Reactive hypoglycaemia is characterised by symptomatic hypoglycaemia occurring several hours after food intake and can significantly impair quality of life. Management is often challenging, particularly in patients who fail dietary modification or cannot tolerate conventional pharmacological therapies. We present the case of a 50-year-old woman with longstanding, debilitating reactive hypoglycaemia who experienced marked symptomatic and biochemical improvement following treatment with semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist. The patient presented with recurrent episodes of dizziness, profound fatigue, tremulousness, and syncope despite adherence to dietary recommendations. Previous treatment with acarbose was discontinued because of gastrointestinal intolerance, and metformin failed to improve symptoms. Continuous glucose monitoring and an oral glucose tolerance test confirmed reactive hypoglycaemia. Following initiation of semaglutide, the patient experienced a substantial reduction in hypoglycaemic episodes with corresponding improvement in glucose profiles and quality of life. This case highlights the potential role of semaglutide as a novel therapeutic option in patients with refractory reactive hypoglycaemia and contributes to the emerging evidence supporting the use of GLP-1 receptor agonists in this condition.

Natural products such as glucosidase inhibitors and aminoglycoside antibiotics are target agents that play an important role in the development of new drugs. A novel class of glucosidase inhibitors based on aminocyclitols was synthesized using a new method. This method involves arranging the α-, β-unsaturated structure by attacking the ammonia compound on the acetate group in the γ-position forming, to form the amide in the β-position. The method has enabled the synthesis of new types of C8N, such as C7N (C8N generally exhibits structural and characteristic biological properties similar to C7N) compounds. After purification and structure elucidation of the resulting substances, α-, β-glucosidase, and amylase tests were performed against acarbose; additionally, an enzyme kinetic study of well-active compounds was conducted. Subsequently, the anticancer activity of substances was analyzed using a viability assay and AO/PI staining. Our results suggest that different derivatives of new carbosugar isomers exert potential enzymatic and anticancer activity against breast cancer cells.

Persicaria odorata (Lour.) contains considerable amounts of phytochemicals, including phenolics and essential oils, which have been reported to inhibit α-glucosidase activity. However, which bioactive compounds play a key role in inhibiting the α-glucosidase activity is unclear. To address this issue, the methanolic extract of P. odorata was assayed via in vitro studies, and forty-four compounds in P. odorata extracts were elucidated using in silico studies. The extract strongly inhibited yeast α-glucosidase with an IC50 value of 0.31 µg/mL, which was 450-fold more potent than acarbose (IC50 = 139.47 µg/mL), under experimental conditions. The Lineweaver-Burk plots indicated that the inhibition type of the extract on α-glucosidase is a noncompetitive inhibitor. Molecular docking demonstrated that procyanidin B (P9) and rutin (P19), which belong to the flavonoids, were predicted by computational approaches to be bioactive compounds that have more favorable binding interactions to yeast α-glucosidase residues compared to forty-four other compounds and acarbose. Molecular dynamics simulations revealed that P9 and P19 complexes with yeast α-glucosidase remained stable during the 500 ns simulations. Moreover, both P9 and P19 were predicted to qualify as α-glucosidase inhibitors with low toxicity. These findings suggest that P. odorata could be used as an alternative edible plant to manage postprandial hyperglycemia in T2DM, and could serve as basic scientific data. Further experimental studies of the pure bioactive compounds are necessary to support these findings.

In this study, due to the side effect profiles and low efficacy of currently used inhibitors, novel benzimidazole-oxadiazole derivatives (6a-6e, 7a-7e) were synthesized as dual inhibitors of α-GLY and AR. Their structures were elucidated using [13]C-NMR and [1]H-NMR techniques. Their binding properties were investigated by molecular docking studies, and their ADME properties were screened in silico. AR and α-GLY inhibitory effects of the synthesized compounds were examined. The compounds were observed to exhibit partially similar inhibitory effects to the reference drug epalrestate (IC50: 0.78 nM; KI: 0.74 ± 0.0 nM) on AR inhibition. Among them, compounds 6a, 6b, and 6c showed the highest activity with KI values of 8.6 ± 0.4, 3.5 ± 0.3 and 6.3 ± 0.5 nM, respectively. Compounds 6a and 7e were found to have higher inhibitory activity against the α-GLY enzyme than the reference drug Acarbose (IC50: 128.4 µM; KI: 96.2 ± 5.7 µM) with KI values of 5.8 ± 0.4 and 7.9 ± 0.8 µM, respectively. Overall, the newly synthesized compounds demonstrated pronounced AR inhibitory activity and notable α-GLY inhibition. Nevertheless, further pharmacological and toxicity evaluations are required to confirm their therapeutic potential. Among the tested molecules, compounds 6a and 7e may therefore be considered potential candidates for further investigation as anti-diabetic agents.

