Analysis of the Chemical and Medicinal Properties of Armillaria ostoyae (Agaricomycetes) Extracts and the Presence of Heavy Metals in Dry Basidiocarps.

We investigated the chemical and medicinal properties of methanolic and acetonic extracts of Armillaria ostoyae and the presence of heavy metals in its dry basidiocarps. The chemical content of extracts was analyzed with the HPLC-DAD-MS/MS method. According to our results, the most abundant mineral was potassium; the most abundant organic acid was malic acid; the most abundant carbohydrate was fructose, and the most abundant polyphenol was chlorogenic acid. The antimicrobial potential was evaluated using the microdilution assay, and the results ranged from 0.62 to 20 mg/mL. Antioxidant potential was studied by DPPH [half-maximal inhibitory concentration (IC50) of the methanolic extract was 619.67 µg/mL and of the acetonic extract was 533.65 µg/mL] and reducing power assays (the results ranged from 0.025 to 0.078 µg/mL). Total phenolic content was presented as gallic acid equivalent (methanolic extract, 6.12 mg GAE/g; acetonic extract, 3.99 mg GAE/g). The antidiabetic potential was explored by applying the α-amylase (the results ranged from 39.62 to 44.33%) and α-glucosidase assays (the results were in the range of 0.27-2.51%). The neuroprotective activity was asserted by the acetylcholinesterase inhibition assay (the results were in the range of 3.06-6.09%). The cytotoxic potential was investigated using the microtetrazolium assay, and the IC50 values ranged from 221.96 to > 400 µg/mL. Heavy metal content of the dry basidiocarps was evaluated using the AAS method and iron was the most abundant metal. A. ostoyae is a conditionally edible mushroom, which was not studied thoroughly before, thus this research will provide valuable knowledge about this species.

Fabrication of novel vildagliptin loaded ZnO nanoparticles for anti diabetic activity.

Diabetes mellitus (DM) is a rapidly prevailing disease throughout the world that poses boundless risk factors linked to several health problems. Vildagliptin is the standard dipeptidyl peptidase-4 (DPP-4) inhibitor type of medication that is used for the treatment of diabetes anti-hyperglycemic agent (anti-diabetic drug). The current study aimed to synthesize vildagliptin-loaded ZnO NPs for enhanced efficacy in terms of increased retention time minimizing side effects and increased hypoglycemic effects. Herein, Zinc Oxide (ZnO) nanoparticles (NPs) were constructed by precipitation method then the drug vildagliptin was loaded and drug loading efficiency was estimated by the HPLC method. X-ray diffraction analysis (XRD), UV-vis spectroscopy, FT-IR, scanning electron microscope (SEM), and EDX analysis were performed for the characterization of synthesized vildagliptin-loaded ZnO NPs. The UV-visible spectrum shows a distinct peak at 363 nm which confirms the creation of ZnO NPs and SEM showed mono-dispersed sphere-shaped NPs. EDX analysis shows the presence of desired elements along with the elemental composition. The physio-sorption studies, which used adsorption isotherms to assess adsorption capabilities, found that the Freundlich isotherm model explains the data very well and fits best. The maximum adsorption efficiency of 58.83% was obtained. Further, In vitro, anti-diabetic activity was evaluated by determining the α-amylase and DPP IV inhibition activity of the product formed. The formulation gave maximum inhibition of 82.06% and 94.73% of α-amylase and DPP IV respectively. While at 1000 µg/ml concentration with IC50 values of 24.11 µg/per ml and 42.94 µg/ml. The inhibition of α-amylase can be ascribed to the interactive effect of ZnO NPs and vildagliptin.

Isolation and Quantification of Palmatine from Fibraurea tinctoria Lour: In Vitro Antioxidant Activity and In Silico Antidiabetic Activity Evaluation.

