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AbstractAstragalus 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. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a multi-systematic chronic metabolic disorder and life-threatening disease resulting from impaired glucose homeostasis. The inhibition of glucosidase, particularly α-glucosidase, could serve as an effective methodology in treating diabetes. Attributed to the catalytic function of glucosidase, the present research focuses on the synthesis of sulfonamide-based acyl pyrazoles (5a-k) followed by their in vitro and in silico screening against α-glucosidase. The envisaged structures of prepared compounds were confirmed through NMR and FTIR spectroscopy and mass spectrometry. All compounds were found to be more potent against α-glucosidase than the standard drug, acarbose (IC50 = 35.1 ± 0.14 µM), with IC50 values ranging from 1.13 to 28.27µM. However, compound 5a displayed the highest anti-diabetic activity (IC50 = 1.13 ± 0.06 µM). Furthermore, in silico studies revealed the intermolecular interactions of most potent compounds (5a and 5b), with active site residues reflecting the importance of pyrazole and sulfonamide moieties. This interaction pattern clearly manifests various structure-activity relationships, while the docking results correspond to the IC50 values of tested compounds. Hence, recent investigation reveals the medicinal significance of sulfonamide-clubbed pyrazole derivatives as prospective therapeutic candidates for treating type 2 diabetes mellitus (T2DM). [ABSTRACT FROM AUTHOR]

Ethnobotanically in Indonesia, Diospyros celebica Bakh is recognized as having antidiabetic activity. This study aimed to isolate antidiabetic compounds from the leaves of Eboni (Diospyros celebica). D. celebica leaves were dried and extracted with 96% ethanol, then fractionated and purified guided by antioxidant activity test, a-glucosidase inhibitory test, and dipeptidyl peptidase-4 (DPP-4) inhibitory test until bioactive isolates were obtained. The isolates were identified and their structures were determined based on NMR 1H, 13C, 2D, and LCMS/MS spectroscopic data. Extracts and fractions have potential antioxidant (DPPH), glucosidase inhibitor, and DPP-4 inhibitor activities as well as containing flavonoids and polyphenols. From the ethyl acetate fraction, isolate 26a-2 namely 3,5-digalloyl-(-)- epiafzelechin was obtained which was active as a DPPH scavenger, glucosidase inhibitor, and DPP4 inhibitor. The extracts, fractions, and flavonoid compounds in D. celebica leaves have the potential for antidiabetic drug candidates. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is a metabolic dreadful disease caused by an uncontrolled glucose level in the bloodstream, particularly high after a meal. Inhibitors of glucosidases, involved in the digestion of carbohydrates, can regulate this post‐prandial increase in glucose concentration. The traditional drugs act as competitive inhibitors of both pancreatic α‐amylase and α‐glucosidases and this unselective inhibition is behind severe gastrointestinal side effects related to the concomitant inhibition of α‐amylase. We described herein some perglycosylated cyclodextrins as efficient and selective inhibitors of α‐glucosidase with low micromolar IC50 (3.64‐7.98 μM) compared to the acarbose (IC50 212 μM), clinically used for patients suffering from type 2 diabetes. On the other hand, they do not inhibit α‐amylase (IC50>500 μM). Structure/activity relationship rationalization suggests multiple interactions between the described inhibitors and α‐glucosidase, which support the existence of both active site and allosteric interactions. [ABSTRACT FROM AUTHOR]

Two libraries of quinoline‐based hybrids 1‐(7‐chloroquinolin‐4‐yl)‐1H‐pyrazolo[3,4–d]pyrimidin‐4‐amine and 7‐chloro‐N‐phenylquinolin‐4‐amine were synthesized and evaluated for their α‐glucosidase inhibitory and antioxidant properties. Compounds with 4‐methylpiperidine and para‐trifluoromethoxy groups, respectively, showed the most promising α‐glucosidase inhibition activity with IC50=46.70 and 40.84 μM, compared to the reference inhibitor, acarbose (IC50=51.73 μM). Structure‐activity relationship analysis suggested that the cyclic secondary amine pendants and para‐phenyl substituents account for the variable enzyme inhibition. Antioxidant profiling further revealed that compounds with an N‐methylpiperazine and N‐ethylpiperazine ring, respectively, have good DPPH scavenging abilities with IC50=0.18, 0.58 and 0.93 mM, as compared to ascorbic acid (IC50=0.05 mM), while the best DPPH scavenger is NO2‐substituted compound (IC50=0.08 mM). Also, compound with N‐(2‐hydroxyethyl)piperazine moiety emerged as the best NO radical scavenger with IC50=0.28 mM. Molecular docking studies showed that the present compounds are orthosteric inhibitors with their quinoline, pyrimidine, and 4‐amino units as crucial pharmacophores furnishing α‐glucosidase binding at the catalytic site. Taken together, these compounds exhibit dual potentials; i. e., potent α‐glucosidase inhibitors and excellent free radical scavengers. Hence, they may serve as structural templates in the search for agents to manage Type 2 diabetes mellitus. Finally, in preliminary assays investigating the anti‐tubercular potential of these compounds, two pyrazolopyrimidine series compounds and a 7‐chloro‐N‐phenylquinolin‐4‐amine hybrid showed sub‐10 μM whole‐cell activities against Mycobacterium tuberculosis. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is common and involves α‐glucosidase inhibition to regulate glucose. We synthesized twenty E‐arylidene steroids with hydroxy and methoxy groups on the aromatic ring. Compounds 3 a, 5 a, 5 b, and 5 d showed notable inhibition, with IC50 values ranging from 1.84±0.28 to 9.25±2.53 μM. Key features for bioactivity include ortho methoxy and α‐hydroxy. Various inhibition mechanisms were observed. In silico studies elucidate the possible binding modes of E‐arylidene steroids, confirming their enzymatic mechanisms of non/un‐competitive inhibitors. Allosteric site 2 emerges as a potential binding site for compounds 3 a, 5 a, and 5 b. Compound 5 d holds promise as a potent α‐glucosidase inhibitor compared to acarbose at the orthosteric receptor binding site. [ABSTRACT FROM AUTHOR]

In a search for novel nonsugar α‐glucosidase inhibitors for diabetes treatment, a series of N‐(phenylsulfonyl)thiazole‐2‐carboxamide derivatives were designed and synthesized, the α‐glucosidase inhibitory activities were then evaluated. Several compounds with promising α‐glucosidase inhibitory effects were identified. Among these, compound W24 which shows low cytotoxicity and good α‐glucosidase inhibitory activity with an IC50 value of 53.0 ± 7.7 μM, is more competitive compared with the commercially available drug acarbose (IC50 = 228.3 ± 9.2 μM). W24 was identified as a promising candidate in the development of α‐glucosidase inhibitors. Molecular docking studies and molecular dynamics simulation were also performed to reveal the binding pattern of the active compound to α‐glucosidase, and the binding free energy of the best compound W24 was 36.3403 ± 3.91 kcal/mol. [ABSTRACT FROM AUTHOR]

