Identification, characterization, and insights into the mechanism of novel dipeptidyl peptidase-IV inhibitory peptides from yak hemoglobin by in silico exploration, molecular docking, and in vitro assessment.

Dipeptidyl peptidase IV (DPP-IV) inhibitory peptides were screened and identified from yak hemoglobin for the first time by in silico analysis, molecular docking, and in vitro evaluation. Results showed that yak hemoglobin had a high potential to produce DPP-IV inhibitory peptides based on the sequence alignment and bioactive potential evaluation. Furthermore, "pancreatic elastase + stem bromelain" was the optimal combined-enzymatic strategy by simulated proteolysis. Additionally, 25 novel peptides were found from its simulated hydrolysate, among which 10 peptides had high binding affinities with DPP-IV by molecular docking. Most of these peptides were also in silico characterized with favorable physicochemical properties and biological potentials, including relatively low molecular weight, high hydrophobicity, several net charges, good water solubility, nontoxicity, acceptable sensory quality, and good human intestinal absorption. Finally, six novel DPP-IV inhibitory peptides were identified via in vitro assessment, among which EEKA (IC50 = 235.26 µM), DEV (IC50 = 339.45 µM), and HCDKL (IC50 = 632.93 µM) showed the strongest capacities. The hydrogen bonds and electrostatic attractions formed with core residues within the S2 pocket of DPP-IV could be mainly responsible for their inhibition performances. This work provided a time-saving method and broadened application for yak by-products development as sources of functional foods.

Usage of vildagliptin among patients with type 2 diabetes mellitus attending a public primary healthcare clinics in Kuala Selangor District, Selangor.

INTRODUCTION: Studies showed that vildagliptin can lower HbA1c levels by 0.8%-1%. However, there is limited data looking at vildagliptin use among suburban populations. The efficacy of vildagliptin use may differ among different populations, especially those with low socio-economic status. Thus, this study aimed to assess the HbA1c reduction after vildagliptin initiation, treatment patterns and the reason for its initiation among patients with type 2 diabetes mellitus attending outpatient clinics in Kuala Selangor District, Selangor. MATERIALS AND METHODS: This is a cross-sectional, retrospective study design. All patients who received vildagliptin in the Pharmacy Integrated Health System (PHIS) registry database from 2016 to 2021 were included as study samples. The exclusion criteria were being less than 18 years old and having type 1 diabetes mellitus. Patients' medical records were retrieved after sampling, and data were collected. One medical record was missing, thus SPSS analysis were performed on 144 vildagliptin users. RESULTS: In total, 84 females (58.3%) and 60 males (41.7%) with a mean age of 62.1 (±10.1) years were analysed in this study. Mean HbA1c pre-therapy was 8.5 ± 2.1%; while posttherapy 6 months demonstrated a mean HbA1c of 7.9 ± 1.8%. Use of vildagliptin alone or as an adjunct was associated with a mean reduction of 0.6% in HbA1c (p = 0.01). Factors influencing this HbA1c reduction were advancing age, specifically individuals aged 62 years and older (p = 0.02), patients who are already receiving insulin therapy (p=0.00) and those who express a willingness to commence insulin treatment during the counselling session prior to initiating the treatment plan (p = 0.00). Reasons for vildagliptin initiation documented by prescribers were non-insulin acceptance (n = 59, 40.97%), frequent hypoglycaemia (n = 6, 4.1%) and non-compliance with medications (n = 23, 15.9%). There was no association between demographic, medical background and reason for starting vildagliptin variables and HbA1c reduction (p < 0.001). CONCLUSION: This study showed that initiating vildagliptin alone or as an adjunct therapy significantly reduced HbA1c and is beneficial for uncontrolled diabetes patients. While advancing age, concurrent administration of insulin and the patients' willingness to accept insulin treatment prior to the commencement of therapy were the factors that influenced HbA1c reduction among patients receiving vildagliptin therapy, we recommend primary care providers prioritise all of the significant variables discovered before initiating vildagliptin for their patients.

Pharmacological and Clinical Studies of Medicinal Plants That Inhibit Dipeptidyl Peptidase-IV.

