Search Results (483)

Deoxynojirimycin (DNJ), the first isolated iminosugar, is a natural alkaloid acting as a potent inhibitor of α-glucosidase with high nutritional value. It naturally occurs in plants (especially Morus spp.), microbes, and insects or can be synthesized. Diverse biological activities, such as antihyperglycemic, lipid-lowering, antitumor, antiviral, and anti-inflammatory, have been recognized for this compound. However, DNJ has not been approved as a food supplement until now. Several studies, also in clinics, are carried out on Morus spp. containing DNJ. Among Morus spp., Morus alba L. (white mulberry), Morus nigra L. (black mulberry), and Morus rubra L. (red mulberry) are the three main species that grow all over the world. Some spurious studies have been conducted on Reducose^® and Glubloc™, two products that contain DNJ and Morus alba, respectively. However, mulberry allergy, including respiratory allergy, airborne contact urticaria, anaphylaxis, oral allergy syndrome, and food induced urticaria, may be observed. This review aims to explore a crucial and timely question: how DNJ exerts its biological effects and what role it may play in therapeutic applications. We provide a comprehensive summary of the current understanding of DNJ’s pharmacological potential and the methods used for its production. We also report recent developments in clinical studies on Morus alba, Reducose^® and Glubloc™. Full article

Type 2 diabetes mellitus (T2DM) demands safer and more effective therapies to control postprandial hyperglycemia. Here, we report the synthesis and in vitro evaluation of ten salicylic acid-derived Schiff base derivatives (4a–4j) as α-glucosidase inhibitors. Compounds 4e, 4g, 4i, and 4j exhibited potent enzyme inhibition, with IC₅₀ values ranging from 14.86 to 18.05 µM—substantially better than acarbose (IC₅₀ = 45.78 µM). Molecular docking and 500 ns molecular dynamics simulations revealed stable enzyme–ligand complexes driven by π–π stacking, halogen bonding, and hydrophobic interactions. Density Functional Theory (DFT) calculations and molecular electrostatic potential (MEP) maps highlighted key electronic factors, while ADMET analysis confirmed favorable drug-like properties and reduced nephrotoxicity. Structure–activity relationship (SAR) analysis emphasized the importance of halogenation and aromaticity in enhancing bioactivity. Full article

Background: Reducing postprandial blood glucose (PBG) is a crucial strategy for treating diabetes and minimizing the risk of complications. Developing efficient and safe α-glycosidase inhibitors from natural products to lower PBG has attracted much attention. Silphium perfoliatum L. (SP), a traditional herbal medicine of North American Indigenous tribes, has efficacy of treating metabolic diseases, but its hypoglycemic activity and bioactive components have not been fully studied. Methods: In vitro α-glucosidase inhibition and in vivo sucrose/maltose/starch tolerance assays were performed to assess the hypoglycemic effects of SP extracts, and UPLC-Triple-TOF-MS/MS analysis was used to tentatively identify its chemical structure composition. In vitro enzyme inhibition and molecular docking were used to verify the effective ingredients. Results: In vitro hypoglycemic activities of four extracts of SP (SP-10/SP-40/SP-60/SP-C) showed that SP-10 exhibited strong α-glucosidase (sucrase and maltase) inhibitory effects with IC₅₀ of 67.81 μg/mL and 62.99 μg/mL, respectively. Carbohydrate tolerance assays demonstrated that SP-10 could significantly reduce the PBG levels of diabetic mice, with a significant hypoglycemic effect at a dosage of 20 mg/kg. A total of 26 constituents, including 11 caffeoylquinic acids (CQAs) and 15 flavonol glycosides, were tentatively identified by mainly analyzing secondary MS fragmentation. Moreover, three CQAs rich in SP-10, namely chlorogenic acid (CGA), neochlorogenic acid (NCGA), and cryptochlorogenic acid (CCGA), may be the main hypoglycemic substances, as evidenced by their inhibitory effects on sucrase and maltase. Conclusions: The α-glucosidase inhibitory effects of SP extract both in vitro and in vivo and its active ingredients were systematically studied for the first time. Results indicated that SP extract, rich in CQAs, had significant hypoglycemic activity, supporting the considerable potential of SP as hypoglycemic functional food or cost-effective therapeutic agents for diabetes treatment. Full article