Purpose: This study aimed to isolate and characterize palmatine from Fibraurea tinctoria Lour stems, quantify its content, and determine its antioxidant and antidiabetic activities. Patients and Methods: Palmatine was isolated from the methanol extract of Fibraurea tinctoria Lour stems by silica gel column chromatography. Structural elucidation of the isolated compounds was performed using spectral data analysis and comparison with the literature. High-Performance Liquid Chromatography (HPLC) was used to quantitatively determine palmatine in the crude methanol extract and fractions. The DPPH and non-enzymatic SOD mimic methods were used to assess the antioxidant activity of the methanol extract, fractions, and isolated compounds. The antidiabetic activity was evaluated in silico by the molecular docking method of alpha-glucosidase and DPP-IV enzymes. Palmatine was used as a test ligand and was compared with berberine and its native ligand or standard compounds. Results: The isolated compound was identified as palmatine. Quantification of palmatine compound by HPLC showed that palmatine was found in the extract and all fractions. In the in vitro antioxidant activity test using the DPPH method, fraction 4 showed the highest activity, with an IC50 value of 91 ppm. In contrast, using the non-enzymatic SOD mimic method, the methanol extract, fraction 5, and isolated compound (palmatine) exhibited very strong antioxidant activity, with IC50 values of 18, 20, and 28 ppm, respectively. The in silico antidiabetic activity of palmatine is thought to have the potential to inhibit these two enzymes. Conclusion: These results showed that Fibraurea tinctoria Lour stems have potential as an antioxidant and antidiabetic agent. Further research on phytochemical and pharmacological is required to validate the use of this plant species for the treatment of various diseases, especially diabetes mellitus.

[Anti-diabetic active constituents of pomegranate peel-derived extracellular nanovesicles].

Pomegranate peel-derived extracellular nanovesicles(PPENs) were isolated and purified by ultra-high speed centrifugation and sucrose density gradient centrifugation. Their morphology and structure were characterized. In vitro α-glucosidase inhibition assay and model test of insulin resistance(IR) in HepG2 cells showed that PPENs had good anti-diabetic activity. The IC_(50) value of α-glucosidase inhibition was(35.3±1.1) µg·mL~(-1), significantly better than the positive drug acarbose. At a concentration of 100 µg·mL~(-1), PPENs could increase the glucose absorption of IR cells significantly. Lipidome, proteome, and metabolite analysis of PPENs were performed using chromatography-mass spectrometry. MicroRNA(miRNA) sequences were identified, and target genes of miRNA were predicted. The analysis results indicated that PPENs contained abundant lipids and transport proteins, providing a material basis for the transportation and distribution of PPENs in tissue. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis suggested that lipids and miRNAs may be the key components of PPENs to exert anti-diabetic activity.

Pharmacological characterization of the antidiabetic drug metformin in atherosclerosis inhibition: A comprehensive insight.

BACKGROUND: Atherosclerosis (AS) is a progressive disease that interferes with blood flow, leading to cardiovascular complications such as hypertension, ischemic heart disease, ischemic stroke, and vascular ischemia. The progression of AS is correlated with inflammation, oxidative stress, and endothelial dysfunction. Various signaling pathways, like nuclear erythroid-related factor 2 (Nrf2) and Kruppel-like factor 2 (KLF2), are involved in the pathogenesis of AS. Nrf2 and KLF2 have anti-inflammatory and antioxidant properties. Thus, activation of these pathways may reduce the development of AS. Metformin, an insulin-sensitizing drug used in the management of type 2 diabetes mellitus (T2DM), increases the expression of Nrf2 and KLF2. AS is a common long-term macrovascular complication of T2DM. Thus, metformin, through its pleiotropic anti-inflammatory effect, may attenuate the development and progression of AS. AIMS: Therefore, this review aims to investigate the possible role of metformin in AS concerning its effect on Nrf2 and KLF2 and inhibition of reactive oxygen species (ROS) formation. In addition to its antidiabetic effect, metformin can reduce cardiovascular morbidities and mortalities compared to other antidiabetic agents, even with similar blood glucose control by the Nrf2/KLF2 pathway activation. CONCLUSION: In conclusion, metformin is an effective therapeutic strategy against the development and progression of AS, mainly through activation of the KLF2/Nrf2 axis.

Liraglutide improves follicle development in polycystic ovary syndrome by inhibiting CXCL10 secretion.