The global rise in obesity and associated metabolic disorders has fueled the demand for safe, multi-target therapeutics derived from natural sources. In this study, an artificial neural network combined with a genetic algorithm (ANN-GA), was employed to optimize the ultrasound-assisted extraction of loquat leaf extract (LLE). The optimal parameters-0.6% Tween 80, 328 W ultrasonic power, and 49 °C-enhanced extraction efficiency while minimizing energy consumption and surfactant use. In vitro, LLE exhibited potent dose-dependent inhibition of α-glucosidase (IC50 = 3.75 μg/mL, 21.6-fold stronger than acarbose) and pancreatic lipase (IC50 = 78.3 μg/mL), indicating strong inhibitory activity against these digestive enzymes. In high-fat diet-induced obese mice, LLE supplementation dose-dependently reduced body weight gain, serum total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and fasting blood glucose while elevating high-density lipoprotein cholesterol (HDL-C). In addition, LLE ameliorated liver injury (decreased ALT/AST) and oxidative stress (lowered MDA, increased SOD). These findings highlight LLE as a promising multi-target natural product for managing obesity and related metabolic disorders.

α-Amylases (EC 3.2.1.1) are among the most important industrial enzymes in starch saccharification, detergent, paper, and textile industries. Canonical α-amylases typically contain Ca[2+] in their structure, which is not directly involved in catalysis but essential in maintaining the structural integrity of α-amylases. Ca[2+] ions are easily removed by chelating reagents, which may affect the activity and stability of α-amylases and thereby hinder their applications in some industries. Here, we identified a metal-free α-amylase, AmyY, from the bacterium Alkalimonas sp. NCh-2 isolated from an alkaline hot spring. AmyY contains a catalytic module of glycoside hydrolase family 13 (GH13) and a carbohydrate-binding module of family 20 (CBM20). AmyY exhibits high activity under alkaline conditions (pH 8.0-11.0) and tolerance to high salinity, chelating reagents, and surfactants. We solved the structures of AmyY and its complex with acarbose. Although the overall topology and active sites of AmyY resemble those of reported GH13 α-amylases, the structure of AmyY is devoid of metal ions. The inability of AmyY to bind metal ions results from replacements of acidic amino acid residues by neutral ones. Combined with biochemical, structural, and bioinformatic data, we demonstrated that AmyY and its homologs represent a class of metal-free α-amylases in GH13. Moreover, structural analyses revealed that the CBM20 of AmyY is highly flexible, and we obtained a mutant with enhanced thermostability by truncating the CBM20. This mutant demonstrates remarkable wash performance and desizing capability at alkaline pH, which underscores its application potential in the detergent and textile industries.IMPORTANCEWhile canonical GH13 α-amylases typically contain Ca[2+], our biochemical and structural data reveal that AmyY has evolved a metal-free architecture. This is achieved through the replacement of acidic metal-coordinating residues by neutral ones, abolishing metal binding without compromising catalytic efficiency. This work expands the structural and functional diversity of GH13 by defining a class of metal-free α-amylases, with AmyY and its homologs as representatives. Furthermore, the engineered AmyY with enhanced thermostability offers a candidate biocatalyst for industrial applications, such as the detergent industry. The structure of AmyY also offers a blueprint for engineering other α-amylases into metal-independent forms.

Genista albida Willd., an endemic species of Türkiye, represents a largely unexplored source of bioactive phytochemicals with potential applications in functional foods. This study investigated how extraction strategy influences the phytochemical composition and biological activities of G. albida by comparing ultrasonic-assisted extraction (UAE), maceration (MAC), and Soxhlet extraction (SOE). Total phenolic and flavonoid contents were determined spectrophotometrically, while phenolic constituents were characterized by LC-MS/MS. Antioxidant capacity was evaluated using six complementary assays, and enzyme inhibitory activities against acetylcholinesterase, butyrylcholinesterase, tyrosinase, α-amylase, and α-glucosidase were assessed. Twenty-one of the 31 targeted phenolic compounds were identified, with hesperidin as the predominant constituent (4378-4584 µg per g extract), followed by hyperoside, luteolin 7-O-glucoside, ferulic acid, eriodictyol, apigenin, and luteolin. UAE yielded the highest total phenolic content (43.28 mg GAE per g extract) and the strongest overall antioxidant performance, whereas MAC exhibited the highest flavonoid content (50.59 mg RE per g extract) and acetylcholinesterase inhibitory activity. Notably, all extracts demonstrated stronger α-glucosidase inhibition than acarbose (IC50 = 0.63-0.66 vs. 0.96 mg mL[-1]), highlighting their potential to modulate postprandial hyperglycemia. Overall, extraction strategy markedly affected phytochemical recovery and bioactivity, with UAE providing the most favorable balance between chemical richness and biological performance. These findings position G. albida as a promising natural source of bioactive ingredients for the development of functional foods and nutraceuticals.