Amorpha fruticosa L. (Fabaceae) originates from North America and has become an aggressive invasive plant in many parts of the world. It affects the local biodiversity in many negative ways. Our previous in vivo tests of purified extract of A. fruticosa pods for antihyperglycemic activity in streptozotocin-induced diabetic spontaneously hypertensive rats (SHRs) revealed that the oral administration of purified extract of A. fruticosa (100 mg/kg) for 35 days to SHRs caused significant decreases in the systolic pressure, blood glucose levels, and MDA quantity. The aim of this experimental study is to test the glycosidase inhibition of several extracts of A. fruticosa pods. Methods: GC-MS, NMR, and a glycosidase inhibition assay were performed. Results: The results demonstrate strong inhibition of yeast alpha- and almond beta-glucosidases, rat intestinal hexosaminidase, and bovine beta-glucuronidase, but not of some other glycosidases. The activity is probably due at least in part to the presence of iminosugars and iminosugar acids. We here report on further analysis and activity assessments of A. fruticosa pods and leaves collected in Bulgaria, and for the first time discover glycosidase inhibitors, pinitol, and hydroxylated pipecolic acids in the species and more complex iminosugar-like compounds that may all contribute to antidiabetic potential. Hydroxylated pipecolic acids are probable precursors of iminosugars and common in legumes containing them. Considerable chemical variation was observed over four pod collections. Conclusions: A. fruticosa pods and leaves were found to contain a number of compounds that could contribute to the potential antihyperglycemic activities including pinitol and a complex mixture of iminosugar-related compounds derived from pipecolic acids and prolines. The pods and leaves caused potent selective inhibition of glucosidases and hexosaminidases and beta-glucuronidase. The variation between the collections might reflect the sites differing or wide phenotypic versatility allowing the success of the species as an invasive plant. Full article

This study describes the synthesis of heterocyclic derivatives containing multiple nitrogen atoms serving as important moieties for developing novel antidiabetics through a simple synthetic pathway. We herein describe the synthesis and characterization of novel pyrimidine derivatives using one-pot reactions in a catalyst-free and efficient manner through a two-stage process involving the synthesis of 2-amino-4-hydrazinyl-6-methoxy pyrimidine, followed by a reaction with phenyl isothiocyanate derivatives. The structures of all the new compounds were confirmed via physical and spectral analysis. Furthermore, we evaluated the synthesized pyrimidine derivatives’ biological activities in relation to their potential roles as novel anti-diabetic agents by testing their activity profiles against the enzymes α-glucosidase and α-amylase. Compound 4 expressed the highest level of activity against α-glucosidase and α-amylase, with a greater inhibitory concentration (IC₅₀ of 12.16 ± 0.12 µM and IC₅₀ 11.13 ± 0.12 µM) compared to that of acarbose (IC₅₀ = 10.60 ± 0.17 µM and IC₅₀ = 11.30 ± 0.12 µM), which is widely used as a standard antidiabetic drug. The primary structure activity relationship analysis identified the impact of an electron- withdrawing group, especially with respect to fluorine on inhibitory activity. This was further confirmed in molecular docking studies, which demonstrated that both compounds exhibited similar inhibition patterns and emphasized the significance of incorporating a lipophilic electron-withdrawing substituent on the phenyl ring, along with the 2,4-diaminopyrimidine scaffold. Full article

