaryl compounds in plants and fungi is well understood; however, polyketide aglycone synthesis and dimerization in bacteria remain unclear. Thus, the biosynthetic gene cluster (BGC) responsible for antibacterial setomimycin production from Streptomyces nojiriensis JCM3382 was examined in comparison with the BGCs of spectomycin, julichromes, lincolnenins, and huanglongmycin. The setomimycin BGC includes post-polyketide synthase (PKS) assembly/cycling enzymes StmD (C-9 ketoreductase), StmE (aromatase), and StmF (thioesterase) as key components. The heterodimeric TcmI-like cyclases StmH and StmK are proposed to aid in forming the setomimycin monomer. In addition, StmI (P-450) is predicted to catalyze the biaryl coupling of two monomeric setomimycin units, with StmM (ferredoxin) specific to the setomimycin BGC. The roles of StmL and StmN, part of the nuclear transport factor 2 (NTF-2)-like protein family and unique to setomimycin BGCs, could particularly interest biochemists and combinatorial biologists. α-Glucosidase, a key enzyme in type 2 diabetes, hydrolyzes carbohydrates into glucose, thereby elevating blood glucose levels. This study aimed to assess the α-glucosidase inhibitory activity of EtOAc extracts of JCM 3382 and setomimycin. The JCM 3382 EtOAc extract and setomimycin exhibited greater potency than the standard inhibitor, acarbose, with IC 50 values of 285.14 ± 2.04 μg/mL and 231.26 ± 0.41 μM, respectively. Molecular docking demonstrated two hydrogen bonds with maltase-glucoamylase chain A residues Thr205 and Lys480 (binding energy = -6.8 kcal·mol -1 ), two π-π interactions with Trp406 and Phe450, and one π-cation interaction with Asp542. Residue-energy analysis highlighted Trp406 and Phe450 as key in setomimycin's binding to maltase-glucoamylase. These findings suggest that setomimycin is a promising candidate for further enzymological research and potential antidiabetic therapy.

N -Glycan-dependent endoplasmic reticulum quality control (ERQC) primarily mediates protein folding, which determines the fate of the polypeptide. Monoglucose residues on N -glycans determine whether the nascent N -glycosylated proteins enter into and escape from the calnexin (CANX)/calreticulin (CALR) cycle, which is a central system of the ERQC. To reveal the impact of ERQC on glycosylation and protein fate, we performed comprehensive quantitative proteomic and glycoproteomic analyses using cells defective in N -glycan-dependent ERQC. Deficiency of MOGS encoding the ER α-glucosidase I, CANX, or/and CALR broadly affected protein expression and glycosylation. Among the altered glycoproteins, the occupancy of oligomannosidic N -glycans was significantly affected. Besides the expected ER stress, proteins and glycoproteins involved in pathways for lysosome and viral infection are differentially changed in those deficient cells. We demonstrated that lysosomal hydrolases were not correctly modified with mannose-6-phosphates on the N -glycans and were directly secreted to the culture medium in N -glycan-dependent ERQC mutant cells. Overall, the CANX/CALR cycle promotes the correct folding of glycosylated peptides and influences the transport of lysosomal hydrolases.