BACKGROUND: At present, a number of clinical trials have been carried out on GLP-1 receptor agonist liraglutide in the treatment of polycystic ovary syndrome (PCOS). However, the effect of liraglutide on follicle development and its specific mechanism are still unclear. METHODS: RNA sequencing was used to explore the molecular characteristics of granulosa cells from patients with PCOS treated with liraglutide. The levels of C-X-C motif chemokine ligand 10 (CXCL10) in follicular fluid were detected by ELISA, the expression levels of ovulation related genes and inflammatory factor genes in follicles and granulosa cells were detected by qPCR and the protein levels of connexin 43 (Cx43), Janus Kinase 2 (JAK2) and phosphorylated JAK2 were detected by Western blot. The mouse ovarian follicles culture system in vitro was used to detect the status of follicle development and ovulation. RESULTS: In the present study, we found that liraglutide inhibited the secretion of inflammatory factors in PCOS granulosa cells, among which CXCL10 was the most significant. In addition, CXCL10 was significantly higher in granulosa cells and follicular fluid in PCOS patients than in non-PCOS patients. We applied in vitro follicle culture and other techniques to carry out the mechanism exploration which revealed that CXCL10 disrupted the homeostasis of gap junction protein alpha 1 (GJA1) between oocyte and granulosa cells before physiological ovulation, thus inhibiting follicular development and ovulation. Liraglutide inhibited CXCL10 secretion in PCOS granulosa cells by inhibiting the JAK signaling pathway and can improved dehydroepiandrosterone (DHEA)-induced follicle development disorders, which is reversed by CXCL10 supplementation. CONCLUSIONS: The present study suggests that liraglutide inhibits CXCL10 secretion in granulosa cells through JAK signaling pathway, thereby improving the homeostasis of GJA1 between oocyte and granulosa cells before physiological ovulation and ultimately improving the follicular development and ovulation of PCOS, which provides more supportive evidence for the clinical application of liraglutide in the treatment of ovulatory disorders in PCOS. TRIAL REGISTRATION: Not applicable.

Receptors and Signaling Pathways Controlling Beta-Cell Function and Survival as Targets for Anti-Diabetic Therapeutic Strategies.

Preserving the function and survival of pancreatic beta-cells, in order to achieve long-term glycemic control and prevent complications, is an essential feature for an innovative drug to have clinical value in the treatment of diabetes. Innovative research is developing therapeutic strategies to prevent pathogenic mechanisms and protect beta-cells from the deleterious effects of inflammation and/or chronic hyperglycemia over time. A better understanding of receptors and signaling pathways, and of how they interact with each other in beta-cells, remains crucial and is a prerequisite for any strategy to develop therapeutic tools aimed at modulating beta-cell function and/or mass. Here, we present a comprehensive review of our knowledge on membrane and intracellular receptors and signaling pathways as targets of interest to protect beta-cells from dysfunction and apoptotic death, which opens or could open the way to the development of innovative therapies for diabetes.

Mechanisms of action and therapeutic applications of GLP-1 and dual GIP/GLP-1 receptor agonists.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic ß-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.

Investigation of the phytochemical profiling and antioxidant, anti-diabetic, anti-inflammatory, and MDA-MB-231 cell line antiproliferative potentials of extracts from Ephedra alata Decne.

Ephedra is one of the many medicinal herbs that have been used as folk/traditional medicine in Jordan and other countries to cure various illnesses. Plants of this genus are well known for their antioxidant and antibacterial properties. In this study, three different solvents were used to obtain Ephedra extracts. When evaluated, the Ephedra alata Decne ethanolic extract reportedly had the greatest levels of total phenolic compounds (TPC) and total flavonoid compounds (TFC). The aqueous extracts displayed the highest antioxidant activity in the DPPH and ABTS assays, demonstrating their considerable capacity to neutralize free radicals. However, when evaluated using the FRAP method, the acetone extracts showed the strongest antioxidant activity, indicating their high reducing power. LC-MS/MS, a potent method of analysis that combines the liquid chromatographic separation properties with mass spectrometry detection and identification capabilities, was used in this study to detect and measure phytochemical content of a total of 24 phenolic compounds and 16 terpene compounds present in the extracts of Ephedra alata Decne. Various concentrations of these chemicals were found in these extracts. The extracts' inhibitory effects on albumin denaturation and alpha-amylase activity were also assessed; the findings demonstrated the potentials of these extracts as anti-inflammatory and anti-diabetic medicines, with the acetone extract having the lowest IC50 values in the concomitant tests (306.45 µg/ml and 851.23 µg/ml, respectively). Furthermore, the lowest IC50 value (of 364.59 ± 0.45 µg/ml) for the 80% ethanol extract demonstrated that it has the strongest antiproliferative impact regarding the MDA-MB-231 breast cancer cell line. This finding indicates that this particular extract can be potentially used to treat cancer.

