Search Results (87)

As the prevalence of type 2 diabetes increases rapidly, the demand for natural origin dipeptidyl peptidase-IV (DPP-IV) inhibitors with fewer side effects is increasing. In this study, protein-rich Limnospira platensis was investigated as a source of bioactive peptides to enhance its value as a functional food ingredient. Hydrolysates were prepared using three food-processing proteases, individually and in two-step combinations, followed by in silico analysis and peptide identification via liquid chromatography–tandem mass spectrometry. Subsequently, the thermal stability, gastrointestinal resistance, and intestinal permeability (using Caco-2 cells) of the identified peptides were evaluated. It was revealed that the Orientase 22BF digest exhibited high DPP-IV inhibitory activity. From the digest, three novel peptides—SPSPN (IC₅₀ = 144.1 ± 2.2 μM), VPSV (IC₅₀ = 93.6 ± 5.8 μM), and IPIGG (IC₅₀ = 13.4 ± 2.3 μM)—were identified, exhibiting DPP-IV inhibitory potencies comparable to or higher than previously reported Limnospira-derived peptides. Although VPSV exhibited low epithelial permeability (P_app = 4.02 ± 0.69 × 10⁻⁸ cm/s), it remained stable under simulated gastrointestinal digestion conditions, suggesting potential local luminal inhibitory activity within the small intestine. Overall, these findings highlight Limnospira-derived VPSV as a promising functional ingredient candidate with high bioactivity and digestive stability. Full article

Marine rest raw materials are often undervalued or wasted despite their nutrient and bioactive composition. Calanus finmarchicus, harvested primarily for its omega-3-rich oil, yields a side-stream protein hydrolysate, C. finmarchicus hydrolysate (CFH), during commercial enzyme-assisted extraction. Although currently used as a feed ingredient, CFH contains low-molecular-weight peptides and free amino acids with potential for human health applications. This study evaluated the gastrointestinal stability of CFH and the impact of digestion on bioactivity using a static in vitro gastrointestinal digestion model. Fresh-frozen and freeze-dried C. finmarchicus were included to provide comparative data. Antioxidant capacity was measured by ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays, and antidiabetic activity by dipeptidyl peptidase-IV (DPP-IV) and protein tyrosine phosphatase 1B (PTP1B) inhibition assays. The hydrolysate maintained its antioxidant capacity throughout digestion (at 165 min: FRAP: 27.5 ± 0.6 µmol TE/g dry weight (DW); ORAC: 411 ± 37 µmol TE/g DW). Digestion increased its DPP-IV inhibitory activity, with the inhibitory concentration (IC₅₀) decreased from 3.73 to 1.96 mg/mL (p ≥ 0.05). PTP1B inhibitors were nonselective and detected only at 0 and 30 min. These findings support our hypothesis that CFH may serve as a nutraceutical for humans and provide a rationale for subsequent in vivo studies. However, further identification of bioactive components and in vivo validation are warranted. Full article

Natural food-derived proteins are increasingly explored as alternatives to synthetic inhibitors for managing Type 2 diabetes mellitus. Despite the recognized health-promoting properties of Morchella esculenta, the potential of its bioactive proteins to modulate glucose metabolism remains largely unexplored. This study systematically investigated the structural basis and hypoglycemic mechanisms of MEP5 (Morchella esculenta Protein 5), a fucose-specific lectin from M. esculenta, using an integrated in silico pipeline. MEP5 (33.12 kDa) adopts a stable β-sheet-rich conformation and harbors a conserved fucose-binding carbohydrate-recognition domain. Protein–protein docking revealed that intact MEP5 binds directly to surface glycans of human α-glucosidase, generating steric hindrance that obstructs the catalytic pocket. Simulated gastrointestinal digestion yielded a highly bioavailable peptide profile. Following a rigorous multiparametric screening for toxicity, allergenicity, and water solubility, 11 short oligopeptides were identified as potent dipeptidyl peptidase-IV (DPP-IV) inhibitors. Molecular docking demonstrated that the top-ranked peptides, QPPR, DGTY, and DPDSH, occupy the S2 pocket of DPP-IV and form hydrogen bonds with catalytic triad residues (Ser630/His740). These findings delineate a dual-stage hypoglycemic mechanism, pre-digestion enzymatic blockade and post-digestion incretin regulation, and support the potential of MEP5 as a multifunctional candidate for glucose homeostasis-oriented functional foods. Full article