Dipeptidyl peptidase IV (DPP-IV) is an enzyme responsible for the degradation of the incretin hormone glucagon-like peptide-1 (GLP-1). DPP-IV plays a significant role in regulating blood glucose levels by modulating the activity of GLP-1. In the context of diabetes, DPP-IV inhibitors effectively block the activity of DPP-IV, hence mitigating the degradation of GLP-1. This, in turn, leads to an extension of GLP-1's duration of action, prolongs gastric emptying, enhances insulin sensitivity, and ultimately results in the reduction of blood glucose levels. Nonetheless, reported adverse events of DPP-IV inhibitors on T2DM patients make it essential to understand the activity and mechanism of these drugs, particularly viewed from the perspective of finding the effective and safe add-on medicinal plants, to be implemented in clinical practice. This review is intended to bring forth a thorough overview of plants that work by reducing DPP-IV activity, from computational technique, enzymatic study, animal experiments, and studies in humans. The articles were searched on PubMed using "Plants", "DPP-IV", "DPP-IV inhibitor", "GLP-1", "Type 2 diabetes", "diabetes", "in silico", "in vitro", "in vivo", "studies in human", "clinical study" as the query words, and filtered for ten years of publication period. Eighteen plants showed inhibition against DPP-IV as proven by in silico, in vitro, and in vivo studies; however, only ten plants were reported for efficacy in clinical studies. Several plant-based DPP-IV inhibitors, eg, Allium sativum, Morus Alba, Curcuma longa, Pterocarpus marsupium, and Taraxacum officinale, have established their functional role in inhibiting DPP-IV and have proven their effectiveness through studies in humans earning them a prominent place in therapeutic discovery.

Integration of Deep Learning and Sequential Metabolism to Rapidly Screen Dipeptidyl Peptidase (DPP)-IV Inhibitors from Gardenia jasminoides Ellis.

Traditional Chinese medicine (TCM) possesses unique advantages in the management of blood glucose and lipids. However, there is still a significant gap in the exploration of its pharmacologically active components. Integrated strategies encompassing deep-learning prediction models and active validation based on absorbable ingredients can greatly improve the identification rate and screening efficiency in TCM. In this study, the affinity prediction of 11,549 compounds from the traditional Chinese medicine system's pharmacology database (TCMSP) with dipeptidyl peptidase-IV (DPP-IV) based on a deep-learning model was firstly conducted. With the results, Gardenia jasminoides Ellis (GJE), a food medicine with homologous properties, was selected as a model drug. The absorbed components of GJE were subsequently identified through in vivo intestinal perfusion and oral administration. As a result, a total of 38 prototypical absorbed components of GJE were identified. These components were analyzed to determine their absorption patterns after intestinal, hepatic, and systemic metabolism. Virtual docking and DPP-IV enzyme activity experiments were further conducted to validate the inhibitory effects and potential binding sites of the common constituents of deep learning and sequential metabolism. The results showed a significant DPP-IV inhibitory activity (IC50 53 ± 0.63 µg/mL) of the iridoid glycosides' potent fractions, which is a novel finding. Genipin 1-gentiobioside was screened as a promising new DPP-IV inhibitor in GJE. These findings highlight the potential of this innovative approach for the rapid screening of active ingredients in TCM and provide insights into the molecular mechanisms underlying the anti-diabetic activity of GJE.

Modifiable statin characteristics associated with potential statin-related prescribing cascades.

STUDY OBJECTIVE: Clinicians may prescribe new medications (marker drug) to treat statin-related (index drug) adverse events, constituting a prescribing cascade. We aimed to identify modifiable statin characteristics (intensity and individual statin agents) associated with lower risk of prescribing cascades to inform clinical decisions in the presence of statin-related adverse events. DESIGN: A secondary analysis based on our previous work, a high-throughput sequence symmetry analysis screening for potential statin-related prescribing cascades. DATA SOURCE: MarketScan Commercial and Medicare Supplemental Insurance claims databases between 2005 and 2019. PATIENTS: Adults who initiated a statin between 2007 and 2018, and who were continuously enrolled in the same healthcare plan for at least 720 days before and 360 days after statin initiation. INTERVENTION: Among the previously identified 57 potential prescribing cascades, 42 statin-marker class dyad with a sample size of ≥ 500 were assessed in this study. MEASUREMENTS: We measured patients' baseline characteristics within -360 days of statin initiation and reported by modifiable statin characteristics. We also performed logistic regression and reported the adjusted odds ratios (aOR) with 95% confidence intervals (CI) of modifiable statin characteristics after adjusting for baseline characteristics. MAIN RESULTS: We identified 1,307,867 statin initiators who met the study criteria (21% elderly, 52% female). Compared with patients initiating low-intensity statins, those initiating moderate- or high-intensity statins had significantly greater odds to develop 29 (69%) prescribing cascades, including antidiabetic drugs such as dipeptidyl peptidase 4 (DPP-4) inhibitors (aOR 1.22; 95% CI, 1.11-1.35) and glucagon-like peptide-1 (GLP-1) analogs (aOR 1.31; 95% CI, 1.16-1.47), and opioids (aOR 1.18; 95% CI, 1.13-1.23). Individual statin agent selection also had a differential effect on 34 (81%) of the prescribing cascades. For example, compared with simvastatin initiators, the probability of initiating osmotically acting laxatives was significantly higher for lovastatin initiators (aOR 1.09; 95% CI, 1.03-1.15) and significantly lower in atorvastatin initiators (aOR 0.92; 95% CI, 0.89-0.94). CONCLUSION: Compared with low-intensity statins, high-intensity statins are associated with increased risk in many potential prescribing cascades, while the choice of individual statin agents affects the risk of prescribing cascades bidirectionally.