Proteins and Peptides Studied In Silico and In Vivo for the Treatment of Diabetes Mellitus: A Systematic Review.

Bioinformatics has expedited the screening of new efficient therapeutic agents for diseases such as diabetes mellitus (DM). The objective of this systematic review (SR) was to understand naturally occurring proteins and peptides studied in silico and subsequently reevaluated in vivo for treating DM, guided by the question: which peptides or proteins have been studied in silico for the treatment of diabetes mellitus? The RS protocol was registered in the International Prospective Register of Systematic Reviews database. Articles meeting the eligibility criteria were selected from the PubMed, ScienceDirect, Scopus, Web of Science, Virtual Health Library (VHL), and EMBASE databases. Five studies that investigated peptides or proteins analyzed in silico and in vivo were selected. Risk of bias assessment was conducted using the adapted Strengthening the Reporting of Empirical Simulation Studies (STRESS) tool. A diverse range of assessed proteins and/or peptides that had a natural origin were investigated in silico and corresponding in vivo reevaluation demonstrated reductions in glycemia and/or insulin, morphological enhancements in pancreatic ß cells, and alterations in the gene expression of markers associated with DM. The in silico studies outlined offer crucial insights into therapeutic strategies for DM, along with promising leads for screening novel therapeutic agents in future trials.

Glucagon-like peptide receptor-1 receptor agonists: The emerging fourth pillar in type 2 diabetes and chronic kidney disease?

Previously, no randomized controlled trials investigated the renoprotective effects of glucagon-like peptide-1 receptor agonists (GLP-1RA) as the primary endpoint in patients with diabetes and chronic kidney disease. In the FLOW trial, Perkovic et al. showed that once-weekly semaglutide reduced kidney failure, kidney-related death, and cardiovascular death by 24% as compared with placebo in patients with type 2 diabetes at high risk of renal progression.1.

An Investigation into the Phytochemical Content and Antioxidant, Antidiabetic, and Wound-Healing Activities of Curculigo latifolia Found in Brunei Darussalam.

This present study aimed to investigate the phytochemical content and antioxidant and antidiabetic activities of Curculigo latifolia leaves (CL) and C. latifolia roots (CR) found in Brunei Darussalam. Phytochemical screening showed that CL and CR extracts contain saponins, tannins, glycosides, and terpenoids. CR showed higher total phenolic content (TPC), but lower total flavonoid content (TFC) when compared to CL. The high TPC in CR contributed to its potent radical scavenging activity (RSA) against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and strong ferric reducing antioxidant power (FRAP). Additionally, CR exerted significant inhibition of ∝-glucosidase and ∝-amylase, suggesting a potential link between the chemical compounds and its antioxidant and antidiabetic effects. In the animal study of antihyperglycemic activity, treatment with 250 mg/kg body weight (b.w.) of the CL extract normalised the blood glucose levels and improved body weight gain of alloxan-induced diabetic rats within 14 weeks. Furthermore, our investigation into the wound-healing effects of young C. latifolia leaves (YCL) and matured C. latifolia leaves (MCL) showed a significant reduction in wound size on Day 3, 5, and 7 of the experimental study, indicating its wound-healing potential. Based on our findings, C. latifolia can be consumed as part of a balanced diet due to its antioxidant and antidiabetic properties.

The Anti-Diabetic Effects of Medicinal Plants Belonging to the Liliaceae Family: Potential Alpha Glucosidase Inhibitors.