Cellular stress, notably oxidative, inflammatory, and endoplasmic reticulum (ER) stress, is implicated in the pathogenesis of cardiovascular disease. Modifiable risk factors for cardiovascular disease such as diabetes, hypercholesterolemia, saturated fat consumption, hypertension, and cigarette smoking cause ER stress whereas currently known cardioprotective drugs with diverse pharmacodynamics share a common pleiotropic effect of reducing ER stress. Selective targeting of oxidative stress with known antioxidative vitamins has been ineffective in reducing cardiovascular risk. This "antioxidant paradox" is partially attributed to the unexpected aggravation of ER stress by the antioxidative agents used. In contrast, some of the contemporary antihyperglycemic drugs inhibit both oxidative stress and ER stress in human coronary artery endothelial cells. Unlike sulfonylureas, meglitinides, α glucosidase inhibitors, and thiazolidinediones, metformin, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors are the only antihyperglycemic drugs that reduce ER stress caused by pharmacological agents (tunicamycin) or hyperglycemic conditions. Clinical trials with selective ER stress modifiers are needed to test the suitability of ER stress as a therapeutic target for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is one of the chronic non-communicable diseases and has been rapidly increasing globally. Alpha glucosidase is an important enzyme that hydrolyzes polysaccharides into monosaccharides before being absorbed into the bloodstream. The alpha glucosidase inhibitors, such as acarbose are expensive and have several adverse effects. The use of herbal products to prevent or treatment of disease is becoming popular. There are many herbal products that can reduce blood sugar levels. However, taking herbal products with anti-DM medicines may cause herb-drug interactions that affect either the pharmacokinetics or pharmacodynamics of the drugs, leading to adverse effects or ineffective treatment. The aim of this study is to examine the effect of herbal extracts on alpha-glucosidase activity and the level of cytochrome P450 3A4 (CYP3A4) by using HepaRG as a model. Three herbs that reported blood glucose-lowering activity were selected including Moringa oleifera, Momordica charantia, and Morus alba. All herbs were extracted with 95% ethanol and tested for their in vitro alpha glucosidase inhibitory activity. The results showed that M. alba extract exhibits the highest activity (IC50= 83.75 µg/mL). Then, the extracts were evaluated for their cytotoxicity on the HepaRG cell line. All extracts showed no cytotoxicity at concentrations up to 250 µg/mL. The sub-cytotoxic concentration of each extract was selected to test for the effect on the CYP3A4 enzyme. The results showed that only M. alba extract elevated the level of CYP3A4, while the others slightly reduce the level of CYP3A4. However, this is a preliminary study that the major compounds of each extract must be isolated and evaluated in the future. [ABSTRACT FROM AUTHOR]

A new series of trisubstituted-1,2,4-triazin-6-one derivatives (III–VIII) containing cinnmylidene and disubstituted phenyl (bearing acetoxy and methoxy) moieties have been synthesized, using 1,3-oxazolinone derivatives (IIa,b) and thiosemicarbazide as the key starting materials. The structures of the new 1,2,4-triazine-6-ones were confirmed by spectral data along with elemental microanalyses. The tittle compounds were screened for their cytotoxicity against breast cancer cell lines (MCF-7) as well as normal breast HDF. The tested 1,2,4-triazine-6-one derivatives revealed good cytotoxicity and selectivity towards breast cancer cell lines (MCF-7) relative to normal cells. Also, the compounds were tested for their potential to inhibit the activity of enzyme α-glucosidase. Meanwhile, most of the compounds exhibit the strongest enzyme inhibitory activity, while three compounds 5-cinnamylidene-3-(3,4-dimethoxy) phenyl-6(1H)-oxo-1,2,4-triazin-2-thiocarboxamide (IIIb), N-(4-chlorobenzoyl) methyl-5-cinnamylidene-6H-oxo-3-(3,4-dimethoxy) phenyl-1,2,4-triazin-3-thiocarboxamide (VI) and 5-cinnamylidene-3-(3,4-dimethoxy) phenyl-1,2,4-triazin-6-one (VIII) exhibited excellent activity with IC50 values 0.20, 0.33 and 0.080 mg/mL for α-glucosidase compared to1.22 mg/mL of Acarbose is used as a standard. [ABSTRACT FROM AUTHOR]

Among antihyperglycemic drugs used for treating diabetes, α-glucosidase inhibitors generate the least adverse effects. This contribution aimed to evaluate the potential antidiabetic activity of Rumex crispus L. by testing its in vitro α-glucosidase inhibition and in vivo antihyperglycemic effects on rats with streptozotocin (STZ)-induced diabetes. Better inhibition of α-glucosidase was found with the methanol extract versus the n-hexane and dichloromethane extracts. The methanol extract of the flowers (RCFM) was more effective than that of the leaves (RCHM), with an IC50 of 7.3 ± 0.17 μg/mL for RCFM and 112.0 ± 1.23 μg/mL for RCHM. A bioactive fraction (F89s) also showed good α-glucosidase inhibition (IC50 = 3.8 ± 0.11 μg/mL). In a preliminary study, RCHM and RCFM at 150 mg/kg and F89s at 75 mg/kg after 30 days showed a significant effect on hyperglycemia, reducing glucose levels (82.2, 80.1, and 84.1%, respectively), and improved the lipid, renal, and hepatic profiles of the rats, comparable with the effects of metformin and acarbose. According to the results, the activity of R. crispus L. may be mediated by a diminished rate of disaccharide hydrolysis, associated with the inhibition of α-glucosidase. Thus, R. crispus L. holds promise for the development of auxiliary drugs to treat diabetes mellitus. [ABSTRACT FROM AUTHOR]

Caesalpinia sappan (CS) has been commonly used in beverage and folk medicine in China and ASEAN countries because of its various therapeutic properties. Only the heartwood has long been used in traditional medicines due to the presence of high concentration of brazilin (one of the most important bioactive compounds), whereas the other parts are limited in use. Thus, this work aimed to investigate ways of utilizing other parts of CS. This information is important for further use of other CS parts to promote zero waste and hence sustainable resource utilization. Herein, the crude ethanolic (CEE) and crude aqueous (CAE) extracts from twelve parts of CS were evaluated for their biological activities for the first time. Our work demonstrates that not only the heartwood, but also other parts of CS exhibit interesting biological activities. CAE from heartwood of branches exhibits the highest antioxidant activity, which is higher than that of the positive control, butylated hydroxytoluene. CEE from florets shows the highest inhibitory effect against α-amylase, while CAE of barks shows better α-glucosidase inhibitory activity than the existing glucosidase inhibitor (acarbose). Molecular docking of brazilin (key bioactive compound) to both α-amylase and glucosidase can also confirm the tight binding of brazilin to α-glucosidase. [ABSTRACT FROM AUTHOR]

Summary: In order to make full use of Sargassum fusiforme (S. fusiforme), subcritical water treatment, an environmentally friendly method, was used to degrade polysaccharides to enhance their functional activity. Results revealed that average molecular weight decreased with increasing subcritical water treatment time or temperature. The depolymerisation kinetic was found to follow a first‐order kinetics model fitted to 1/Mt – 1/M0 = k • t. Structural characterisation exhibited that subcritical water treatment changed the molar ratio composition of monosaccharides, while the main functional groups of S. fusiforme polysaccharides did not change significantly. Rheological characterisation demonstrated that the three degraded polysaccharides displayed shear‐thinning behaviour and viscoelasticity. Except for natural polysaccharides, the α‐glucosidase inhibitory activity of the three degraded polysaccharides was superior to that of acarbose. Consequently, this study can provide scientific evidence for subcritical water treatment as a green and efficient method to prepare bioactive polysaccharides with low molecular weight. [ABSTRACT FROM AUTHOR]

α-Glucosidase inhibitors in natural products are one of the promising drugs for the treatment of type 2 diabetes. However, due to the complexity of the matrix, it is challenging to comprehensibly clarify the specific pharmacodynamic substances. In this study, a novel high-throughput inhibitor screening strategy was established based on covalent binding of α-glucosidase on chitosan-functionalized multi-walled carbon nanotubes coupled with high-resolution mass spectrometry. The synthesized MWCNTs@CS@GA@α-Glu was characterized by TEM, SEM, FTIR, Raman, and TG. Performance studies showed that the microreactor exhibited stronger thermostability and pH tolerance than that of the free one while maintaining its inherent catalytic activity. Feasibility study applying a model mixture of known α-glucosidase ligand and non-ligands indicated the selectivity and specificity of the system. By integrating ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-QTOF-MS) with ion mobility mass spectrometry (IMS), 15 ligands were obtained and tentatively identified from Tribulus terrestris L., including 8 steroidal saponins, 4 flavonoids, and 3 alkaloids. These inhibitors were further validated by in vivo experiments and molecular docking simulation. [ABSTRACT FROM AUTHOR]