Ripened pu-erh tea is known to have beneficial hypoglycemic properties. However, it remains unclear whether the bioactive peptides produced during fermentation are also related to hypoglycemic potential. This study aimed to identify hypoglycemic peptides in ripened pu-erh tea and to elucidate their bioactive mechanisms using physicochemical property prediction, molecular docking, molecular dynamics simulations, and cell experiments. Thirteen peptides were identified by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Among them, AADTDYRFS (AS-9) and AGDGTPYVR (AR-9) exhibited high α-glucosidase inhibitory activity, with half-maximal inhibitory concentration (IC 50 ) values of 0.820 and 3.942 mg/mL, respectively. Molecular docking and dynamics simulations revealed that hydrogen bonding, hydrophobic interactions, and van der Waals forces assist peptides AS-9 and AR-9 in forming stable and tight complexes with α-glucosidase. An insulin-resistance (IR)-HepG2 cell model was established. AS-9 was non-toxic to IR-HepG2 cells and significantly increased the glucose consumption capacity, hexokinase, and pyruvate kinase activities of IR-HepG2 cells (p < 0.05). AS-9 alleviated glucose metabolism disorders and ameliorated IR by activating the IRS-1/PI3K/Akt signaling pathway and increasing the expression levels of MDM2, IRS-1, Akt, PI3K, GLUT4, and GSK3β genes. In addition, no hemolysis of mice red blood cells red blood cells occurred at concentrations below 1 mg/mL. This work first explored hypoglycemic peptides in ripened pu-erh tea, providing novel insights for enhancing its functional value., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

A diminutive chemical library of acyl thiotriazinoindole (ATTI) based bioactive scaffolds was synthesized, instigated by taking the economical starting material Isatin, through a series of five steps. Isatin was first nitrated followed by the attachment of pentyl moiety via nucleophilic substitution reaction. The obtained compound was reacted with thiosemicarbazide to obtain thiosemicarbazone derivative, which was eventually cyclized using basic conditions in water as solvent. Finally, the reported series was obtained through reaction of nitrated thiotriazinoindole moiety with differently substituted phenacyl bromides. The synthesized compounds were characterized using NMR spectroscopy and elemental analysis. Finally, the synthesized motifs were scrutinized for their potential to impede urease, α-glucosidase, DPPH, and α-amylase. Compound 5 h with para cyano group manifested the most pivotal biological activity among all, displaying IC 50 values of 29.7 ± 0.8, 20.5 ± 0.5 and 36.8 ± 3.9 µM against urease, α-glucosidase, and DPPH assay, respectively. Simultaneously, for α-amylase compound 5 g possessing a p-CH 3 at phenyl ring unfolded as most active, with calculated IC 50 values 90.3 ± 1.1 µM. The scaffolds were additionally gauged for their antifungal and antibacterial activity. Among the tested strains, 5d having bromo as substituent exhibited the most potent antibacterial activity, while it also demonstrated the highest potency against Aspergillus fumigatus. Other derivatives 5b, 5e, 5i, and 5j also exhibited dual inhibition against both antibacterial and antifungal strains. The interaction pattern of derivatives clearly displayed their SAR, and their docking scores were correlated with their IC 50 values. In molecular docking studies, the importance of interactions like hydrogen bonding was further asserted. The electronic factors of various substituents engendered variety of interactions between the ligands and targets implying their importance in the structures of the synthesized heterocyclic scaffolds. To conclude, the synthesized compounds had satisfactory biological activity against various important targets. Further studies are therefore encouraged by attachment of different substitutions in the structure at various positions to enhance the activity of these compounds., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The present paper is a comprehensive study on the optimization of ultrasonic assisted extraction and characterization of valued components from the newly developed garlic cultivar NARC-G1. The response surface methodology was employed to optimize the extraction time, solvent-to-solid ratio and extraction temperature, for optimal total phenolic contents (TPC), DPPH radical scavenging activity, α-amylase inhibition, and α-glucosidase inhibition. Under the optimized conditions (23 min extraction time, 60 °C temperature, and 39 : 1 solvent-to-solute ratio) the optimal TPC (13.76 mg GAE/g), DPPH radical scavenging activity (62.76 %), α-amylase inhibition (71.43 %), and α-glucosidase inhibition (79.43 %) were obtained. Significant correlations were observed between actual values and predicted values for the selected responses. Gas chromatography-mass spectrometry (GC-MS), revealed 26 high-value bioactives, with diallyl disulphide being the most abundant (16.22 %), followed by 2,3-dihydro-3,5-dihydroxy-6-methyl, 4H-pyran-4-one and 5-Hydroxymethylfurfural. Additionally, in silico investigation indicated that stigmasterol, arbutin, squalene, α-tocopherol and linoleic acid were responsible for antihyperglycemic potential. Moreover, antimicrobial activity revealed that S. mutans (19.25±1.98 mm) and L. monocytogenes (19.34±2.04 mm) were