Background: Diabetes mellitus is a complex metabolic disorder that has an enormous impact on people's quality of life and health. Although there is no doubt about the effectiveness of oral hypoglycemic agents combined with lifestyle management in controlling diabetes, no individual has ever been reported to have been completely cured of the disease. Globally, many medicinal plants have been used for the management of diabetes in various traditional systems of medicine. A deep look in the literature has revealed that the Liliaceae family have been poorly investigated for their antidiabetic activity and phytochemical studies. In this review, we summarize medicinal plants of Liliaceae utilized in the management of type II diabetes mellitus (T2DM) by inhibition of α-glucosidase enzyme and phytochemical content. Methods: The literature search was conducted using databases including PubMed, ScienceDirect, and Google Scholar to find the significant published articles about Liliaceae plants utilized in the prevention and treatment of antidiabetics. Data were filtered to the publication period from 2013 to 2023, free full text and only English articles were included. The keywords were Liliaceae OR Alliaceae OR Amaryllidaceae AND Antidiabetic OR α-glucosidase. Results: Six medicinal plants such as Allium ascalonicum, Allium cepa, Allium sativum, Aloe ferox, Anemarrhena asphodeloides, and Eremurus himalaicus are summarized. Phytochemical and α-glucosidase enzymes inhibition by in vitro, in vivo, and human studies are reported. Conclusion: Plants of Liliaceae are potential as medicine herbs to regulating PPHG and prevent the progression of T2DM and its complication. In silico study, clinical application, and toxicity evaluation are needed to be investigated in the future.

Assessing anti oxidant, antidiabetic potential and GCMS profiling of ethanolic root bark extract of Zanthoxylum rhetsa (Roxb.) DC: Supported by in vitro, in vivo and in silico molecular modeling.

Zanthoxylum rhetsa (ZR) is used traditionally to manage a variety of ailments, including diabetes. Oxidative stress may accelerate the diabetic condition. The available antidiabetic and antioxidant drugs have many shortcomings including resistance, inefficiency, higher dose, side effects and costs. The goal of the current investigation was to assess the antioxidant capacity and antidiabetic activity of an ethanolic extract of Zanthoxylum rhetsa root bark (ZRRB) through in vitro, in vivo, and in silico methods. The antioxidant capacity of the ZRRB extract was measured using both the DPPH radical assay and the total antioxidant activity test. The oral glucose tolerance test (OGTT) and alloxan-induced diabetic mice model were also used to examine in vivo antidiabetic efficacy. Phytochemicals identification was done by GCMS analysis. Additionally, computational methods such as molecular docking, ADMET analysis, and molecular dynamics (MD) modeling were performed to determine the above pharmacological effects. The extract demonstrated significant DPPH scavenging activity (IC50 = 42.65 µg/mL). In the OGTT test and alloxan-induced diabetes mice model, the extract effectively lowered blood glucose levels. Furthermore, in vitro inhibition of pancreatic α-amylase studies demonstrated the ZRRB extract as a good antidiabetic crude drug (IC50 = 81.45 µg/mL). GCMS investigation confirmed that the crude extract contains 16 major phytoconstituents, which were docked with human peroxiredoxin-5, α-amylase, and sulfonylurea receptor 1. Docking and pharmacokinetic studies demonstrated that among 16 phytoconstituents, 6H-indolo[3,2,1-de] [1,5]naphthyridin-6-one (CID: 97176) showed the highest binding affinity to targeted enzymes, and imitated Lipinski's rule of five. Furthermore, MD simulation data confirmed that the aforementioned compound is very steady to the binding site of α-amylase and sulfonylurea receptor 1 receptors. Findings from in vitro, in vivo and in silico investigation suggest that ZRRB extract contains a lead compound that could be a potent source of antidiabetic drug candidate.

Insulin combined with N-acetylcysteine attenuates type 1 diabetes-induced splenic inflammatory injury in canines by inhibiting the MAPKs-NF-κB signaling pathway and pyroptosis.