Abstract Diabetes is one of the fastest-growing and most widespread diseases worldwide. Approximately 90% of diabetic patients have type 2 diabetes. In 2019, there were about 463 million diabetic patients worldwide. Inhibiting the dipeptidyl peptidase IV (DPP-IV) and α-glucosidase activity is an effective strategy for the treatment of type 2 diabetes. Currently, various anti-diabetic bioactive peptides have been isolated and identified. This review summarizes the preparation methods, structure-effect relationships, molecular binding sites, and effectiveness validation of DPP-IV and α-glucosidase inhibitory peptides in cellular and animal models. The analysis of peptides shows that the DPP-IV inhibitory peptides, containing 2-8 amino acids and having proline, leucine, and valine at their N-terminal and C-terminal, are the highly active peptides. The more active α-glucosidase inhibitory peptides contain 2-9 amino acids and have valine, isoleucine, and proline at the N-terminal and proline, alanine, and serine at the C-terminal. [ABSTRACT FROM AUTHOR]

Among ten extracts of indigenous medicinal plants, the MeOH extract of Terminalia triptera Stapf. (TTS) showed the most efficient mammalian α-glucosidase inhibition for the first time. The data of screening bioactive parts used indicated that the TTS trunk bark and leaves extracts demonstrated comparable and higher effects compared to acarbose, a commercial anti-diabetic drug, with half-maximal inhibitory concentration (IC50) values of 181, 331, and 309 µg/mL, respectively. Further bioassay-guided purification led to the isolation of three active compounds from the TTS trunk bark extract and identified as (−)-epicatechin (1), eschweilenol C (2), and gallic acid (3). Of these, compounds 1 and 2 were determined as novel and potent mammalian α-glucosidase inhibitors. The virtual study indicated that these compounds bind to α-glucosidase (Q6P7A9) with acceptable RMSD values (1.16–1.56 Å) and good binding energy (DS values in the range of −11.4 to −12.8 kcal/mol) by interacting with various prominent amino acids to generate five and six linkages, respectively. The data of Lipinski's rule of five and absorption, distribution, metabolism, excretion and toxicity (ADMET)-based pharmacokinetics and pharmacology revealed that these purified compounds possess anti-diabetic drug properties, and the compounds are almost not toxic for human use. Thus, the findings of this work suggested that (−)-epicatechin and eschweilenol C are novel potential mammalian α-glucosidase inhibitor candidates for type 2 diabetes treatment. [ABSTRACT FROM AUTHOR]

Panax ginseng was a traditional Chinese medicine with various pharmacological activities and one of its important activities was hypoglycemic activity; therefore, panax ginseng has been used in China as an adjuvant in the treatment of diabetes mellitus. In vivo and in vitro tests have revealed that ginsenosides, which are derived from the roots and rhizomes of panax ginseng have anti-diabetic effects and produce different hypoglycemic mechanisms by acting on some specific molecular targets, such as SGLT1, GLP-1, GLUTs, AMPK, and FOXO1. α-Glucosidase is another important hypoglycemic molecular target, and its inhibitors can inhibit the activity of α-Glucosidase so as to delay the absorption of dietary carbohydrates and finally reduce postprandial blood sugar. However, whether ginsenosides have the hypoglycemic mechanism of inhibiting α-Glucosidase activity, and which ginsenosides exactly attribute to the inhibitory effect as well as the inhibition degree are not clear, which needs to be addressed and systematically studied. To solve this problem, affinity ultrafiltration screening coupled with UPLC-ESI-Orbitrap-MS technology was used to systematically select α-Glucosidase inhibitors from panax ginseng. The ligands were selected through our established effective data process workflow based on systematically analyzing all compounds in the sample and control specimens. As a result, a total of 24 α-Glucosidase inhibitors were selected from panax ginseng, and it was the first time that ginsenosides were systematically studied for the inhibition of α-Glucosidase. Meanwhile, our study revealed that inhibiting α-Glucosidase activity probably was another important mechanism for ginsenosides treating diabetes mellitus. In addition, our established data process workflow can be used to select the active ligands from other natural products using affinity ultrafiltration screening. [ABSTRACT FROM AUTHOR]

A series of 24 new 1H-1,2,3-triazole hybrids of 3-O-acetyl-11-keto-β-boswellic acid (β-AKBA (1)) and 11-keto-β-boswellic acid (β-KBA (2)) was designed and synthesized by employing "click" chemistry in a highly efficient manner. The 1,3-dipolar cycloaddition reaction between β-AKBA-propargyl ester intermediate 3 or β-KBA-propargyl ester intermediate 4 with substituted aromatic azides 5a–5k in the presence of copper iodide (CuI) and Hünig's base furnished the desired products—1H-1,2,3-triazole hybrids of β-AKBA (6a–6k) and β-KBA (7a–7k)—in high yields. All new synthesized compounds were characterized by 1H-, 13C-NMR spectroscopy, and HR-ESI-MS spectrometry. Furthermore, their α-glucosidase-inhibitory activity was evaluated in vitro. Interestingly, the results obtained from the α-glucosidase-inhibitory assay revealed that all the synthesized derivatives are highly potent inhibitors, with IC50 values ranging from 0.22 to 5.32 µM. Among all the compounds, 6f, 7h, 6j, 6h, 6g, 6c, 6k, 7g, and 7k exhibited exceptional inhibitory potency and were found to be several times more potent than the parent compounds 1 and 2, as well as standard acarbose. Kinetic studies of compounds 6g and 7h exhibited competitive and mixed types of inhibition, with ki values of 0.84 ± 0.007 and 1.18 ± 0.0012 µM, respectively. Molecular docking was carried out to investigate the binding modes of these compounds with α-glucosidase. The molecular docking interactions indicated that that all compounds are well fitted in the active site of α-glucosidase, where His280, Gln279, Asp215, His351, Arg442, and Arg315 mainly stabilize the binding of these compounds. The current study demonstrates the usefulness of incorporating a 1H-1,2,3-triazole moiety into the medicinally fascinating boswellic acids skeleton. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) and dementia cause heavy health burden in mainland China, where few studies have investigated the association between glucose‐lowering agents and dementia risk. We aimed to assess the association between use of thiazolidinediones (TZDs) and dementia incidence in a mainland Chinese population with T2DM. Methods: A retrospective cohort of T2DM patients who were new users of TZDs or alpha glucosidase inhibitors (AGIs) was assembled using the Yinzhou Regional Health Care Database. A Cox model with inverse probability of treatment weighting (IPTW) for controlling potential founding was applied to estimate the hazard ratio (HR) of the association between use of TZDs and dementia risk. Results: A total of 49 823 new users of AGIs and 12 752 new users of TZDs were included in the final cohort. In the primary analysis, the incidence of dementia was 195.7 and 78.2 per 100 000 person‐years in users of AGIs and TZDs respectively. TZD use was associated with a reduced risk of incident dementia after adjusting for potential confounding using IPTW, with a HR of 0.51 (95% CI, 0.38–0.67). The results in various subgroup analyses and sensitivity analyses were consistent with the findings of the primary analysis. Conclusions: Use of TZDs is associated with a decreased risk of dementia incidence in a mainland Chinese population with T2DM. [ABSTRACT FROM AUTHOR]

Acacia saligna growing in Australia has not been fully investigated for its bioactive phytochemicals. Sequential polarity-based extraction was employed to provide four different extracts from individual parts of A. saligna. Bioactive extracts were determined using in vitro antioxidant and yeast α-glucosidase inhibitory assays. Methanolic extracts from barks, leaves, and flowers are the most active and have no toxicity against 3T3-L1 adipocytes. Compound isolation of bioactive extracts provided us with ten compounds. Among them are two novel natural products; naringenin-7-O-α-L-arabinopyranoside 2 and (3S*,5S*)-3-hydroxy-5-(2-aminoethyl) dihydrofuran-2(3H)-one 9. D-(+)-pinitol 5a (from barks and flowers), (−)-pinitol 5b (exclusively from leaf), and 2,4-di-t-butylphenol 7 are known natural products and new to A. saligna. (−)-Epicatechin 6, quercitrin 4, and myricitrin 8 showed potent antioxidant activities consistently in DPPH and ABTS assays. (−)-Epicatechin 6 (IC50 = 63.58 μM),D-(+)-pinitol 5a (IC50 = 74.69 μM), and naringenin 1 (IC50 = 89.71 μM) are the strong inhibitors against the α-glucosidase enzyme. The presence of these compounds supports the activities exerted in our methanolic extracts. The presence of 2,4-di-t-butylphenol 7 may support the reported allelopathic and antifungal activities. The outcome of this study indicates the potential of Australian A. saligna as a rich source of bioactive compounds for drug discovery targeting type 2 diabetes. [ABSTRACT FROM AUTHOR]