The Current Place of DPP4 Inhibitors in the Evolving Landscape of Type 2 Diabetes Management: Is It Time to Bid Adieu?

During the last decade, the landscape of type 2 diabetes (T2D) management has been completely transformed, moving from a glucose-centric perspective to a holistic approach that also takes into account weight control and organ protection. Dipeptidyl peptidase-4 inhibitors (DPP4i) are oral agents that have been used for the treatment of T2D for almost 20 years. Although they present an excellent safety profile, including the risk of hypoglycemia, they lack the spectacular cardiorenal benefits and weight-loss effects of the newer antidiabetic agents. This poses the question of whether they still deserve a place in the arsenal of drugs against T2D. In this article, we use a hypothetical case scenario to illustrate possible patient profiles where DPP4i could prove useful in the clinical setting. We discuss the advantages and disadvantages of the category, focusing on glycemic control, weight management, and cardiorenal protection, which are the pillars of modern T2D management, also considering its safety profile and cost-effectiveness. We conclude that in most cases, DPP4i present a more favorable risk-benefit ratio compared to sulfonylureas, which are still widely prescribed throughout the world. We also suggest that future research should clarify the reasons behind the contradictory findings between human and animal studies on cardiorenal effects of the class and identify subgroups of patients who would derive most benefit with DPP4i treatment.

Exploring antidiabetic potential of a polyherbal formulation Madhurakshak Activ: An in vitro and in silico study.

Madhurakshak Activ (MA), a commercial polyherbal antidiabetic preparation is known to manage diabetes mellitus (DM) by reducing blood glucose levels. However, lacks systematic mechanistic evaluation for their molecular and cellular mode of actions. In the present study, hydro-alcoholic and aqueous extract of MA were evaluated for their effects on glucose adsorption, diffusion, amylolysis kinetics and transport across the yeast cells using in vitro techniques. Bioactive compounds identified from MA by LC-MS/MS were assessed for their binding potential against DPP-IV and PPARγ via an in silico approach. Our results revealed that the adsorption of glucose increased dose dependently (5 mM -100 mM). Both extracts exhibited linear glucose uptake into the yeast cells (5 mM - 25 mM), whereas glucose diffusion was directly proportional to time (30-180 min). Pharmacokinetic analysis revealed drug-like properties and low toxicity levels for all the selected compounds. Among the tested compounds, 6-hydroxyluteolin (-8.9 against DPP-IV and PPARγ) and glycyrrhetaldehyde (DPP-IV -9.7 and PPARγ -8.5) have exhibited higher binding affinity compared to the positive control. Therefore, the above compounds were further considered for molecular dynamics simulation which showed stability of the docked complexes. Hence, studied mode of actions might produce a concerted role of MA in increasing the rate of glucose absorption and uptake followed by the in silico studies which suggest that the compounds identified from MA may inhibit DPP-IV and PPARγ phosphorylation.

Efficacy and Safety of Triple Therapy with SGLT-2 Inhibitor, DPP-4 Inhibitor, and Metformin in Type 2 Diabetes: A Meta-Analysis.