PURPOSE: Type 1 diabetes (T1DM) is a chronic metabolic disorder that can cause damage to multiple organs including the spleen. Sole insulin therapy is not satisfactory. This study aims to investigate the effects and mechanisms of combined treatment with insulin and N-acetylcysteine (NAC) on spleen damage in T1DM canines, in order to identify drugs that may better assist patients in the management of diabetes and its complications. METHODS: The canine model of T1DM was established by intravenous injection of alloxan (ALX) and streptozotocin (STZ). The therapeutic effects of insulin and NAC were evaluated by clinical manifestations, spleen protein and mRNA expression. RESULTS: The results indicate that the combined treatment of insulin and NAC can alleviate hyperglycemia and hematologic abnormalities, improve splenic histopathological changes, prevent fibrous tissue proliferation, and glycogen deposition. In addition, we observed that this combination treatment significantly suppressed the protein expression of p-P65/P65 (17.6 %, P < 0.05), NLRP3 (46.8 %, P < 0.05), and p-P38/P38 (37.1 %, P < 0.05) induced by T1DM when compared to insulin treatment alone. Moreover, it also significantly decreased the mRNA expression of TLR4 (45.0 %, P < 0.01), TNF-α (30.3 %, P < 0.05), and NLRP3 (43.3 %, P < 0.05). CONCLUSIONS: This combination has the potential to mitigate splenic inflammatory injury in T1DM canines by suppressing the activation of MAPKs-NF-κB pathway and pyroptosis. These findings provide a reference for the treatment strategies of diabetes and its complications.

Changes in the Sensitivity of MCF-7 and MCF-7/DX Breast Cancer Cells to Cytostatic in the Presence of Metformin.

Multidrug resistance is a serious problem in modern medicine and the reason for the failure of various therapies. A particularly important problem is the occurrence of multidrug resistance in cancer therapies which affects many cancer patients. Observations on the effect of metformin-a well-known hypoglycemic drug used in the treatment of type 2 diabetes-on cancer cells indicate the possibility of an interaction of this substance with drugs already used and, as a result, an increase in the sensitivity of cancer cells to cytostatics. The aim of this study was to evaluate the effect of metformin on the occurrence of multidrug resistance of breast cancer cells. The MCF-7-sensitive cell line and the MCF-7/DX cytostatic-resistant cell line were used for this study. WST-1 and LDH assays were used to evaluate the effects of metformin and doxorubicin on cell proliferation and viability. The effect of metformin on increasing the sensitivity of MCF-7 and MCF-7/DX cells to doxorubicin was evaluated in an MDR test. The participation of metformin in increasing the sensitivity of resistant cells to the effect of the cytostatic (doxorubicin) has been demonstrated.

Antioxidant and Antidiabetic Activity of Cornus mas L. and Crataegus monogyna Fruit Extracts.

The present study evaluated three green extraction methods, accelerated solvent extraction (ASE), ultrasound-assisted extraction (UAE), and laser irradiation extraction (LE), for the polyphenolic compounds and vitamin C extraction of Cornus mas L. and Crataegus monogyna fruit extracts. The polyphenols and vitamin C of extracts were quantified using HPLC-DAD, and the total phenolic content, flavonoid content, antioxidant activity (DPPH and reducing power), and antidiabetic activity were also studied. The antidiabetic activity was examined by the inhibition of α-amylase and α-glucosidase, and in vitro on a beta TC cell line (ß-TC-6). The results showed significant differentiation in the extraction yield between the methods used, with the ASE and LE presenting the highest values. The C. mas fruit extract obtained by ASE exhibited the best antioxidant activity, reaching an IC50 value of 31.82 ± 0.10 µg/mL in the DPPH assay and 33.95 ± 0.20 µg/mL in the reducing power assay. The C. mas fruit extracts obtained by ASE and LE also have the highest inhibitory activity on enzymes associated with metabolic disorders: α-amylase (IC50 = 0.44 ± 0.02 µg/mL for the extract obtained by ASE, and 0.11 ± 0.01 µg/mL for the extract obtained by LE at combined wavelengths of 1270 + 1550 nm) and α-glucosidase (IC50 of 77.1 ± 3.1 µg/mL for the extract obtained by ASE, and 98.2 ± 4.7 µg/mL for the extract obtained by LE at combined wavelengths of 1270 + 1550 nm). The evaluation of in vitro antidiabetic activity demonstrated that the treatment with C. mas and C. monogyna fruit extracts obtained using ASE stimulated the insulin secretion of ß-TC-6 cells, both under normal conditions and hyperglycemic conditions, as well. All results suggest that C. mas and C. monogyna fruit extracts are good sources of bioactive molecules with antioxidant and antidiabetic activity.