The antioxidant content of Baper tea was determined using phytochemical testing, and the potential of these contents as immunomodulatory agents and candidates for standardized herbal medications was investigated. A randomized design was used in this experimental study. Phytochemical assays are used to determine the antioxidant content of Baper tea, whereas organoleptic studies are performed using hedonic tests. A literature review was used to assess the content's potential as an immunomodulatory agent and candidate for standardized herbal medicine. The study lasted four months at the Biology and National Food and Drug Agency Laboratory in Bali Province. Data analysis is based on descriptive methods. Baper tea is prepared in a 2.1.1 ratio. According to the hedonic test results, 41 panelists (87.23 %) prefer Baper tea products based on their color assessment, flavor, aroma, community reception, and acceptability. The matrix and security test revealed a water content of 4.43 %, an IC50 of 24.27 ppm, α-glucosidase inhibitors of 12.18 ppm, a total phenolic content of 28.00 %, and a total flavonoid content of 15.57 %. Baper tea raw materials contain components that have the potential to act as immunomodulatory agents and candidates for standardized herbal medications based on local wisdom. [ABSTRACT FROM AUTHOR]

Background: There are multiple glucose-lowering drugs available as alternative initial monotherapy for type 2 diabetes patients with contraindications or intolerance to metformin. However, little comparative and systematic data are available for them as initial monotherapy. This study estimated and compared the treatment effects of glucose-lowering drugs as initial monotherapy for type 2 diabetes. Methods: PubMed, Web of Science, Embase, CNKI, Chongqing VIP, and WanFang Data from 1 January 1990 until 31 December 2020 were searched for randomized controlled trials which compared a glucose-lowering drug with placebo/lifestyle-intervention for type 2 diabetes. Drug classes included metformin, sulfonylureas (SUs), thiazolidinediones (TZDs), glinides (NIDEs), α-glucosidase inhibitors (AGIs), dipeptidyl peptidase-4 inhibitors (DPP-4is), sodium-glucose cotransporter-2 inhibitors (SGLT2is), insulins (INSs), and glucagon-like peptide-1 receptor agonists (GLP-1RAs). Results: A total of 185 trials were included, identifying 38,376 patients from 56 countries across six continents. When choosing an initial drug monotherapy alternative to metformin, SUs were most efficacious in reducing HbA1c (−1.39%; 95% CI −1.63, −1.16) and FPG (−2.70 mmol/L; 95% CI −3.18, −2.23), but increased hypoglycemia risks (5.44; 95% CI 2.11, 14.02). GLP-1RAs were most efficacious in reducing BMI (−1.05 kg/m2; 95% CI −1.81, −0.29) and TC (−0.42 mmol/L; 95% CI −0.61, −0.22). TZDs were most efficacious in increasing HDL-C (0.12 mmol/L; 95% CI 0.07, 0.17). SGLT2is were most efficacious in lowering SBP (−4.18 mmHg; 95% CI −4.84, −3.53). While AGIs conferred higher risk of AE-induced discontinuations (2.57; 95% CI 1.64, 4.03). Overall, only GLP-1RAs showed an integrated beneficial effect on all outcomes. Our results also confirmed the intraclass differences in treatment effects across drugs. Most trials were short-term, and no significant differences in mortality, total vascular events, myocardial infarction, heart failure, stroke, or diabetic nephropathy were observed across drug classes. Conclusions: Our results suggest a potential treatment hierarchy for decision-makers, with GLP-1RAs being the preferred alternative therapy to metformin regarding their favorable efficacy and safety profiles. [ABSTRACT FROM AUTHOR]

The aim of the study is to screen the morphological, anatomical, biological, and chemical profiles of the leave extracts of endemic Polyscias species namely P. dichroostachya (PD), P. gracilis (PG), and P. mauritiana (PM) from Mauritius. The morphology and anatomy of the leaves were studied using a microscope. Phytochemical screening of extracts using LC-MS/MS was carried out by ionization in both positive and negative modes. The leaves are pinnately compound, hypostomatic, dorsiventral, with a prominent mid vein with secretion cavities, and they can be distinguished by their midrib shape and anatomy. From the molecular mass and fragmentation data, 31 terpenoid saponins, 19 flavonoids, 17 acids, 7 terpenes, and 10 miscellaneous compounds including pyrrolidines and acetylenes in different extracts (hexane, ethanol, and aqueous) were identified. Extracts from the three species using DPPH radical scavenging activity exhibited good to moderate antioxidant activities with IC50 values in the range of 2.1- 70.8 mg/ml and the ethanolic extract of PD showing the highest activity. Aqueous extracts of PG and PM potently inhibited alpha-glucosidase with IC50 values of 0.50 and 2.62 mg/ml. The different leaf extracts exhibited moderate activity against a panel of gram-positive and gram-negative bacteria. This is probably the first report on the extensive chemical profiling and morphology of these endemic Polysias spp. from Mauritius and the results indicate that these leaf extracts have beneficial health properties and are thus worth exploiting further. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a chronic metabolic disorder in which the pancreas secretes insulin but the body cells do not recognize it. As a result, carbohydrate metabolism causes hyperglycemia, which may be fatal for various organs. This disease is increasing day by day and it is prevalent among people of all ages, including young adults and children. Acarbose and miglitol are famous alpha-glucosidase inhibitors but they complicate patients with the problems of flatulence, pain, bloating, diarrhea, and loss of appetite. To overcome these challenges, it is crucial to discover new anti-diabetic drugs with minimal side effects. For this purpose, benzotriazinone sulfonamides were synthesized and their structures were characterized by FT-IR, 1H-NMR and 13C-NMR spectroscopy. In vitro alpha-glucosidase inhibition studies of all synthesized hybrids were conducted using the spectrophotometric method. The synthesized compounds revealed moderate-to-good inhibition activity; in particular, nitro derivatives 12e and 12f were found to be the most effective inhibitors against this enzyme, with IC50 values of 32.37 ± 0.15 µM and 37.75 ± 0.11 µM. In silico studies, including molecular docking as well as DFT analysis, also strengthened the experimental findings. Both leading compounds 12e and 12f showed strong hydrogen bonding interactions within the enzyme cavity. DFT studies also reinforced the strong binding interactions of these derivatives with biological molecules due to their lowest chemical hardness values and lowest orbital energy gap values. [ABSTRACT FROM AUTHOR]

Alpha-glucosidase inhibitor (αGIs)-induced pneumatosis intestinalis (PI) has been narrated in case reports but never systematically investigated. This study aimed to investigate the concurrency of PI and αGIs. A literature search was performed in PubMed, Google Scholar, WorldCat, and the Directory of Open-Access Journals (DOAJ) by using the keywords "pneumatosis intestinalis", "alpha-glucosidase inhibitors", and "diabetes". In total, 29 cases of αGIs-induced PI in 28 articles were included. There were 11 men, 17 women, and one undefined sex, with a median age of 67. The most used αGI was voglibose (44.8%), followed by acarbose (41.4%) and miglitol (6.8%). Nine (31%) patients reported concomitant use of prednisone/prednisolone with or without immunosuppressants. The main symptoms were abdominal pain (54.5%) and distention (50%). The ascending colon (55.2%) and the ileum (34.5%) were the most affected. Nineteen (65.5%) patients had comorbidities. Patients with comorbidities had higher rates of air in body cavities, the portal vein, extraintestinal tissues, and the wall of the small intestine. Only one patient was found to have non-occlusive mesenteric ischemia. Twenty-five patients were treated with conservative therapy alone, and two patients received surgical intervention. All patients recovered. In conclusion, comorbidities, glucocorticoids, and immunosuppressants aggravate αGIs-induced PI. Conservative therapy is recommended when treating αGIs-induced PI. [ABSTRACT FROM AUTHOR]