Objective: Type 2 diabetes poses significant pain, economic burden, and health risks. This meta-analysis evaluates the efficacy and safety of triple therapy with SGLT-2 inhibitor add-on to DPP-4 inhibitor plus metformin for type 2 diabetes treatment. Methods: A comprehensive search was conducted in PubMed, Embase, and the Cochrane Library to identify randomized controlled trials evaluating the efficacy and safety of triple therapy (SGLT-2 inhibitor + DPP-4 inhibitor + metformin) compared to dual therapy (DPP-4 inhibitor + metformin) in type 2 diabetes. The search covered the period from inception to December 2018. Two reviewers independently screened the literature, extracted data, and assessed study quality. Meta-analysis was performed using RevMan 5.3 software. Results: A total of eight randomized controlled trials were included in this meta-analysis. The results showed that compared to dual therapy with DPP-4 inhibitor add-on to metformin, triple therapy with SGLT-2 inhibitor add-on to DPP-4 inhibitor plus metformin was associated with greater reductions in HbA1c, fasting blood glucose, postprandial blood glucose, body weight, and blood pressure (P < .05). However, the risk of genital tract infection was higher in the triple therapy group (OR = 4.43, 95% CI (2.26, 8.70), P < .0001), while there were no statistically significant differences in the incidence of adverse events, hypoglycemia episodes, urinary tract infection, and fractures between the two groups (P > .05). Conclusions: Based on current evidence, triple therapy was found to significantly improve blood glucose, body weight, and blood pressure when compared to dual therapy. Safety indicators did not show significant differences, except for an increased risk of genital tract infection.

Discovery of anthraquinones as DPP-IV inhibitors: Structure-activity relationships and inhibitory mechanism.

Dipeptidyl peptidase IV (DPP-IV) is an integrated type II transmembrane protein that reduces endogenous insulin contents and increases plasma glucose levels by hydrolyzing glucagon-like peptide-1 (GLP-1). Inhibition of DPP-IV regulates and maintains glucose homeostasis, making it an attractive drug target for the treatment of diabetes II. Natural compounds have tremendous potential to regulate glucose metabolism. In this study, we examined the DPP-IV inhibitory activity of a series of natural anthraquinones and synthetic structural analogues on DPP-IV using fluorescence-based biochemical assays. The inhibitory efficiency differed among anthraquinone compounds with different structures. Alizarin (7), aloe emodin (11), emodin (13) emerged the outstanding inhibitory potential for DPP-IV with IC50 values lower than 5 µM. To clarifying the inhibitory mechanism, inhibitory kinetics were performed, which showed that alizarin red S (8) and 13 were effective non-competitive inhibitors of DPP-IV, while alizarin complexone (9), rhein (12), and anthraquinone-2-carboxylic acid (23) were mixed inhibitors. Emodin was determined as inhibitor with the strongest DPP-IV-binding affinity determined via molecular docking. Structure-activity relationship (SAR) demonstrated that hydroxyl group at C-1 and C-8 sites and hydroxyl, hydroxymethyl or carboxyl group at the C-2 or C-3 site were very essential for DPP-IV inhibition, replacement of hydroxyl group with amino group at C-1 could led to an increase of the inhibitory potential. Further fluorescence imaging showed that both compounds 7 and 13 significantly inhibited DPP-IV activity in RTPEC cells. Overall, the results indicated that anthraquinones would be a natural functional ingredient for inhibiting DPP-IV and provided new ideas for searching and developing potential antidiabetic compounds.

Linagliptin exacerbates heart failure due to energy deficiency via downregulation of glucose utilization and absorption in a mouse model.

Use of dipeptidyl peptidase-4 (DPP4) inhibitor in some clinical trials might have caused heart failure (HF), leading to increased hospitalizations. The aim of the present study was to determine whether linagliptin has any effect on chronic dilated HF, and its underlying mechanisms. Physiologic and pathologic studies were conducted on heart/muscle-specific manganese superoxide dismutase-deficient mice, which exhibited dilated cardiomyopathy, and were randomized to receive a low dose (1 mg/kg, HF-L group) or high dose (10 mg/kg, HF-H group) mixed with food, or normal food (HF group), for 8 weeks. Linagliptin increased mortality and heart/body weight ratio in mice with HF. Cardiac contractility and fibrosis worsened, whereas hepatic glycogen content and individual carbohydrate consumption decreased significantly in the HF-H group, when compared with the HF control group. Therefore, we performed a complementary experiment by supplementing glucose to the mice treated with high-dose linagliptin (HF-HG group). Adequate glucose supplementation reduced heart/body weight ratio and cardiac fibrosis, and improved cardiac contractility, without changing mortality. Following oral administration of 13C glucose, the respiratory 13C decreased in the HF-H and HF-HG groups, when compared with that in the HF group; the fecal 13C increased, suggesting that linagliptin inhibited glucose absorbance in the intestine. In addition, the expression of GLUT2, a glucose transporter was downregulated in the small intestine. Linagliptin treatment exacerbated HF, which increased mortality, cardiac function, and fibrosis. DPP4 inhibitors might boost cardiac cachexia and exacerbate HF, at least in part, through the modification of glucose utilization and absorption.