We present a patient who developed symptomatic hypoglycemia following surgical treatment for median arcuate ligament syndrome (MALS). The patient experienced predominately postprandial hypoglycemia after higher carbohydrate meals. Clinical findings revealed postprandial hyperinsulinemic hypoglycemia possibly related to celiac ganglionectomy performed during MALS surgery and non-insulin-mediated fasting hypoglycemia likely because of poor glycogen stores from restricting carbohydrates. Management consisted of dietary counseling, continuous glucose monitoring, and acarbose administered with meals. Following intervention, continuous glucose monitoring demonstrated improvement in hypoglycemia and overall improved glycemic stability. To our knowledge, this represents a novel report of hypoglycemia occurring after MALS surgery, highlighting a previously underrecognized metabolic consequence of celiac ganglionectomy.

Inhibiting α-glucosidase (AG) enzyme is recognized as a key therapeutic approach for diabetes treatment. Nine saturated anacardic acid derivatives (2-10) were synthesized, well-characterized, and evaluated for their inhibitory activity against AG. All six sulfonylhydrazide saturated anacardic acid analogues (5-10) were disclosed as novel compounds, and their structures were endorsed by NMR spectroscopy, X-ray crystallography, and mass spectrometry. They exhibited strong inhibition against AG with IC50 in a range of 0.24-6.01 µM, significantly surpassing the reference antidiabetic drug acarbose (IC50 = 817.38 µM). Notably, 10 was found to be a potent α-glucosidase inhibitor with an IC50 of 0.24 µM. The strong inhibitory effect of the side chain against AG was demonstrated through a comparison between 10 and a structurally similar salicylic acid analogue. Kinetic studies revealed that 10 functioned as a competitive inhibitor, binding to the free enzyme with an equilibrium constant Ki = 0.96 µM. Molecular docking studies further strengthened that compound 10 predominantly binds to the orthosteric site of AG with strong binding affinity and multiple stabilizing interactions, supporting its superior inhibitory activity compared to its precursor, the saturated anacardic acid 2. These findings contribute to the development of potent therapeutic agents for diabetes treatment.

Though inhibiting the RBPJ transcription complex reduces PD-L1 expression and alleviates T cell dysfunction in hepatocellular carcinoma (HCC), the tumor immunomodulatory function of RBPJ in T cells is unclear. This study used patient-derived xenograft models to illustrate the role of RBPJ disruption in clinical outcomes and sensitivity to immunotherapy. Immunoprecipitation was performed to identify whether HUWE1 is the E3 ubiquitin ligase for RBPJ. CUT&Tag, ChIP-/ATAC-qPCR, flow cytometry, and CyTOF were used to investigate the molecular mechanism of how RBPJ regulated the function of HCC-infiltrating T cells. Mice with conditional knockout or knock-in of Huwe1 or Rbpj in T cells were used to evaluate their role in the tumor growth. Furthermore, virtual screening, molecular dynamics simulation, immunoprecipitation, and DNA pull-down assays revealed the role of acarbose in RBPJ transcription complex. Our study found that RBPJ expression rose in exhausted T cells, aggravating their exhaustion. Mechanistically, HUWE1 facilitated the K341 ubiquitination of RBPJ through K48 linkage. RBPJ contributed to T cell exhaustion by enhancing the transcription of exhaustion-related genes as a transcription factor, recruiting RUVBL1 to elevate H3K4me3 levels on the promoters of exhaustion-related genes or H3K27ac on their enhancers, and induced the transcription of the KMT2C, thereby increasing H3K4me1 levels on the enhancers of exhaustion-related genes. Furthermore, acarbose-induced damage in the RBPJ transcriptional complex indicated that targeting T cell exhaustion may be a promising HCC treatment. Collectively, our research results indicated that inhibiting the RBPJ in T cells changed the tumor microenvironment from "cold" to "hot".