A group of sulfonium and selenonium salts bearing diverse benzylidene acetal substituents on their side chain moiety were designed and synthesized. Compared with our previous study, structural modifications in this study focused on multi-substitution of the phenyl ring and bioisosteric replacements at the sulfonium cation center. In vitro biological evaluation showed that selenonium replacement could significantly improve their α-glucosidase inhibitory activity. The most potent inhibitor 20c (10.0 mg/kg) reduced postprandial blood glucose by 48.6% (15 min), 52.8% (30 min), and 48.1% (60 min) in sucrose-loaded mice, outperforming acarbose (20.0 mg/kg). Docking studies of 20c with ntMGAM presented a new binding mode. In addition to conventional hydrogen bonding and electrostatic interaction, amino residue Ala-576 was first identified to contribute to binding affinity through π-alkyl and alkyl interactions with the chlorinated substituent and aromatic ring. The selected compounds exhibited a high degree of safety in cytotoxicity tests against normal cells. Kinetic characterization of α-glucosidase inhibition confirmed a fully competitive inhibitory mode of action for these sulfonium salts. Full article

The current study investigates the chemical profiling, antioxidant activities, and enzyme inhibitory and cytotoxic potential of the water and methanolic extracts of different parts (flower, leaf, and bulb) of Muscari armeniacum. Chemical profiling was performed using UHPLC-MS/MS. At the same time, different in vitro assays were employed to support the results for antioxidant potential, such as DPPH, ABTS, FRAP, CUPRAC, metal chelation, and PBD, along with the measurement of total phenolic and flavonoid contents. Enzyme inhibition was investigated for cholinesterase (AChE and BChE), α-amylase, α-glucosidase, and tyrosinase enzymes. Additionally, the relative expression of NRF2, HMOX1, and YGS was evaluated by qPCR. LC-MS/MS analysis indicated the presence of some significant compounds, including apigenin, muscaroside, hyacinthacine A, B, and C, and luteolin. According to the results, the highest TPC and TFC were obtained with both extracts of the leaves, followed by the water extract (flower) and methanolic extract of the bulb. In contrast, the methanolic extract from the bulb exhibited the highest antioxidant potential using DPPH, ABTS, CUPRAC, and FRAP, followed by the extracts of leaves. In contrast, the leaf extracts had the highest values for the PBD assay and maximum chelation ability compared to other tested extracts. According to the enzyme inhibition studies, the methanolic extract from the bulb appeared to be the most potent inhibitor for all the tested enzymes, with the highest values obtained for AChE (1.96 ± 0.05), BChE (2.19 ± 0.33), α-amylase (0.56 ± 0.02), α-glucosidase (2.32 ± 0.01), and tyrosinase (57.19 ± 0.87). Interestingly, the water extract from the bulb did not inhibit most of the tested enzymes. The relative expression of NRF2 based on qPCR analysis was considerably greater in the flower methanol extract compared to the other extracts (p < 0.05). The relative expression of HMOX1 was stable in all the extracts, whereas YGS expression remained stable in all the treatments and had no statistical differences. The current results indicate that the components of M. armeniacum (leaves, flowers, and bulb) may be a useful source of natural bioactive compounds that are effective against oxidative stress-related conditions, including hyperglycemia, skin disorders, and neurodegenerative diseases. Complementary in silico approaches, including molecular docking, dynamics simulations, and transcription factor (TF) network analysis for NFE2L2, supported the experimental findings and suggested possible multi-target interactions for the selected compounds. Full article

Aim: Myricetin, a natural bioflavonoid, is reported as an anti-diabetic agent since it possesses the ability to inhibit α-glucosidase activity, stimulate insulin action and secretion, manage ROS, and prevent diabetes complications. Myricetin was identified as a new insulin secretagogue that enhances glucose-stimulated insulin secretion and seems like a better antidiabetic drug candidate. Here, we explored the insulinotropic mechanism(s) of myricetin in vitro in mice islets and in silico. Methods: Size-matched pancreatic islets were divided into groups and incubated in the presence or absence of myricetin and agonists/antagonists of major insulin signaling pathways. The secreted insulin was measured by ELISA. Molecular docking studies were performed with the key player of insulin secretory pathways. Results: Myricetin dose-dependently enhanced insulin secretion in isolated mice islets, and its insulinotropic effect was exerted at high glucose concentrations distinctly different from glibenclamide. Myricetin-induced insulin secretion was significantly inhibited using the diazoxide. Furthermore, myricetin amplified glucose-induced insulin secretion in depolarized and glibenclamide-treated islets. Myricetin showed an additive effect with forskolin- and IBMX-induced insulin secretion. Interestingly, H89, a PKA inhibitor, and MAY0132, an Epac-2 inhibitor, significantly inhibited myricetin-induced insulin secretion. The in silico molecular docking studies further validated these in vitro findings in isolated pancreatic islets. Conclusions: Myricetin, a potential natural insulin secretagogue, amplifies glucose-induced insulin secretion via the cAMP-PKA-Epac-2 signaling pathway. Full article