the most sensitive, while P. aeruginosa was the least sensitive bacterial strains against the optimized NARC-G1 garlic extract. This research effectively explains the optimal recovery of high-valued components from NARC-G1 and may contribute to nutra-pharmaceutical and functional food developments., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Pompe disease is a rare genetic disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA). This enzyme is responsible for breaking down glycogen, leading to the abnormal accumulation of glycogen, which results in progressive muscle weakness and metabolic dysregulation. In this study, we investigated the hypothesis that the small molecule inhibition of glycogen synthase I (GYS1) may reduce muscle glycogen content and improve metabolic dysregulation in a mouse model of Pompe disease. To address this hypothesis, we studied four groups of male mice: a control group of wild-type (WT) B6129SF1/J mice fed either regular chow or a GYS1 inhibitor (MZ-101) diet (WT-GYS1), and Pompe model mice B6;129-Gaatm1Rabn/J fed either regular chow (GAA-KO) or MZ-101 diet (GAA-GYS1) for 7 days. Our findings revealed that GAA-KO mice exhibited abnormal glycogen accumulation in the gastrocnemius, heart, and diaphragm. In contrast, inhibiting GYS1 reduced glycogen levels in all tissues compared with GAA-KO mice. Furthermore, GAA-KO mice displayed reduced spontaneous activity during the dark cycle compared with WT mice, whereas GYS1 inhibition counteracted this effect. Compared with GAA-KO mice, GAA-GYS1 mice exhibited improved glucose tolerance and whole body insulin sensitivity. These improvements in insulin sensitivity could be attributed to increased AMP-activated protein kinase phosphorylation in the gastrocnemius of WT-GYS1 and GAA-GYS1 mice. Additionally, the GYS1 inhibitor led to a reduction in the phosphorylation of GS S641 and the LC3 autophagy marker. Together, our results suggest that targeting GYS1 could serve as a potential strategy for treating glycogen storage disorders and metabolic dysregulation. NEW & NOTEWORTHY We investigated the effects of small molecule inhibition of glycogen synthase I (GYS1) on glucose metabolism in a mouse model of Pompe disease. GYS1 inhibition reduces abnormal glycogen accumulation and molecular biomarkers associated with Pompe disease while also improving glucose intolerance. Our results collectively demonstrate that the GYS1 inhibitor represents a novel approach to substrate reduction therapy for Pompe disease.

Crotamine (Ctm) is a peptide isolated from Crotalus durissus terrificus venom. This molecule has been demonstrated to diminish body weight gain and enhance browning in adipose tissue, glucose tolerance, and insulin sensitivity; hence, it has been postulated as an anti-obesogenic peptide. However, the mechanism to elicit the anti-obesogenic effects has yet to be elucidated. Thus, we investigated the possible interaction of Ctm with receptors involved in obesity-related metabolic pathways through protein-protein docking and molecular dynamics refinement. To test the anti-obesogenic mechanism of Ctm, we selected and retrieved 18 targets involved in obesity-related drug discovery from Protein Data Bank. Then, we performed protein-protein dockings. The best three Ctm-target models were selected and refined by molecular dynamics simulations. Molecular docking demonstrated that Ctm was able to interact with 13 of the 18 targets tested. Having a better docking score with glucagon-like peptide-1 receptor (GLP-1R) (-1430.2 kcal/mol), DPP-IV (dipeptidyl peptidase-IV) (-1781.7 kcal/mol) and α-glucosidase (-1232.3 kcal/mol). These three models were refined by molecular dynamics. Ctm demonstrated a higher affinity for GLP-1R (ΔG: -41.886 ± 2.289 kcal/mol). However, Ctm interaction was more stable with DPP-IV (RMSD: 0.360 ± 0.015 nm, Radius of gyration: 2.781 ± 0.009 nm). Moreover, the number of interactions and the molecular mechanics energies of Ctm residues suggest that the interaction of Ctm with these receptors is mainly mediated by basic-hydrophobic dyads Y1-K2, W31-R32, and W33-R34. Together, all these results allow elucidating a possible molecular mechanism behind the previously described anti-obesogenic effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Amomum dealbatum Roxb. parts have been traditionally used as remedies for joint pain, diabetes, muscular rheumatism, antiseptic, and abscesses in Arunachal Pradesh, Assam, and Tripura. Ethyl acetate sub-fraction E3 had significantly inhibited the α-glucosidase (IC 50 5.385 μg/mL). The molecular docking revealed quercetin-3-O-galactoside to be the most potent α-glucosidase inhibitor (binding energy -43.214 kcal/mol). Using the QSAR model, the pIC 50 values of myricetin, gallic acid, quercetin-3-O-galactoside, and acarbose were predicted to be 5.65235, 4.39858, 5.65235, and 6.03058, respectively. For the first time, quercetin-3-O-galactoside, myricetin, and gallic acid have been isolated from the flowers of A. dealbatum (ADF). E3 decreased blood glucose level to a near-normal concentration (100.60 ± 2.94 mg/dL) in comparison to diabetic control rats (575.20 ± 24.80 mg/dL). The results have strongly suggested the potential of ADF in treating diabetes. This lesser-known plant has the potential to uncover its full medicinal properties through further in-depth research.