Many current studies show an association of diabetes and secondary complications with chronic inflammation. Evidence of these immunological changes include altered levels of cytokines and chemokines, changes in the numbers and activation states of various leukocyte populations, apoptosis, and fibrosis during diabetes. Therefore, correcting inflammation may be beneficial to stop, impede, and improve diabetes status and its associated complications. Apart from anti-inflammatory drugs, various hypoglycaemic agents have also been found to reduce inflammation that could contribute to improved outcomes in diabetic patients. Various studies have been carried out with thiazolidinediones, dipeptidyl peptidase-4 inhibitors and Metformin showing moderateto-strong anti-inflammatory action. Sulfonylureas and alpha glucosidase inhibitors exert modest antiinflammatory effects, while the injectable agents, insulin and glucagon-like peptide-1 receptor agonists, may improve secondary complications due to their anti-inflammatory potential. Currently, there is paucity of human clinical data on anti-inflammatory effects of sodium-glucose cotransporter type-2 (SGLT) inhibitors. Nevertheless, it is essential to distinguish between anti-inflammatory effects resulting from better glucose control and effects related to intrinsic anti-inflammatory actions of the glucose-lowering agents. Also, it is important to define what role the anti-inflammatory effects of these anti-diabetic agents may play in the prevention of macrovascular and microvascular diabetic complications. [ABSTRACT FROM AUTHOR]

Pleurotus ostreatus cv. Florida is one of the widely used edible mushroom. The polysaccharides from this mushrooms have been studied for antidiabetic potential; however, no efforts have been made to explore the potential of this mushroom to influence carbohydrate metabolizing enzymes viz. α-amylase and α-glucosidase. The present work was undertaken to investigate the inhibitory potential of Pleurotus ostreatus cv. Florida on enzymes α-amylase and α-glucosidase. Several concentrations of extracts were used to study inhibition of enzymatic activity of α-amylase and α-glucosidase. A dose dependent inhibitory effect on enzymes was observed. The current study, for the first time, uncovered α-amylase and α-glucosidase inhibitory potential of Pleurotus ostreatus cv. Florida. The study could be helpful to isolate and characterize compounds responsible for it. [ABSTRACT FROM AUTHOR]

Background: Multiple glucose-lowering drugs are available as add-ons to metformin for a second-line treatment for type 2 diabetes. However, no systematic and comparative data are available for them in China. We aimed to compare the effects of glucose-lowering drugs added to metformin in China. Methods: PubMed, Embase, Web of Science, CNKI, WanFang Data, and Chongqing VIP from 1 January 2000 until 31 December 2020 were systematically searched for randomized controlled trials comparing a glucose-lowering drug added to metformin with metformin in Chinese type 2 diabetes patients. Drug classes included sulfonylureas (SUs), glinides (NIDEs), thiazolidinediones (TZDs), α-glucosidase inhibitors (AGIs), dipeptidyl peptidase-4 inhibitors (DPP-4is), sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and insulins (INSs). Two reviewers independently screened studies, extracted data, and appraised the risk of bias. Results: 315 trials were included. In patients receiving metformin alone, the addition of NIDEs produced the greatest additional HbA1c reductions (1.29%; 95% CI 0.97, 1.60); while INSs yielded both the largest additional FPG reductions (1.58 mmol/L; 95% CI 1.22, 1.94) and 2 hPG reductions (2.52 mmol/L; 95% CI 1.83, 3.20). INS add-ons also conferred the largest additional HDL-C increases (0.40 mmol/L; 95% CI 0.16, 0.64), whereas AGI add-ons generated the greatest TC reductions (1.08 mmol/L; 95% CI 0.78, 1.37). The greatest incremental SBP reductions (6.65 mmHg; 95% CI 4.13, 9.18) were evident with SGLT2i add-ons. GLP-1RA add-ons had the greatest BMI reductions (1.96 kg/m2, 95% CI 1.57, 2.36), meanwhile with the lowest (0.54 time) hypoglycemia risk. Overall, only the GLP-1RA add-ons demonstrated a comprehensive beneficial effect on all outcomes. Furthermore, our results corroborated intraclass differences among therapies. Given the limited evidence, we could not reach a conclusion about the optimal therapies regarding mortality and vascular outcomes. Conclusion: The results suggested a potential treatment hierarchy for clinicians and patients, with the GLP-1RA add-ons being most preferred based on their favorable efficacy and safety profiles; and provided a unified hierarchy of evidence for conducting country-specific cost-effectiveness analyses. [ABSTRACT FROM AUTHOR]

Recently, the strategy of multivalency has been widely employed to design glycosidase inhibitors, as glycomimetic clusters often induce marked enzyme inhibition relative to monovalent analogs. Polyhydroxylated pyrrolidines, one of the most studied classes of iminosugars, are an attractive moiety due to their potent and specific inhibition of glycosidases and glycosyltransferases, which are associated with many crucial biological processes. The development of multivalent pyrrolidine derivatives as glycosidase inhibitors has resulted in several promising compounds that stand out. Herein, we comprehensively summarized the different synthetic approaches to the preparation of multivalent pyrrolidine clusters, from total synthesis of divalent iminosugars to complex architectures bearing twelve pyrrolidine motifs. Enzyme inhibitory properties and multivalent effects of these synthesized iminosugars were further discussed, especially for some less studied therapeutically relevant enzymes. We envision that this comprehensive review will help extend the applications of multivalent pyrrolidine iminosugars in future studies. [ABSTRACT FROM AUTHOR]

Phytochemical study of the root bark of Paeonia suffruticosa plant led to the isolation and characterization of paeoniflorigenone (1), benzoylpaeoniflorin (2), betulinic acid (3), oleanolic acid (4), β-sitosterol (5), and caffeic acid octadecyl ester (6). The enzymatic activities of compounds 1-6 were evaluated by in vitro inhibition assay of α-glucosidase and α-amylase. Compounds 1-6 with IC50 values ranging from 30 to 180 μM inhibited α-glucosidase more efficiently than the standard compound acarbose (IC50 = 1463.0 ± 29.5 μM). Conversely, these compounds (with IC50 values ranging from 40 to 200 μM) were less potent against α-amylase compared to acarbose (IC50 = 16.6 ± 0.9 μM). Kinetic analysis showed that compound 1 was a mixed-type inhibitor, compounds 3 and 4 were noncompetitive inhibitors, while compound 6 was an uncompetitive inhibitor of glucosidase. [ABSTRACT FROM AUTHOR]