Background: Inhibition of intestinal α-glucosidase is a key strategy for controlling postprandial hyperglycemia in diabetes. Astragali Radix (AR), a traditional medicinal and dietary herb widely consumed in China, is rich in flavonoids that are believed to exhibit hypoglycemic properties. Methods: A total of 29 AR-related flavonoids, including both original constituents and metabolites, were screened for α-glucosidase inhibitory activity using in vitro enzymatic assays. Mechanistic investigations were conducted through enzyme kinetics, circular dichroism (CD) spectroscopy, surface plasmon resonance (SPR), and molecular docking. The in vivo hypoglycemic effects were assessed using a postprandial hyperglycemic mouse model. Additionally, potential mixture effects of flavonoid combinations were evaluated. Results: Of the 29 flavonoids, 16 demonstrated significant α-glucosidase inhibitory activity, with five (C3, C17, C19, C28, and C29) identified as novel inhibitors. Structure–activity relationship (SAR) analysis revealed that hydroxylation, particularly at the C-3 position, enhanced activity, while glycosylation and methoxylation reduced it. Mechanistic studies demonstrated that these compounds bind to distinct amino acid residues within the active site of α-glucosidase, inducing conformational changes and exerting different types of inhibition, leading to varying inhibitory mechanisms. Additionally, 15 compounds reduced postprandial blood glucose levels, with C3, C16, C17, C19, and C28 confirmed as novel in vivo inhibitors. Notably, two compositions of flavonoids combined at their individually ineffective concentrations exhibited significant inhibitory effects. Conclusions: This study provides a comprehensive evaluation of AR-related flavonoids as α-glucosidase inhibitors and offers valuable insights for the development of highly effective, low-toxicity, flavonoid-based, antidiabetic therapeutics and functional foods. Full article

Marine Streptomyces are an important source of naturally occurring active compounds. Out of 23 marine Streptomyces strains, 1 strain of Streptomyces sp. FJ0218 was selected for its high activity in inhibiting α-glucosidase. Two polyketides, phaeochromycins D (2) and E (1), were isolated from the fermentation broth of this strain using bioactivity-guided column chromatography over RP-18, Sephadex LH-20, and silica gel. Their structures were determined using NMR data, HR-EI-MS, and single-crystal X-ray crystallography. Phaeochromycins D (2) and E (1) exhibited inhibitory activity against α-glucosidase, with IC₅₀ values of 10 mM and 25 mM, respectively. Lineweaver–Burk plots revealed that phaeochromycin E (1) acts as an uncompetitive inhibitor, while phaeochromycin D (2) acts as a non-competitive inhibitor. These findings suggest that there is potential for the pharmacological regulation of glucose levels through the use of polyketide phaeochromycins, emphasizing their significant impact on glucose management. Full article