Diabetes mellitus type 2 (T2DM) can be managed by targeting dipeptidyl peptidase-4 (DPP-4), an enzyme that breaks down and deactivates peptides such as GIP and GLP-1. In this context, a new series of 2-(2-substituted hydrazineyl)thiazole derivatives 4, 5, 6, 8, 10, and 11 conjugated with the 2-hydroxy-5-(pyrrolidin-1-ylsulfonyl)benzylidene fragment were designed and synthesized. The virtual screening of the designed derivatives inside DPP-4 demonstrated good to moderate activity, with binding affinity ranging from -6.86 to -5.36 kcal/mol compared to Sitagliptin (S=-5.58 kcal/mol). These results encourage us to evaluate DPP-4 using in-vitro fluorescence-based assay. The in-vitro results exhibited inhibitory percentage (IP) values ranging from 40.66 to 75.62 % in comparison to Sitagliptin (IP=63.14 %) at 100 µM. Subsequently, the IC 50 values were determined, and the 5-aryl thiazole derivatives 10 and 11 revealed strong potent IC 50 values 2.75 ± 0.27 and 2.51 ± 0.27 µM, respectively, compared to Sitagliptin (3.32 ± 0.22 µM). The SAR study exhibited the importance of the substituents on the thiazole scaffold, especially with the hydrophobic fragment at C5 of the thiazole, which has a role in the activity. Compounds 10 and 11 were further assessed toward α-glucosidase and α-amylase enzymes and give promising results. Compound 10 showed good activity against α-glucosidase with IC 50 value of 3.02 ± 0.23 µM compared to Acarbose 3.05 ± 0.22 µM and (11 = 3.34 ± 0.10 µM). On the other hand, for α-amylase, compound 11 was found to be most effective with IC 50 value of 2.91 ± 0.23 µM compared to compound 10 = 3.30 ± 0.16 µM and Acarbose (2.99 ± 0.21 µM) indicating that these derivatives could reduce glucose by more than one target. The most active derivatives 10 and 11 attracted great interest as candidates for oral bioavailability and safe toxicity profiles compared to positive controls. The in-silico docking simulation was performed to understand the binding interactions inside the DPP-4, α-glucosidase, and α-amylase pockets, and it was found to be promising antidiabetic agents through a number of interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bioactivity screening revealed that the EtOAc extract from the culture broth of Phellinus igniarius SY489 exhibited remarkable α-glucosidase inhibitory activity, with an IC 50 value of 1.92 μg/mL. Activity- and ultraviolet (UV) profile-guided isolation led to the discovery of four anti-diabetic styrylpyrones (1-4), including two novel compounds, phelignidins A (1) and B (2). Compounds 1 and 2 represent a rare structural type of styrylpyrone dimer, in which one of the pyrone moieties exists in an open-ring state. The absolute configurations of the new compounds 1 and 2, as well as the previously unresolved compound 3, were established. Compounds 1-4 were effective in α-glucosidase inhibition, anti-glycation, and antioxidant assays, surpassing or being comparable to the positive control drugs, with minimal cytotoxicity. Furthermore, studies on α-glucosidase inhibition mechanisms suggested that these compounds interact with α-glucosidase at a single binding site, causing secondary structure unfolding and exerting inhibitory activity via a mixed-type mechanism. These results provide an important basis for developing novel, low-toxicity, multi-target anti-diabetic drugs from edible and medicinal fungi., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The control of α-glucosidase activity has been associated with managing diabetes. We previously identified three peptides with high bioactive indices derived from protein hydrolysates of fermented spent coffee grounds. In this study, the peptides YGF, GMCC, and RMYRY were synthesized and tested in vitro for their α-glucosidase inhibition activity, complemented by in silico analyses. Two of the three peptides significantly inhibited α-glucosidase activity, with the more efficient peptides being YGF and GMCC (0.42 mg/mL), resulting in decreased enzymatic activity of 95.31% and 89.79%, respectively. These peptides exhibited binding free energies with the α-glucosidase complex of -8.5 and - 6.6 kcal/mol, respectively, through hydrogen bonds and van der Waals interactions with amino acids from the active site. Pharmacokinetic analysis indicated that YGF and GMCC profiles were unrelated to toxicity. These results underscore the importance of focusing on food waste bioprocessing products to expand the range of alternatives that could aid in diabetes treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)