Efeito de bebidas à base de café em cápsula em enzimas do metabolismo glicídico e captação de glicose em células Caco-2 / Effect of capsule coffee beverages on enzymes of glucose metabolism and glucose uptake in Caco-2 cells

Introdução: A diabetes mellitus (DM) é uma doença crônica não transmissível importante e crescente problema de saúde pública no mundo. Mudanças no estilo de vida, como um hábito alimentar saudável, contribuem para redução da glicemia e controle do diabetes. O café é um alimento amplamente consumido e rico em compostos fenólicos com propriedades antioxidantes, com estudos sugerindo que seu maior consumo pode estar associado a um menor risco de mortalidade no diabetes. Objetivos: Analisar os efeitos das bebidas à base de café em cápsula em enzimas do metabolismo glicídico e captação de glicose em modelo de células intestinais Caco-2. Métodos: As amostras de bebidas foram preparadas com cápsulas de café espresso regular e descafeinado com ou sem adição de leite. Essas bebidas à base de café foram submetidas à digestão in vitro e seus compostos fenólicos foram quantificados e identificados. Foram realizados ensaios de permeação e quantificação de glicose nas células Caco-2, ensaios da inibição da α-glicosidase, inibição α-amilase e inibição de dipeptidil peptidase-IV (DPP-IV). Análises da capacidade antioxidante foram realizadas por meio de ensaio da capacidade de absorbância de radical oxigênio (ORAC), inibição da peroxidação lipídica (TBARS) e, também foram analisados kits comerciais o ensaio da catalase e atividade antioxidante total (TAC). Os resultados foram expressos como média e desvio padrão. Resultados Não houve diferença estatística (p>0,05) na permeação de glicose entre as diferentes bebidas de café nas células Caco-2. Na análise da capacidade de inibição da enzima α-amilase o café regular apresentou melhor inibição na fase oral, e na fase intestinal o café descafeinado apresentou melhor resultado. A inibição da e α-glicosidase os cafés descafeinado e puro foram mais efetivos. Quanto à atividade da enzima catalase na porção apical, as menores concentrações de café regular e descafeinado foram mais efetivas. A melhor capacidade antioxidante foi observada no café descafeinado. Leite e cafeína foram efetivos em estimular a enzima DPPIV. Conclusão: Todas as bebidas apresentaram capacidade antioxidante, onde se destaca a superior capacidade antioxidante do café descafeinado. As bebidas puras foram mais efetivas para inibição das enzimas α-amilase e α-glicosidase após digestão e nas células Caco-2, leite e cafeína foram melhor ativadores de DPPIV.

Background: Diabetes mellitus (DM) is an important chronic non-communicable disease and a growing public health problem worldwide. Lifestyle changes, such as healthy eating habits, contribute to lowering blood glucose levels and controlling diabetes. Coffee is a widely consumed food rich in phenolic compounds with antioxidant properties, with studies suggesting that its higher consumption may be associated with a lower risk of mortality in diabetes. Aims: To analyze the effects of capsule coffee drinks on enzymes of glucose metabolism and glucose uptake in a Caco-2 intestinal cell model. Methods: The beverage samples were prepared with espresso and decaffeinated coffee capsules with or without added milk. These coffee drinks were subjected to in vitro digestion and their phenolic compounds were quantified and identified. Glucose permeation and quantification tests were carried out on Caco-2 cells, as well as α-glucosidase inhibition, α-amylase inhibition and dipeptidyl peptidase-IV (DPP-IV) inhibition tests. Antioxidant capacity analyses were carried out using the oxygen radical absorbance capacity (ORAC) assay, lipid peroxidation inhibition (TBARS), and the catalase assay and total antioxidant activity (TAC) were also analyzed using commercial kits. The results were expressed as mean and standard deviation. Results: There was no statistical difference (p>0.05) in glucose permeation between the different coffee drinks in Caco-2 cells. In the analysis of the ability to inhibit the α-amylase enzyme, regular coffee showed better inhibition in the oral phase, and decaffeinated coffee showed better results in the intestinal phase. Decaffeinated and pure coffees were more effective at inhibiting α-glucosidase. As for the activity of the enzyme catalase in the apical portion, the lower concentrations of normal and decaffeinated coffee were more effective. The best antioxidant capacity was observed in decaffeinated coffee. Milk and caffeine were effective in stimulating the DPPIV enzyme. Conclusion: All the beverages showed antioxidant capacity, with the superior antioxidant capacity of decaffeinated coffee standing out. The pure drinks were more effective in inhibiting the enzymes α-amylase and α-glucosidase after digestion and, in Caco-2 cells, milk and caffeine were better activators of DPPIV.