Ulcerative colitis (UC) is a chronic inflammation disease with severe impact on quality of life, with limited treatment options. Ramulus Mori alkaloids (SZ-A) from Morus alba show promise for UC treatment due to their safety and pharmacological effects, including anti-inflammation and barrier repair. However, their clinical use has been limited by gastrointestinal flatulence as a side effect due to their pharmacological action as an α-glucosidase inhibitor targeting the small intestine following oral administration. Therefore, constructing a colon-targeted formulation to deliver SZ-A is an advantageous strategy to improve UC therapy. In this study, we used the complex formed by thiolated hyaluronic acid, which has mucosal adhesion and inflammation-targeting properties, and SZ-A as an intermediate carrier and prepared sodium alginate-modified PLGA microspheres (SZ-A@MSs) with the double emulsion method to achieve efficient encapsulation of SZ-A. Specifically, sodium alginate serves as a gastric acid protectant and microbiota-responsive material, enabling the precise and responsive release of microspheres in the colonic region. SZ-A@MSs have a particle size of about 30 µm, a drug loading of about 12.0%, and an encapsulation efficiency of about 31.7% and function through intestinal adhesion to and targeting of inflammatory sites. SZ-A@MSs showed antioxidant and anti-inflammatory abilities in Raw264.7 cells. In vivo imaging results suggest that SZ-A@MSs have good colon site retention and sustained-release effect. Pharmacodynamic results show that SZ-A@MSs display good efficacy, including the ability to inhibit weight loss, inhibit colonic atrophy, and inhibit the secretion of inflammatory factors. In conclusion, SZ-A@MSs have good colon-targeting properties, can improve therapeutic effects, and provide a potential treatment method for UC. Full article

Leaves of Eriobotrya japonica have long been utilized in traditional Chinese medicine (TCM) for treating pulmonary inflammation and stomach disorders. This study extends their pharmacological applications by evaluating the antioxidant, anti-α-glucosidase, anti-acetylcholinesterase (AChE), and anti-inflammatory activities of solvent extracts and isolated bioactive components through an integrative approach combining extraction, bioassays, and molecular docking. Solvent extracts prepared with varying polarities exhibited distinct bioactivities, with the 100 °C water and methanol extracts displaying the strongest antioxidant potential. The ethyl acetate extract exhibited potent α-glucosidase inhibition, whereas the n-hexane extract demonstrated significant AChE inhibitory activity. Among the isolated compounds, epicatechin (5) (SC₅₀ = 7.83 ± 0.34 μM) and rutin (6) (SC₅₀ = 6.69 ± 0.25 μM) showed superior ABTS and superoxide scavenging activities, respectively, compared to the positive controls (BHT and cynaroside). Ursolic acid (2) exhibited stronger α-glucosidase inhibition (IC₅₀ = 10.68 ± 0.76 μM) than acarbose (IC₅₀ = 419.93 ± 29.15 μM), while tormentic acid (4) demonstrated superior AChE inhibition compared to chlorogenic acid. Ursolic acid (2) also displayed NO inhibition (IC₅₀ = 20.18 ± 1.46 μM) comparable to quercetin (IC₅₀ = 17.05 ± 1.63 μM), with Western blot analysis confirming its potent iNOS inhibitory activity. Molecular docking further supported these findings, revealing that ursolic acid (2) exhibited stronger binding affinity to α-glucosidase (−8.7 kcal/mol) than acarbose (−5.1 kcal/mol), tormentic acid (4) displayed higher binding energy to AChE (−8.8 kcal/mol) compared to chlorogenic acid (−7.8 kcal/mol), and ursolic acid (2) (−7.5 kcal/mol) showed a binding affinity to iNOS similar to that of quercetin (−7.7 kcal/mol). These results highlight the strong potential of E. japonica leaf extracts and bioactive compounds as natural antioxidants, enzyme inhibitors, and anti-inflammatory agents, supporting their development as dietary supplements or therapeutic candidates for managing oxidative stress, hyperglycemia, neurodegenerative diseases, and inflammatory disorders. Full article