Dipeptidyl-peptidase IV (DPP4) inhibitors have shown potential anti-tumor properties. This study investigates the therapeutic potential of evogliptin, a DPP4 inhibitor, both as a single agent and in combination with temozolomide (TMZ), in glioma models. In vitro studies were performed using U87 and U373 glioma cell lines exposed to different concentrations of TMZ (250, 500 μM) and evogliptin (250, 500 ng/mL), either alone or together, for 24, 48, and 72 h. Cell viability was determined with the MTT assay. In vivo effectiveness was tested in a xenograft mouse model treated with intraperitoneal injections of evogliptin (60 mg/k g/day), TMZ (15 mg/kg/day), or their combination over 3 weeks. The combination of TMZ and evogliptin markedly reduced cell viability compared to single-agent treatments. DPP4 mRNA levels decreased more substantially with combination therapy. miRNA expression profiling with Affymetrix arrays indicated that certain miRNAs, such as miR-4440 and miR-6780b-5p, were upregulated after treatment with evogliptin or the combination regimen, whereas others were downregulated. These miRNAs could play a role in limiting glioma growth through DPP4 regulation. In the animal model, evogliptin alone did not provide a survival advantage. Analysis of TCGA data showed that glioma patients with decreased DPP4 expression had improved survival rates. The co-administration of evogliptin and temozolomide resulted in distinct miRNA profile changes. Nevertheless, both in vitro and in vivo, the added cytotoxicity from the combination was minimal. Full article

Dry-cured ham is a traditional food in the Mediterranean diet, which, in addition to its sensory qualities, is a natural source of bioactive peptides generated during the curing process through the action of endogenous enzymes on muscle and sarcoplasmic proteins. These low-molecular-weight peptides have attracted growing interest due to their multiple bioactivities, including antihypertensive, antioxidant, antimicrobial, antidiabetic, and anti-inflammatory effects described in vitro, in vivo, and in preliminary human studies. The identification of specific sequences, such as AAPLAP, KPVAAP, and KAAAAP (ACE inhibitors), SNAAC and GKFNV (antioxidants), RHGYM (antimicrobial), and AEEEYPDL and LGVGG (dipeptidyl peptidase-IV and α-glucosidase inhibitors), has been possible thanks to the use of peptidomics techniques, tandem mass spectrometry, and bioinformatics tools that allow their activity to be characterized, their digestive stability to be predicted, and their bioavailability to be evaluated. This review article summarizes current knowledge on the bioactivities of peptides derived from dry-cured ham, advances in their functional characterization, and challenges associated with their application in functional foods and nutraceuticals, with the aim of providing a comprehensive overview of their potential in health promotion and chronic disease prevention. Full article

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are among the most widespread drugs for the prevention of cardiovascular mortality and morbidity. Nevertheless, they are known to cause bradykinin (BK)-mediated angioedema (AE), a paroxysmal, localized, self-limiting, and potentially fatal swelling of the subcutaneous and/or submucosal tissue, due to a temporary increase in vascular permeability. Unlike hereditary angioedema (HAE), which can be mediated similarly by BK, no diagnostic tools, guidelines, or drugs have yet been approved for the diagnosis and treatment of acute non-allergic drug-induced AE. Besides ACEIs and ARBs, inhibitors of dipeptidyl peptidase-IV, neprilysin inhibitors, and tissue plasminogen activators are known to cause AE as an adverse effect. Currently, there are insufficient data on the prevention of AE caused by pharmacological therapies. In addition, the molecular mechanisms underlying BK-mediated AE caused by drugs, which are discussed here, are not fully explained. Specific approved drugs and a structured diagnostic workflow are unmet needs and are required for the management of this kind of AE. The aim of this review is to provide physicians with accurate knowledge of potentially life-threatening drug reactions so that they can be better understood and managed. Full article