This study evaluated the clinical value of a "immuno-metabolic co-management" strategy by investigating the association between glucose-lowering agents (metformin, insulin, and acarbose) and readmission risk in patients with rheumatoid arthritis (RA) and comorbid type 2 diabetes mellitus (T2DM). This study included up to 10 years of longitudinal follow-up data from 616 patients with RA and comorbid T2DM. A shared Gamma frailty model was utilized to analyze unplanned readmission. Furthermore, inverse probability of treatment weighting (IPTW) was employed to control for confounding, followed by validation. Subgroup interaction tests and sensitivity analyses were conducted to evaluate model robustness. In the weighted multivariable analysis, metformin and insulin use were significantly associated with a lower risk of readmission (metformin: HR = 0.56, 95%CI: 0.46-0.70, P < 0.001; insulin:HR = 0.65, 95%CI: 0.52-0.81, P < 0.001), respectively, whereas acarbose showed no statistically significant correlation with the readmission risk (HR = 0.97, P = 0.790). Subgroup interaction analyses indicated that the observed associations were largely consistent across clinical strata. Notably, the inverse association with metformin was more pronounced among patients receiving concomitant glucocorticoids (P for interaction = 0.003). These primary findings remained robust in multiple sensitivity analyses. In conclusion, metformin and insulin are associated with a lower risk of unplanned readmission in patients with RA and comorbid T2DM. These findings highlight the potential clinical relevance of "immuno-metabolic co-management", although future prospective studies are needed to validate these observations.

The increasing global burden of Type 2 diabetes mellitus (T2DM) and the side effects of conventional drugs have driven the search for natural therapeutic alternatives. This study investigates the antidiabetic potential of South African essential oils - specifically Artemisia afra, Agathosma betulina, and Cymbopogon citratus - which are traditionally used in diabetes treatment but lack comprehensive scientific validation. Using an integrated research framework: mining the phytochemical metabolites of the plant source from Dr. Duke's Phytochemical and Ethnobotanical Database and relevant literature; screening of metabolites using molecular docking and molecular dynamics (MD) to identify potential leads; and in vitro enzymatic assays of the oils for α-amylase (AA) and α-glucosidase (AG) inhibition. Computational results identified quercetin-3,7-diglucoside (Q37DG), quercetin-7-O-glucoside (Q7G), and rutin as promising lead compounds. Notably, Q37DG demonstrated favorable inhibitory potential, with ΔGbind values of -52.73 kcal/mol for AA and -36.60 kcal/mol for AG, exceeding the known inhibitor acarbose (-43.59 and -34.41 kcal/mol, respectively). MD simulations further supported Q37DG's role in enhancing enzyme stability upon binding, indicating a competitive inhibition mechanism through strong interactions with catalytic residues such as ASP469 (AG) and ASP197 (AA). Genetic Algorithm-based Quantitative Structure-Activity Relationship (GA-QSAR) models predict impressive IC50 values for Q37DG (3.47 μM for AG and 0.68 μM for AA) compared to acarbose (6.92 and 2.51 μM). Experimental in vitro assays confirmed A. betulina essential oil as the oil with the most activity (IC50 = 6.02 μg/ml for AA and 6.70 μg/ml for AG). Surprisingly, the lead compounds identified via computational screening are reported constituents of A. betulina, thereby validating the integrated data mining and in silico approach. This work promotes green chemistry by valuing indigenous plant resources and suggests that these leads warrant further investigation for nano-formulation and therapeutic development.

To discover novel potential enzyme inhibitors based on natural products, a series of N-acyl pregnane alkaloid ester derivatives were designed, synthesized, and evaluated for their inhibitory activity against acetylcholinesterase (AChE) and α-glucosidase. The bioassay test results revealed that the target compounds generally showed more potent inhibition against α-glucosidase than against AChE. Notably, compounds 6e and 6i demonstrated significant α-glucosidase inhibitory activity, with IC50 values of 29.85 µM and 38.11 µM (acarbose IC50: 16.49 µM), respectively, and exhibited low cytotoxicity toward Thle-2 cells, with IC50 values of 112.70 µM and 73.65 µM, respectively. Structure-activity relationship (SAR) analysis indicated that derivatives bearing an N-tigloyl group and nitro or pyridine substituents at the C-20 position contributed to enhanced α-glucosidase inhibition. Enzyme kinetics confirmed that 6e and 6i function as reversible, noncompetitive inhibitors of α-glucosidase. Molecular docking studies further illustrated that both compounds bind to the lateral surface of the α‑glucosidase through hydrogen bonds and hydrophobic interactions, rather than occupying the catalytic active site. These findings highlight that 6e and 6i exhibit certain inhibitory activity, providing a basis for the design of subsequent derivatives.