Inhibition of α-glucosidase is a therapeutic approach that slows down the hydrolysis of oligosaccharides and disaccharides to glucose. Therefore, delaying the digestion and absorption of carbohydrates by inhibiting α-glucosidase can reduce blood glucose levels. Herein, the methanol extract of Scutellaria barbata D. Don was screened for α-glucosidase inhibitors using an in vitro inhibition assay and chromatographic techniques (column chromatography, TLC, and HPLC). Six known flavonoids were isolated, including chrysin (1), wogonin (2), apigenin (3), hispidulin (4), pinocembrin (5) and 6-methoxyaringenin (6), and their structures were identified by spectroscopic methods (NMR and MS) and by comparing their spectral data to reported values. Compounds 1 – 6 exhibited higher inhibitory activities against α-glucosidase with IC50 values between 17 μM and 192 μM compared to the reference drug acarbose (1463.0 ± 29.5 μM). The kinetic analysis showed that flavonoid 1 was a competitive inhibitor, flavonoids 2 and 4 were mixed-type inhibitors, while flavonoids 3, 5 and 6 were noncompetitive inhibitors of α-glucosidase. Computer modeling showed that the primary amino acid residue interacted with the flavonoids primarily through hydrogen bonding, with binding energies ranging from –5.44 to –1.85 kcal/mol. These results indicate that compounds 1 – 6 are potential α-glucosidase inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] • Five pairs of novel merosesquiterpenoid enantiomers were isolated and identified. • Dauresorcinol A (1) possesses an unprecedented methyl-shifted merosesquiterpenoid carbon skeleton. • Dauresorcinol B (2) bears a novel caged merosesquiterpenoid carbon skeleton. • (+)/(−)- 1 and 3 − 5 showed more potent α -glucosidase inhibitory activity than acarbose. • The structure−activity relationships of isolates were discussed. Five pairs of new merosesquiterpenoid enantiomers, named dauresorcinols A−E (1 − 5), were isolated from the leaves of Rhododendron dauricum. Their structures were elucidated by comprehensive spectroscopic data analysis, quantum chemical calculations, Rh 2 (OCOCF 3) 4 -induced ECD, and single-crystal X-ray diffraction analysis. Dauresorcinols A (1) and B (2) possess two new merosesquiterpene skeletons bearing an unprecedented 2,6,7,10,14-pentamethyl-11-oxatetracyclo[8.8.0.02,7.012,17]octadecane and a caged 15-isohexyl-1,5,15-trimethyl-2,10-dioxatetracyclo[7.4.1.111,14.03,8]pentadecane motif, respectively. Plausible biosynthetic pathways of 1 − 5 are proposed involving key oxa-electrocyclization and Wagner−Meerwein rearrangement reactions. (+)/(−)- 1 and 3 − 5 showed potent α -glucosidase inhibitory activity, 3 to 22 times stronger than acarbose, an antidiabetic drug targeting α -glucosidase. Docking results provide a basis to design and develop merosesquiterpenoids as potent α -glycosidase inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] • Flavonoids with hypoglycemic activity from the waste leaves of Rheum tanguticum were studied for the first time. • Extraction and enrichment process of active flavonoids were optimized based on an activity-oriented strategy. • Thirty-six flavonoids in the fraction with best α-glycosidase inhibition activity were identified by UPLC-QTOF-MS/MS. • Six flavonoids with higher α-glycosidase inhibition activity were screened by molecular docking and in vitro validation. • The interaction mechanism between six flavonoids and protein was investigated using multispectral approaches. In the present study, an efficient strategy has been established for rapid screening of potential α-glucosidase inhibitors from the waste leaves of Rheum tanguticum by activity-oriented extraction and enrichment optimization, UPLC-QTOF-MS/MS, molecular docking, and in vitro validation. With α-glucosidase inhibitory activity as the evaluation index, the extraction process was optimized by response surface methodology and the enrichment process by macroporous resins was optimized by adsorption and desorption experiments. The active flavonoids yield was 8.85 mg/g under the optimized extraction conditions. After AB-8 macroporous resins enrichment, the active flavonoids purity increased from 2.89 % to 47.6 %, a 17-fold increase, while the IC 50 of α-glucosidase reduced from 13.97 mg/mL to 412 μg/mL, a 33.9-fold reduction. Thirty-six flavonoids in the active flavonoids fraction were identified by UPLC-QTOF-MS/MS. Molecular docking screening, in vitro activity assay and multispectral approaches verification confirmed the potential of six flavonoids as novel α-glucosidase inhibitors. [ABSTRACT FROM AUTHOR]

• Pleurospermum candollei possess high inhibition activity against DPPH radicals and alpha glucosidase enzyme. • P. candollei can reduce the diabetic effects of streptozotocin. • P. candollei can normalize the production of antioxidant enzymes and free radicals in rat kidney. • P. candollei can regulate the inhibition of inflammatory, and apoptotic mediators. • P. candollei can be used as potent drug against diabetes induced nephropathy. Pleurosepermum candollei is a local vegetable that is traditionally used to cure abdominal problems, pain, and infertility. The purpose of this study was to evaluate the therapeutic potential of P. candollei ethanolic extract against T2DM through modulation of renal genetic markers. Biochemical composition of extract was investigated through high performance liquid chromatography and quantitative phytochemical analyses. In rats, T2DM was induced by injecting streptozotocin (STZ), and P. candollei ethanol extract was administered for 21 days. Antioxidant enzymes and renal biomarkers were assessed in homogenized kidney samples of treated groups. qRT-PCR analysis of isolated RNA was performed for estimation of inflammatory and apoptotic markers. These biochemical analyses revealed that plant extract significantly normalized the levels of catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH) after 21 days of treatment. However, high dose of plant extract (300 mg/kg) exhibited more prominent results in restoring the inflammatory (IL-6, IL-β1, and TNF-α) and apoptotic markers than low dose (150 mg/kg). Similarly, histological studies also revealed that there was minor inflammation and necrosis in kidney of plant treated rats. Generally, the present study showed that administration of P. candollei extract exhibits renal protective, anti-hyperglycemic, and anti-glycation properties. However, further research is required to assess the mechanism of action of PCE at clinical level. [Display omitted] [ABSTRACT FROM AUTHOR]

Identifying medicinally relevant compounds from natural resources generally involves the tedious work of screening plants for the desired activity before capturing the bioactive molecules from them. In this work, we created a paper-based ligand fishing platform to vastly simplify the discovery process. This paper-based method exploits the enzymatic cascade reaction between α -glucosidase (GAA), glucose oxidase (GOx), and horseradish peroxidase (HRP), to simultaneously screen the plants and capture the GAA inhibitors from them. The designed test strip could capture ligands in tandem with screening the plants, and it features a very simply operation based on direct visual assessment. Multiple acylated flavonol glycosides from the leaves of Quercus variabilis Blume were newly found to possess GAA inhibitory activities, and they may be potential leads for new antidiabetic medications. Our study demonstrates the prospect of the newly discovered GAA ligands as potential bioactive ingredients as well as the utility of the paper-based ligand fishing method. [Display omitted] • Test strip (GDTS) built on enzyme cascade reaction and dopamine-paper was newly set. • GDTS can screen bioactive plants and concurrently capture α -glucosidase inhibitors. • Four plants were screened by GDTS as targets from fourteen plants. • Twenty-two inhibitors were acquired from target plants via GDTS. • Acylated flavonol glucosides in Quercus variabilis were new GAA inhibitors. [ABSTRACT FROM AUTHOR]

6‐Ethoxy‐2‐mercapto benzothiazole derivatives 1–26 were synthesized by following two different reaction schemes. Products 1–18 were synthesized by treating 6‐ethoxy‐2‐mercaptobenzothiazole with different phenacyl bromides whereas compounds 19–26 were prepared by the reaction of 6‐ethoxy‐2‐mercaptobenzothiazole with benzyl bromide derivatives under basic conditions. Structural characterization of compounds was performed by mass spectrometric and NMR spectroscopic techniques. Spectroscopic data was well supported to confirm the structures of each analog. All synthetic compounds were subjected to check their potential to inhibit the α‐glucosidase enzyme. All scaffolds demonstrated potent inhibitory activity (IC50=60.1±3.6–319.7±7.5 μM) than standard acarbose (IC50=750.0±10.5 μM). Compounds 18 (IC50=60.1±3.6 μM) and 26 (IC50=77.0±4.4 μM) having another electron‐rich heterocyclic ring system were identified as the two top‐most potent compounds of the series. Kinetic studies ascertained the competitive type inhibition by the most potent analogs. Detailed binding interactions analyses with docking simulations were also carried out which revealed a distinct binding pattern of ligands (synthetic molecules) with the enzyme's active site. [ABSTRACT FROM AUTHOR]

Diabetes Mellitus (DM) is one of the leading causes of deaths worldwide and is becoming an epidemic in many countries. Sedentary lifestyles, less physical activity, environmental and genetic changes are some of the factors which are responsible for the disease. It is putting a lot of economic burden especially on developing and under developed countries. Hence there is a dire need for the management of this disease. The use of current available therapies is associated with one or more side effects or financial burden. From the past few years, pyrrolidine derivatives have grabbed much of the attention of the researchers for the development of the novel molecules that can be used as a drug candidate for the treatment of Diabetes Mellitus. The current review attempts and aims at compiling the important work done in this relevant area which will help the researchers to design and synthesize the novel Pyrrolidine derivatives as antidiabetic agents with desired clinical outputs. [ABSTRACT FROM AUTHOR]