Background/Objectives: Essential amino acid (EAA) supplementation is often employed in sportive and clinical nutrition due to EAAs’ role in muscle mass maintenance and growth. EAAs are also involved in insulin and glucagone regulation in diabetes management, but only few reports investigate their possible implication as dipeptidyl peptidase-IV (DPP-IV) inhibitors and their effect on the stability and secretion of enteroendocrine hormones. A blend of EAAs (called GAF) available as a food supplement, in a specific qualitative and quantitative ratio, was investigated to address its in vitro bioaccessibility, its hypoglycemic properties in vitro and in situ on cellular models, and its safety on intestinal Caco-2 cells. Methods: GAF was subjected to the INFOGEST static digestion protocol, producing the iGAF sample. iGAf DPP-IV inhibitory properties were investigated both in vitro and in situ on Caco-2 cells. Then, STC-1 enteroendocrine cells were employed alone and in co-culture with Caco-2 cells to evaluate iGAF’s impact on glucagon-like peptide 1 (GLP-1) hormone secretion. Results: The study demonstrates that the present EAAs blend is stable and bioaccessible after simulated gastrointestinal digestion, and it is safe at the intestinal cellular level. It inhibits DPP-IV enzyme both in vitro and in situ and promotes GLP-1 secretion by enteroendocrine cells. Conclusions: The sample demonstrated safety at the intestinal level and showed hypoglycemic properties by acting on a dual synergic mechanism that involves DPP-IV enzyme inhibition and GLP-1 hormone stimulation. Full article

Type 2 diabetes mellitus (T2DM) is a complex and prevalent metabolic disorder, and dipeptidyl peptidase 4 (DPP4) inhibitors have proven effective, yet the identification of novel inhibitors remains challenging due to the vastness of chemical space. In this study, we developed DPPPRED-IV, a web-based ensembled system integrating both binary classification and continuous regression Quantitative Structure Activity Relationships (QSAR) models to predict human DPP4 inhibitory activity. A curated dataset of 4 676 ChEMBL compounds was subjected to genetic algorithm descriptor selection and multiple machine learning algorithms; classification models were combined via a soft voting ensemble, while regression models estimated IC₅₀ values. All models underwent external 10-fold cross-validation and applicability domain analysis. The final models were integrated into a user-friendly web server, allowing predictions from SMILES inputs. Experimental testing of 29 MolPort compounds at 1.5 µM confirmed that 14 predicted actives exhibited significant inhibition, supporting the tool’s performance in early-stage screening. DPPPRED IV is freely available within the ChemoPredictionSuite and offers a resource to accelerate decision making, reduce costs and minimize animal use in T2DM drug discovery. Full article

Background/Objectives: Evidence on the renal benefits and safety of sodium–glucose cotransporter 2 inhibitors (SGLT2i) in the Asia region is still lacking. This study aimed to evaluate the renal and safety outcomes of SGLT2is compared with dipeptidyl peptidase-4 inhibitors (DPP4i) using real-world data. Methods: A retrospective cohort study was conducted using the nationwide claims data in Republic of Korea. We evaluated kidney outcomes (any new-onset kidney events, acute kidney injury (AKI), chronic kidney disease (CKD), and kidney failure) as primary outcomes and safety outcomes (infection, hemodynamic adverse events, and fracture). Propensity score matching was used to adjust confounders, and the hazard ratios were calculated using the Cox proportional hazards model. Results: The study included 13,649 patients in the SGLT2i group and 35,043 in the DPP4i group after the matching. The SGLT2i group had a lower risk of kidney diseases, AKI, and CKD (HR 0.88 [0.61–0.74]) than the DPP4i group. For secondary outcomes, the risk of genital infection was higher (HR 2.38 [2.12–2.68]), and the risk of hyperkalemia was lower in the SGLT2i group than in the DPP4i group (HRs 0.49 [0.36–0.67]). Conclusions: The SGLT2 inhibitors had a lower risk of new-onset kidney outcomes and CKD than the DPP4 inhibitors. A high incidence of genital infection and a low incidence of hyperkalemia were shown in the SGLT2 inhibitor. Full article