The enzymatic hydrolysis of lignocellulose is often hindered by the glucose-mediated inhibition of β-glucosidases, a major bottleneck in industrial cellulose degradation. Identifying novel glucose-tolerant β-glucosidases is essential for enhancing saccharification efficiency. In this study, we cloned and heterologously expressed a novel β-glucosidase, RpBgl8, from the termite Reticulitermes perilucifugus in Escherichia coli. Sequence and structural analyses classified RpBgl8 as a glycoside hydrolase family 1 enzyme. The purified enzyme exhibited optimal activity at 45 °C and pH 7.0, with broad stability across pH 4.0–8.0. Notably, RpBgl8 demonstrated high tolerance to lignocellulose-derived inhibitors and organic solvents, maintaining 100% activity in 15% ethanol. Furthermore, RpBgl8 exhibited outstanding glucose tolerance, retaining 100% activity at 2.5 M glucose and 82% activity at 4.0 M glucose—outperforming most previously reported β-glucosidases. A structural analysis revealed a narrow, hydrophobic substrate pocket, with residue F124 at the glycone-binding site critical for minimizing glucose accumulation. The F124W mutation significantly reduced glucose tolerance, confirming that hydrophobic interactions at the active site mitigate inhibition. These findings establish RpBgl8 as a promising candidate for high-solid biomass processing and simultaneous saccharification and fermentation applications, highlighting termites as underexplored sources of biocatalysts with unique industrial potential. Full article

Macrophages are specialised cells that degrade a range of substrates during their lifetime. In inherited lysosomal storage disorders, particularly the sphingolipidoses, macrophages transform into storage cells and contribute to pathology. An appropriate cultured macrophage model is desired for fundamental research and the assessment of considered therapeutic interventions. We compared commonly used macrophage cell lines, RAW264.7, J774A.1, and THP-1 cells, with human monocyte-derived macrophages (HMDMs) isolated from peripheral blood. Specific lysosomal glucosidases were analysed by enzymatic activity measurements and visualised with fluorescent activity-based probes. Special attention was given to lysosomal glucocerebrosidase (GBA1), the enzyme deficient in Gaucher disease in which lipid-laden macrophages are a hallmark. In macrophage cell lines and HMDMs, various (glyco)sphingolipids relevant to GBA1 activity were determined. Finally, the feasibility of inactivation of GBA1 with a cell-permeable suicide inhibitor was established, as well as the monitoring of uptake of therapeutic recombinant human GBA1. Major differences among various cell lines were noted in terms of morphology, lysosomal enzyme expression, and glycosphingolipid content. HMDMs appear to be the most suitable model for investigations into GBA1 and Gaucher disease. Moreover, they serve as a valuable model for mannose-receptor mediated uptake of therapeutic human GBA1, effectively mimicking enzyme replacement therapy for Gaucher disease. Full article

A novel series of oleanolic acid (OA, 1) derivatives incorporating phenolic and coumarin moieties were synthesized. This acid was extracted from olive pomace (Olea europaea L.) using an ultrasound-assisted method. The structures of these novel derivatives of OA were characterized through the utilization of ¹H-NMR, ¹³C-NMR and ESI-HRMS analyses. An evaluation of some biological activities of the prepared derivatives was conducted. The evaluation focused principally on the capacity of these structures to inhibit 15-lipoxygenase and α-glucosidase, as well as their anticancer properties when tested against tumour cell lines (HCT-116 and LS-174T) and a non-tumour cell line (HEK-293). In terms of their cytotoxic activity, the majority of the compounds exhibited notable inhibitory effects compared to the starting molecule, OA. Derivatives 4d, 4k and 4m exhibited particularly strong inhibitory effects against the HCT-116 cell line, with IC₅₀ values of 38.5, 39.3, 40.0 µM, respectively. Derivatives 4l, 4e and 5d demonstrated the most effective inhibition against the LS-174T cell line, with IC₅₀ values of 44.0, 44.3, 38.0 µM, respectively. However, compound 2a was the most effective, exhibiting the most potent inhibition of 15-lipoxygenase and α-glucosidase, with IC₅₀ values of 52.4 and 59.5 µM, respectively. Furthermore, molecular docking studies supported in vitro cytotoxic activity, revealing that the most potent compounds exhibited low binding energies and interacted effectively within the EGFR enzyme’s active pocket (PDB: 1M17). These findings highlight the potential of these derivatives as anticancer agents and enzymatic inhibitors, warranting further investigation. Full article