Synthesis, Computational Study, and In Vitro α-Glucosidase Inhibitory Action of Thiourea Derivatives Based on 3-Aminopyridin-2(1H)-Ones.

Reactions with allyl-, acetyl-, and phenylisothiocyanate have been studied on the basis of 3-amino-4,6-dimethylpyridine-2(1H)-one, 3-amino-4-phenylpyridine-2-one, and 3-amino-4-(thiophene-2-yl)pyridine-2(1H)-one (benzoyl-)isothiocyanates, and the corresponding thioureide derivatives 8-11a-c were obtained. Twelve thiourea derivatives were obtained and studied for their anti-diabetic activity against the enzyme α-glucosidase in comparison with the standard drug acarbose. The comparison drug acarbose inhibits the activity of α-glucosidase at a concentration of 15 mM by 46.1% (IC50 for acarbose is 11.96 mM). According to the results of the conducted studies, it was shown that alkyl and phenyl thiourea derivatives 8,9a-c, in contrast to their acetyl-(benzoyl) derivatives and 10,11a-c, show high antidiabetic activity. Thus, 1-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-3-phenylthiourea 9a has the highest inhibitory activity against the enzyme α-glucosidase, exceeding the activity of the comparison drug acarbose, which inhibits the activity of α-glucosidase by 56.6% at a concentration of 15 mm (IC50 = 9,77 mM). 1-(6-methyl-2-oxo 4-(thiophen-2-yl)-1,2-dihydropyridin-3-yl)-3-phenylthiourea 9c has inhibitory activity against the enzyme α-glucosidase, comparable to the comparison drug acarbose, inhibiting the activity of α-glucosidase at a concentration of 15 mm per 41.2% (IC50 = 12,94 mM). Compounds 8a, 8b, and 9b showed inhibitory activity against the enzyme α-glucosidase, with a lower activity compared to acarbose, inhibiting the activity of α-glucosidase at a concentration of 15 mM by 23.3%, 26.9%, and 35.2%, respectively. The IC50 against α-glucosidase for compounds 8a, 8b, and 9b was found to be 16.64 mM, 19.79 mM, and 21.79 mM, respectively. The other compounds 8c, 10a, 10b, 10c, 11a, 11b, and 11c did not show inhibitory activity against α-glucosidase. Thus, the newly synthesized derivatives of thiourea based on 3-aminopyridine-2(1H)-ones are promising candidates for the further modification and study of their potential anti-diabetic activity. These positive bioanalytical results will stimulate further in-depth studies, including in vivo models.

Structurally Diverse Stilbenoids as Potent α-Glucosidase Inhibitors with Antidiabetic Effect from Morus alba.

Fifteen stilbenoid derivatives, including five previously undescribed ones (albaphenols A-E, 1-5) with diverse scaffolds, were obtained from the well-known agricultural economic tree Morus alba. Their structures, including absolute stereochemistries, were fully characterized by detailed interpretation of spectroscopic data and quantum chemical computational analyses of nuclear magnetic resonance (NMR) and electric circular dichroism (ECD). Albaphenol A (1) features an unprecedented rearranged carbon skeleton incorporating a novel 2-oxaspiro[bicyclo[3.2.1]octane-6,3'-furan] motif; albaphenol C (3) is likely derived from a cometabolite through an interesting intramolecular transesterification reaction; and albaphenol E (5) bears a cleavage-reconnection scaffold via a dioxane ring. All of the compounds exhibited significant inhibition against the diabetic target α-glucosidase, with low to submicromole IC50 values (0.70-8.27 µM), and the binding modes of selected molecules with the enzyme were further investigated by fluorescence quenching, kinetics, and molecular docking experiments. The antidiabetic effect of the most active and abundant mulberrofuran G (6) was further assessed in vivo in diabetic mice, revealing potent antihyperglycemic activity and comparable antidiabetic efficacy to the clinical drug acarbose.