A Molecular Modeling Investigation of the Therapeutic Potential of Marine Compounds as DPP-4 Inhibitors.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by elevated levels of blood glucose due to insulin resistance or insulin-secretion defects. The development of diabetes is mainly attributed to the interaction of several complex pathogenic, genetic, environmental and metabolic processes. Dipeptidyl peptidase-4 (DPP-4) is a serine protease that cleaves X-proline dipeptides from the N-terminus of several polypeptides, including natural hypoglycemic incretin hormones. Inhibition of this enzyme restores and maintains glucose homeostasis, making it an attractive drug target for the management of T2DM. Natural products are important sources of bioactive agents for anti-T2DM drug discovery. Marine ecosystems are a rich source of bioactive products and have inspired the development of drugs for various human disorders, including diabetes. Here, structure-based virtual screening and molecular docking were performed to identify antidiabetic compounds from the Comprehensive Marine Natural Products Database (CMNPD). The binding characteristics of two shortlisted compounds, CMNPD13046 and CMNPD17868, were assessed using molecular dynamics simulations. Thus, this study provides insights into the potential antidiabetic activity and the underlying molecular mechanism of two compounds of marine origin. These compounds could be investigated further for the development of potent DPP-4 inhibitors.

Amelioration of intracerebroventricular streptozotocin-induced cognitive dysfunction by Ocimum sanctum L. through the modulation of inflammation and GLP-1 levels.

DPP-4 inhibitors have been shown to reverse amyloid deposition in Alzheimer's disease (AD) patients with cognitive impairment. Ocimum sanctum L. leaves reported the presence of important phytoconstituents which are reported to have DPP-4 inhibitory activity. To investigate the effects of petroleum ether extract of Ocimum sanctum L. (PEOS) in Intracerebroventricular streptozotocin (ICV-STZ) induced AD rats. ICV-STZ (3 mg/kg) was injected bilaterally into male Wistar rats, while sham animals received the artificial CSF. The ICV-STZ-induced rats were administered with three doses of PEOS (100, 200, and 400 mg/kg, p.o.) for thirty days. All experimental rats were subjected to behaviour parameters (radial arm maze task and novel object recognition test), neurochemical parameters such as GLP-1, Aß42, and TNF-α levels, and histopathological examination (Congo red staining) of the left brain hemisphere. PEOS significantly reversed the spatial learning and memory deficit exhibited by ICV-STZ-induced rats. Furthermore, PEOS also shows promising results in retreating Aß deposition, TNF α, and increasing GLP-1 levels. The histopathological study also showed a significant dose-dependent reduction in amyloid plaque formation and dense granule in PEOS -treated rats as compared to the ICV-STZ induced rats (Negative control). The results show that extract of Ocimum sanctum L. attenuated ICV-STZ-induced learning and memory deficits in rats and has the potential to be employed in the therapy of AD.

Purification, biochemical characterization, and DPP-IV and α-amylase inhibitory activity of Berberine from Cardiospermum halicacabum.

Diabetes mellitus (DM) has spread across the globe, increasing the risk of obesity, cardiovascular disease, and other comorbidities. Despite substantial research into the development of diabetic treatments that are effective in lowering blood glucose levels, their efficiency is short-lived due to unpleasant side effects such as weight gain and hypoglycemia. The discovery of secondary metabolites in the prevention and treatment of diabetes and its complications has an incentive to take interest in plant-based medications, and enzyme inhibitors have the potential to aid in the treatment and management of DM. This study aims to isolate, characterize, and analyse the influence of berberine-like alkaloids from alcoholic Cardiospermum halicacabum extract in vitro and in silico, as a possible inhibitor of Dipeptidyl peptidase-IV (DPP-IV) and α-amylase, two essential enzymes involved in diabetes. The alkaloid from C. halicacabum was identified as berberine, with an m/z of 336.1263. Purified berberine inhibits DPP-IV with an IC50 of 16.328 ± 1.344 µM and inhibits α-amylase by 72% at 10 µg/mL. In-silico studies demonstrated that berberine was found to bind to the active site of both DPP-IV and α-amylase. The precise mechanism underlying the observation has to be researched further in order to investigate C. halicacabum's anti-diabetic effects and argue for its possible application as alternative medicine.

Olfactory dysfunction in type II diabetes: Therapeutic options and lessons learned from other etiologies - A scoping review.