[Display omitted] • Changii Radix protein contains α-glucosidase inhibitory peptides. Peptides released from in vitro simulated gastrointestinal digestion method manifested the best α-glucosidase inhibitory activity. • Peptides with smaller molecular weight and being more hydrophobic exerted the best hypoglycemic activity. • The GID-3-SG-2-RP-2 fraction exerted higher effect than the three synthesized peptides indicated peptide that acts synergistically or has greater activity. • Synthesized peptides KVIISAPSKDAPMF, SQHISTAGMEASGTSNMKF and STFQQMW showed α-glucosidase inhibitory activity with an with an IC 50 value of 32 μg/mL, 1.051 mg/mL and 1.104 mg/mL, respectively. • The results indicated that Changii Radix derived peptides may have potential functions in the prevention and management of type 2 diabetes. The objective of this research was to investigate the α-glucosidase inhibitory activity of peptides released from Changii Radix protein under the optimal enzymatic hydrolysis conditions of trypsin, flavourzyme, compound proteinase, papain, alkaline proteinase, neutral protease, and in vitro simulated human gastrointestinal digestive conditions. The hydrolysate with the best activity was further purified by ultrafiltration, size-exclusion chromatography and semi-preparative high performance liquid chromatography. The peptides in the most active fraction were subsequently identified by nano-LC–MS/MS and screened for bioactivity. As a result, the GID-3-SG-2-RP-2 fraction (with smaller molecular weight and more hydrophobic) manifested the highest effect with an IC 50 value of 32 μg/mL. Three peptides of this fraction were synthesized, SQHISTAGMEASGTSNMKF, KVIISAPSKDAPMF, and STFQQMW, and provided an IC 50 of 1.051, 0.032, and 1.104 mg/mL, respectively. Thus, the results indicated that Changii Radix derived peptides may have potential functions in the prevention and management of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Anthranilic acid and its analogues present a privileged profile as pharmacophores for the rational development of pharmaceuticals deliberated for managing the pathophysiology and pathogenesis of various diseases. The substitution on anthranilic acid scaffold provides large compound libraries, which enable a comprehensive assessment of the structure activity relationship (SAR) analysis for the identification of hits and leads in a typical drug development paradigm. Besides, their widespread applications as anti‐inflammatory fenamates, the amide and anilide derivatives of anthranilic acid analogues play a central role in the management of several metabolic disorders. In addition, these derivatives of anthranilic acid exhibit interesting antimicrobial, antiviral and insecticidal properties, whereas the derivatives based on anthranilic diamide scaffold present applications as P‐glycoprotein inhibitors for managing the drug resistance in cancer cells. In addition, the anthranilic acid derivatives serve as the inducers of apoptosis, inhibitors of hedgehog signaling pathway, inhibitors of mitogen activated protein kinase pathway, and the inhibitors of aldo‐keto reductase enzymes. The antiviral derivatives of anthranilic acid focus on the inhibition of hepatitis C virus NS5B polymerase to manifest considerable antiviral properties. The anthranilic acid derivatives reportedly present neuroprotective applications by downregulating the key pathways responsible for the manifestation of neuropathological features and neurodegeneration. Nevertheless, the transition metal complexes of anthranilic acid derivatives offer therapeutic applications in diabetes mellitus, and obesity by regulating the activity of α‐glucosidase. The present review demonstrates a critical analysis of the therapeutic profile of the key derivatives of anthranilic acid and its analogues for the rational development of pharmaceuticals and therapeutic molecules. [ABSTRACT FROM AUTHOR]

α‐Glucosidase inhibition is one of the key targets for controlling diabetes. In consideration of that, new L‐valinol derived fluorinated sultam triazoles were synthesized as α‐glucosidase inhibitors, and their activities were further compared with the precursor molecules (sulfonamides, sultams, and N‐propargyl sultams). Primarily, all the synthesized sultam triazoles and precursor compounds (sulfonamides, sultams, and N‐propargyl sultams) were evaluated for different biological activities, including cytotoxicity, anti‐inflammatory, and α‐glucosidase inhibitory activities. Results revealed that only sultam triazoles exhibited inhibition against α‐glucosidase enzyme (IC50 values: 173 to 194 μM) using acarbose (IC50: 875.85 ± 2.03 μM) as the standard drug. These sultam triazoles were prepared after few steps, starting from enantiopure L‐valinol, which differ electronically (due to the position of fluorine atom and different positions on aromatic ring). Structures of all the compounds were evaluated using different spectroscopic techniques. Kinetics of active compounds were also investigated to find their mode of inhibition. [ABSTRACT FROM AUTHOR]

The article discusses the alpha-glucosidase inhibitors and thiazolidinediones that are older classes of oral type 2 diabetes medication. Topics discussed include acarbose that is an alpha-glucosidase inhibitor available in Australia, diagnosis of impaired glucose tolerance, and safety concerns which were raised about the use of rosiglitazone.

The synthesis and antidiabetic activity of 5-Benzylidene-2,3-diarylthiazolidine-4-one derivatives (6a–w) are presented in the current work. Screening of derivatives 6a–w for their α-glucosidase inhibitory activity, showed higher inhibitory activity of twenty of the screened compounds (IC50: 105–412 µM) in comparison to acarbose (IC50: 750 µM) as a standard. Compounds 6r, 6b, and 6q exerted the best activity with the IC50 value of 105, 110, and 127 µM, respectively. Performing the kinetic studies, revealed the competitive mode of inhibition for 6r. It binds to the active site on the enzyme and competes with the substrate for binding to the active site. based on molecular docking studies, 6b, 6q, and 6r interact with HIS280, ASP307, and PRO312 residues, which show the important role of these residues inside the active site of the enzyme. Cytotoxicity studies also showed IC50 > 750 µM for 6a–w on different cell lines namely, NIH3T3, MCF-7, and HT-29. [ABSTRACT FROM AUTHOR]

Vascular aging is defined as organic and functional changes in blood vessels, in which decline in autophagy levels, DNA damage, MicroRNA (miRNA), oxidative stress, sirtuin, and apoptosis signal-regulated kinase 1 (ASK1) are integral thereto. With regard to vascular morphology, the increase in arterial stiffness, atherosclerosis, vascular calcification and high amyloid beta levels are closely related to vascular aging. Further closely related thereto, at the cellular level, is the aging of vascular endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). Vascular aging seriously affects the health, economy and life of patients, but can be delayed by SGLT2 inhibitors through the improvement of vascular function. In the present article, a review is conducted of recent domestic and international progress in research on SGLT2 inhibitors, vascular aging and diseases related thereto, thereby providing theoretical support and guidance for further revealing the relationship between SGLT2 inhibitors and diseases related to vascular aging. [ABSTRACT FROM AUTHOR]

Mangrove is one of the highly productive ecosystems and contains diverse plants and microbial communities. Bacterial endophytes from mangroves are considered as a prolific source of biological molecules with important functions in the protection of mangrove plants against herbivores, insects as well as pathogens. The present study aimed to isolate endophytic bacteria from the roots of mangrove plant Rhizophora stylosa and to screen antioxidant, α-amylase and α- glucosidase inhibitory activities of ethyl acetate extracts from the isolated endophytic bacteria. A total of 73 endophytic bacterial strains from R. stylosa roots were isolated, of which ethyl acetate extracts of 10 isolated endophytic strains at a concentration of 500 µg/mL showed antioxidant activity with ATBS and DPPH radical scavenging values ranging from 31.3 ± 2.5% to 62.2 ± 6.3% and 21.2 ± 3.2% to 56.7 ± 4.5%, respectively. Additionally, the ethyl acetate extracts of 11 isolated endophytic bacteria at a concentration of 500 µg/mL exhibited α-amylase and α- glucosidase inhibitory activities with values ranging from 31.4 ± 3.1% to 59.7 ± 6.4% and 17.3 ± 3.1% to 54.5 ± 6.1%, respectively. The identification of the five high antioxidant, α-amylase and α-glucosidase inhibitory endophytes by 16S rRNA sequences revealed that the bacterial endophytes belonged to three genera, including Bacillus, Streptomyces, and Pseudovibrio with the similarity of more than 99%. The obtained results suggest that the root endophytic bacteria of R. stylosa are a source of antioxidant and antidiabetic agents. To the best of our knowledge, this is the first report of antioxidant, α-amylase and α-glucosidase activities of the endophytic bacteria from the roots of Vietnam mangrove plants in general and R. stylosa in particular. [ABSTRACT FROM AUTHOR]