INTRODUCTION: Olfactory dysfunction (OD) is highly prevalent amongst type 2 diabetes mellitus (DM2) patients and has many associated health risks. For example, OD can lead to poor nutrition, safety issues related to diminished hazard detection, and increased mortality rates. While limited research exists about therapeutics for DM2-associated OD, recovery of olfactory function is better studied in other pathologic states. The objectives of this scoping review are to synthesize the existing data on interventions for DM2-associated OD and present the evidence for therapies that have been utilized for non-DM2-associated causes of OD. Additionally, the potential therapeutic opportunities for patients with DM2 are explored. METHODS: A scoping review was conducted with a medical librarian to identify studies investigating treatments of DM2-related OD. 6 databases were searched (Embase, CINAHL, the Cochrane Library, Google Scholar, OVID Medline, and Web of Science). Studies were eligible if the primary discussion involved treatment of olfactory deficits in the context of DM2. All publication dates were included, and studies published in languages other than English were excluded. RESULTS: 3631 articles were identified; 3 articles met inclusion criteria and underwent full text review. Hyperbaric oxygen (HBO), the DPP-4 inhibitor Linagliptin and the GLP-1 agonists Exenatide and Liraglutide are the only therapeutics that have been used in the context of DM2. Only HBO and GLP-1 agonists produced statistically significant improvements in olfactory identification. The literature regarding non-DM2-associated OD supports interventions such as olfactory training, dietary supplements, and intranasal insulin. Specifically, olfactory training was very effective in many contexts such as post-viral and traumatic OD while being affordable and non-invasive. CONCLUSION: This scoping review of olfactory rehabilitation options for DM2-induced OD demonstrates a paucity of prospective investigations of plausible therapeutics. Additionally, treatments for OD related to non-DM2-associated etiologies, such as olfactory training, are well-studied, efficacious, and should be investigated in the context of DM2. Future investigation has the potential to enhance the quality of clinical intervention for OD and improve short- and long-term outcomes for DM2 patients.

Metabolic Profiling for Evaluating the Dipeptidyl Peptidase-IV Inhibitory Potency of Diverse Green Tea Cultivars and Determining Bioactivity-Related Ingredients and Combinations.

There are numerous cultivars of tea (Camellia sinensis L.), but the differences in their anti-hyperglycemic-related effects are largely unknown. The inhibition of the dipeptidyl peptidase (DPP)-IV enzyme plays an essential role in controlling hyperglycemia in diabetes by blocking the degradation of incretin hormones, which is necessary for insulin secretion. In this study, we examined the DPP-IV inhibitory activity of leaf extracts from diverse Japanese green tea cultivars. The inhibitory rates differed among tea extracts. Metabolic profiling (MP), using liquid chromatography-mass spectrometry, of all cultivars revealed compositional differences among cultivars according to their DPP-IV inhibitory capacity. Epigallocatechin-3-O-(3-O-methyl)gallate, kaempferol-3-O-rutinoside, myricetin-3-O-glucoside/galactoside, and theogallin were newly identified as DPP-IV inhibitors. The bioactivity of a tea extract was potentiated by adding these ingredients in combination. Our results show that MP is a useful approach for evaluating the DPP-IV inhibitory potency of green tea and for determining bioactivity-related ingredients and combinations.

The Inhibitory Effects of New Zealand Pine Bark (Enzogenol®) on α-Amylase, α-Glucosidase, and Dipeptidyl Peptidase-4 (DPP-4) Enzymes.

The New Zealand pine bark extract (Enzogenol®) has previously been shown to elicit acute hypoglycaemic effects in humans. The present study investigated the underlying mechanisms of Enzogenol® in reducing postprandial glucose in humans. The potential inhibitory action of Enzogenol® against digestive enzymes: α-amylase and α-glucosidase, and dipeptidyl peptidase-4 (DPP-4) enzyme was determined. Enzogenol® demonstrated the ability to inhibit all three enzymes: α-amylase enzyme activity (IC50 3.98 ± 0.11 mg/mL), α-glucosidase enzyme activity (IC50 13.02 ± 0.28 µg/mL), and DPP-4 enzyme activity (IC50 2.51 ± 0.04 mg/mL). The present findings indicate the potential for Enzogenol® to improve postprandial glycaemia by delaying carbohydrate digestion via the inhibition of digestive enzymes (α-amylase and α-glucosidase), and enhancing the incretin effect via inhibiting the dipeptidyl-peptidase-4 enzyme. The inhibitory actions of Enzogenol® on enzymes should therefore be further validated in humans for its potential use in type 2 diabetes mellitus prevention and management.

Chemical characterization and DPP-IV inhibitory activity evaluation of tripeptides from Gynura divaricata (L.) DC.

ETHNOPHARMACOLOGICAL RELEVANCE: Gynura divaricata (L.) DC. (GD), a herbal medicine, has been used for the prevention and treatment of hyperglycemia in China. However, hypoglycemic ingredients within GD have not yet been well studied. AIM OF THE STUDY: The aim of this study was to explore undiscovered compounds with dipeptidyl peptidase IV (DPP-IV) inhibitory activity within GD. MATERIALS AND METHODS: A four-step strategy was developed to explore undiscovered DPP-IV inhibitors within GD. First, the components were preliminarily characterized using UHPLC-HRMS combined with a library search. Second, preliminarily characterized compounds were searched for potential bioactivity. Third, a mixture of these preliminarily characterized compounds was isolated and thoroughly characterized based on fragmentation patterns associated with molecular networking. Fourth, the activities of these compounds were verified using DPP-IV inhibitory assay and molecular docking. RESULTS: Diprotin A, a tripeptide inhibitor against DPP-IV, was identified. Thereafter, a mixture of twenty-five diprotin A analogs was isolated and characterized, which exhibited IC50 of 0.40 mg/mL for DPP-IV. Molecular docking results also confirmed the interactions between the tripeptide analogs and DPP-IV mainly via H-bonds and hydrophobic interactions. CONCLUSIONS: This is the first report of DPP-IV inhibitors within GD. These findings demonstrate that the extract of GD might be beneficial for the treatment of type 2 diabetes mellitus, and is expected to promote further development and utilization of GD in herbal medicine.

Exploration of Dipeptidyl Peptidase-IV (DPP-IV) Inhibitory Peptides from Silkworm Pupae (Bombyx mori) Proteins Based on In Silico and In Vitro Assessments.

This study aimed at exploring dipeptidyl peptidase-IV (DPP-IV) inhibitory peptides from silkworm pupae proteins by in silico analysis and in vitro assessments. In silico analysis of 274 silkworm pupae proteomes indicated that DPP-IV inhibitory peptides can be released from silkworm pupae proteins. In vitro assessments revealed that pepsin and bromelain led to better production of DPP-IV inhibitory peptides from silkworm pupae protein. Notably, peptide fractions (<1 kDa) from pepsin- and bromelain-treated hydrolysates exhibited more potent DPP-IV inhibitory activities. Two novel DPP-IV inhibitory peptides (Leu-Pro-Pro-Glu-His-Asp-Trp-Arg and Leu-Pro-Ala-Val-Thr-Ile-Arg) were identified by LC-MS/MS with IC50 values of 261.17 and 192.47 µM, respectively. Enzyme kinetics data demonstrated that these two peptides displayed a mixed-type DPP-IV inhibition mode, which was further validated by molecular docking data. Overall, in silico analysis combined with in vitro assessments can serve as an effective and rapid approach for discovery of DPP-IV peptides from silkworm pupae proteins.

A novel DPP-4 inhibitor Gramcyclin A attenuates cognitive deficits in APP/PS1/tau triple transgenic mice via enhancing brain GLP-1-dependent glucose uptake.

Enhancing glucagon-like peptide 1 (GLP-1) signaling with a dipeptidyl peptidase IV (DPP-4) inhibitor might exert protective effects on Alzheimer's disease (AD). We found that intragastric administration of Gramcyclin A (10, 20 and 40 mg/kg), a novel DPP-4 inhibitor, for 3 months significantly reversed cognitive decline in APP/PS1/tau triple transgenic mice in a dose-dependent manner. Gramcyclin A treatment markedly reduced Aß plaques as well as the insoluble and soluble forms of Aß40 and Aß42 in the hippocampus of APP/PS1/tau mice. Treatment with Gramcyclin A remarkedly decreased the level of microglia and suppressed neuroinflammation in the hippocampus of APP/PS1/tau mice. Moreover, Gramcyclin A treatment could increase brain glucose uptake in APP/PS1/tau mice, as detected by 18-fluoro-2-deoxyglucose (18 F-FDG) micro-positron emission tomography (micro-PET) imaging. Furthermore, Gramcyclin A significantly increased expression of glucagon-like peptide-1 (GLP-1), GLP-1R, proliferator-activated receptor gamma coactivator (PGC)-1α and glucose transporter 4 (GLUT4), and inhibited insulin receptor (IRS)-1 phosphorylation and tau hyperphosphorylation in the hippocampus of APP/PS1/tau mice. Collectively, Gramcyclin A conferred protective effects against AD via enhancing brain GLP-1-dependent glucose uptake. The DPP-4 inhibitor Gramcyclin A might be a potential therapeutic drug for AD.