Introduction: Merremia peltata is ethnomedicine plant used as traditional medicine in Sulawesi, Sumatra, Maluku and Papua. M. peltata is used for diabetic. Diabetes mellitus therapy with inhibit activity of alpha glucosidase enzyme could delay absorption of monosaccharides after a meal and interrupt glucose transport into the circulation. Objective: This research purpose is to investigate in vitro antioxidant activity and alpha glucosidase enzyme inhibitor leaves and stem extract of M. peltata. Method: The Stem and leaves of M. peltata were extracted sequentially using the UAE method using hexane, ethyl acetate, and methanol as mobile phase/solvent. The M. peltata extracts were subjected to the antioxidant activity assay by the DPPH radical scavenging and FRAP method. Antidiabetic activity was determined by an enzymatic alpha glucosidase inhibitor. Result: The extract which had best performance in antioxidant activity was stem ME with value of IC50 in DPPH 47.41 μg/mL and total antioxidant power 340.04 μmol/g. This study showed that leaves and stem extract of M .peltata have potential alpha glucosidase inhibitors for diabetic therapy. Stem ME had the best activity with IC50 value 47.44 μg/mL, almost two times better than acarbose as a positive control (IC50 = 98.38 μg/mL). Leaves ME, leaves EA, and stem EA also give better activity of alpha glucosidase inhibitors than acarbose with IC50 value 67.24 μg/mL, 69.38 μg/mL, and 72.85 μg/mL, respectively. Conclusion: M. peltata has potential antioxidant and alpha glucosidase inhibitor activity for diabetic therapy. [ABSTRACT FROM AUTHOR]

In an attempt to find novel, potent α-glucosidase inhibitors, a library of poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag have been synthesized through heating a mixture of 2-aminobenzimidazoles 1 and α-azidochalcone 2 under the mild conditions. This efficient, facile protocol has been resulted into the desirable compounds with a wide substrate scope in good to excellent yields. Afterwards, their inhibitory activities against yeast α-glucosidase enzyme were investigated. Showing IC50 values ranging from 16.4 ± 0.36 µM to 297.0 ± 1.2 µM confirmed their excellent potency to inhibit α-glucosidase which encouraged us to perform further studies on α-glucosidase enzymes obtained from rat as a mammal source. Among various synthesized 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines, compound 3k exhibited the highest potency against both Saccharomyces cerevisiae α-glucosidase (IC50 = 16.4 ± 0.36 μM) and rat small intestine α-glucosidase (IC50 = 45.0 ± 8.2 μM). Moreover, the role of amine moiety on the observed activity was studied through substituting with chlorine and hydrogen resulted into a considerable deterioration on the inhibitory activity. Kinetic study and molecular docking study have confirmed the in-vitro results. [ABSTRACT FROM AUTHOR]

Iminosugar compounds are monosaccharide mimetics with broad but generally weak antiviral activities related to inhibition of enzymes involved in glycobiology. Miglustat (N-butyl-1-deoxynojirimycin), which is approved for the treatment of lipid storage diseases in humans, and UV-4 [N-(9-methoxynonyl)-1-deoxynojirimycin] inhibit the replication of hepatitis A virus (HAV) in cell culture (50% inhibitory concentrations [IC50s] of 32.13mM and 8.05mM, respectively) by blocking the synthesis of gangliosides essential for HAV cell entry. We used a murine model of hepatitis A and targeted mass spectrometry to assess the capacity of these compounds to deplete hepatic gangliosides and modify the course of HAV infection in vivo. Miglustat, given by gavage to Ifnar12/2 mice (4,800mg/kg of body weight/day) depleted hepatic gangliosides by 69 to 75% but caused substantial gastrointestinal toxicity and failed to prevent viral infection. UV-4, similarly administered in high doses (400mg/kg/day), was well tolerated but depleted hepatic gangliosides by only 20% after 14 days. UV-4 depletion of gangliosides varied by class. Several GM2 species were paradoxically increased, likely due to inhibition of β-glucosidases that degrade gangliosides. Both compounds enhanced, rather than reduced, virus replication. Nonetheless, both iminosugars had surprising anti-inflammatory effects, blocking the accumulation of inflammatory cells within the liver. UV-4 treatment also resulted in a decrease in serum alanine aminotransferase (ALT) elevations associated with acute hepatitis A. These anti-inflammatory effects may result from iminosugar inhibition of cellular α-glucosidases, leading to impaired maturation of glycan moieties of chemokine and cytokine receptors, and point to the potential importance of paracrine signaling in the pathogenesis of acute hepatitis A. [ABSTRACT FROM AUTHOR]

Purpose: To compare the safety and efficacy of once-weekly prescription of GLP-1 receptor agonists (adlyxin) with those of α-glucosidase inhibitor (voglibose) and other reference drugs (RD). Methods: A total of 1250 stable diabetes-mellitus patients from the Department of Endocrinology, Ningbo No. 6 Hospital, Ningbo, Zhejiang 315040, China were enrolled in this study between Feb 2018 and Jan 2020. They were treated using physical exercise and diet chart therapy. The patients were assigned to three different groups and administered GLP-1 receptor agonist (GLP-1RA) or glucosidase inhibitor (voglibose) and other reference drugs (RDs). The safety and efficacy of these drugs were compared. The primary endpoint was the number of treatment-emergent adverse events (TEAEs), while the secondary endpoints were based on symptomatic hypoglycaemic episodes and other biochemical parameters. Results: Patients who used α-glucosidase inhibitors had the highest percentage of TEAEs, when compared to those on GLP-1RAs and RDs (p < 0.05). No specific cases of severe hypoglycaemia were observed among all the groups. Users of adlyxin also achieved significant glycaemic control at the end of the study period, when compared to voglibose users, with a mean HbA1c baseline of 8.2 % (p < 0.05). Conclusion: These results indicate that the GLP-1 receptor agonist adlyxin achieved good glycaemic control. Thus, it has beneficial potential for use among type 2 diabetes in the Chinese population. [ABSTRACT FROM AUTHOR]

An alpha-glucosidase inhibitor Voglibose is used for lowering blood glucose levels in people with diabetes A very straight forward, quick, responsive and accurate UV-Spectrophotometric method of analysis have been developed for assessment of Voglibose in pharmaceutical formulation. Since Voglibose only absorbs UV in the low wavelength area, it cannot be identify with high sensitivity. Voglibose has shown successful results for various analytical instruments only in the permutation of Taurine and Sodium periodate. The API was derivatives using Taurine and Sodium periodate in water and methanol. Drug exhibited distinct λmax in methanol at 281nm. Linearity was observed in the concentration range 10-80 µg/ml. The method was validated by recovery studies. The methods used are inexpensive and sensitive for the inference of Voglibose in bulk drug and tablet dosage forms. [ABSTRACT FROM AUTHOR]

Background: In insulin-treated patients with type 2 diabetes mellitus (T2DM), glycemic control is usually suboptimal. Methods: This study compared the risks of mortality and cardiovascular events in insulin-treated patients adding or not adding alpha-glucosidase inhibitors (AGIs). Results: This cohort study included data from the Taiwan National Health Insurance Research Database. In total, 17,417 patients newly diagnosed as having T2DM and undergoing insulin therapy during 2000–2012 were enrolled. Overall incidence rates of all-cause mortality, hospitalized coronary artery disease (CAD), stroke, and heart failure were compared between 4165 AGI users and 4165 matched nonusers. The incidence rates of all-cause mortality were 17.10 and 19.61 per 1000 person-years in AGI nonusers and users, respectively. Compared with nonusers, AGI users had a higher mortality risk [adjusted hazard ratio (aHR) = 1.21, 95% confidence interval (CI) = 1.05–1.40; p = 0.01]. Regarding AGI use, aHRs (95% CI) for cardiovascular death, non-cardiovascular death, hospitalized CAD, stroke, and heart failure were 1.20 (0.83–1.74), 1.27 (1.07–1.50), 1.12 (0.95–1.31), 0.98 (0.85–1.14), and 1.03 (0.87–1.22) respectively. Conclusion: AGI use was associated with higher risks of all-cause mortality and non-cardiovascular death in insulin-treated patients with T2DM. Therefore, adding AGIs in insulin-treated patients may not be appropriate. [ABSTRACT FROM AUTHOR]