Bovine milk protein preparations (MPPs), namely micellar casein concentrate (MCC), serum protein concentrate (SPC), and MCC with ultrafiltrated buttermilk permeate (MBP), were analyzed as sources of inhibitors of angiotensin-converting enzyme (i.e., ACE) and dipeptidylpeptidase IV (i.e., DPP-IV) as well as antioxidative peptides. The studies involved in silico predictions of the release of biopeptides from bovine milk proteins. Then, all MPPs were subjected to the simulated gastrointestinal digestion using the INFOGEST protocol. Results using a BIOPEP-UWM database tool indicated that 59 biopeptides exhibiting the above-mentioned activities could be produced upon the action of pepsin, trypsin, and chymotrypsin. Thirty-six biopeptides were identified in at least one of the three MPPs subjected to the INFOGEST protocol. MCC before simulated digestion exhibited the strongest ACE-inhibiting activity among all MPPs (IC₅₀ = 1.856 mg/mL). The weakest ACE inhibitory effect was demonstrated for MBP after duodenal digestion (i.e., MBP D; IC₅₀ = 7.627 mg/mL). The above MPP showed the strongest DPP-IV-inhibiting activity (IC₅₀ = 0.0067 mg/mL). All MPPs exhibited antioxidative activity, with the strongest ABTS^•+ (i.e., 2,2′-azino-bis(3-ethylbenzotialozline-6-sulfonic acid) radical scavenging effect shown for MBP D (IC₅₀ = 2.754 mg/mL), and the strongest DPPH^• (i.e., 2,2-diphenyl-β-picrylhydrazyl) radical scavenging activity (IC₅₀ = 1.238 mg/mL) demonstrated for SPC D. Among all MPPs, SPC D also exhibited the highest FRAP (i.e., Ferric Reducing Antioxidant Power) bioactivity (IC₅₀ = 13.720 mg/mL), whereas MBP D was the MPP with the lowest FRAP potential (IC₅₀ = 20.140 mg/mL). The present study results show the potential of all MPPs as functional additives to support health-beneficial functions of dairy products. Full article

Background: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disease with global implications, necessitating effective management strategies. Dipeptidyl peptidase IV (DPP-4) inhibitors have shown promise as potent agents for T2DM treatment. Methods: This study combines chemical synthesis, molecular modelling, and inhibitory activity assays to characterise the structure–activity relationship of novel isomeric 1,2,4-oxadiazole-substituted derivatives of the 2-azabicyclo[2.2.1]heptane scaffold acylated with (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid. Results: In this article, we demonstrate the efficacy of new compounds as robust inhibitors of DPP-4. The attempts to further modify neogliptin (our lead compound described previously) resulted in a more potent DPP-4 inhibitor 9a (IC₅₀ = 4.3 nM), which did not mediate any substantial inhibition of DPP-8 and DPP-9. Conclusions: This study demonstrates that pseudo peptides incorporating (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, a 2-aza-bicyclo[2.2.1]heptane moiety, and 1,2,4-oxadiazole substituents act as potent and selective DPP-4 inhibitors. By the stereochemical refinement of oxadiazole derivatives of neogliptin, we discovered compound 9a, a strong candidate for further development in T2DM treatment. Full article

Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by the small intestine upon food intake. GLP-1 enhances insulin secretion, suppresses glucagon release, and promotes satiety, resulting in reduced food consumption and subsequent weight loss. Endogenous GLP-1 has a very short half-life and is rapidly degraded by the enzyme dipeptidyl-peptidase-IV (DPP-4). To address this limitation, GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors (DPP-4is) were developed and have demonstrated potency in clinical practice. In recent years, GLP-1RA and DPP4-i therapies are known to have pleiotropic effects, such as a reduction in oxidative stress, autophagy regulation, metabolic reprogramming, enhancement of anti-inflammatory signaling, regulation of gene expression, and being neuroprotective. These effects imply a therapeutic perspective for GLP-1RA and DPP-4i therapies in neuropathic pain treatment. Preclinical and clinical studies increasingly support the hypothesis that these therapies may alleviate neuropathic pain by targeting multiple mechanisms that induce neuropathic pain, such as inflammation, oxidative stress, and mitochondrial dysfunction. This review explores the mechanisms by which GLP-1RAs and DPP-4is alleviate neuropathic pain. It also highlights current advancements in incretin research, focusing on the therapeutic effects of GLP-1RAs and DPP-4-is for neuropathic pain. Full article

The aim of this study was to identify and characterize the bioactive peptide profile of Podolica cow’s milk. This dairy product is known for its nutritional properties related to the presence of peculiar lipids and is a typical breed traditionally reared in southern Italy. Using top-down peptidomics, we identified 2213 peptides in milk samples from four different farms, with 19 matching bioactive sequences. Bioactivities include dipeptidyl peptidase-IV (DPP-IV) inhibition, angiotensin-converting enzyme (ACE) inhibition, antioxidant activity, enhanced calcium uptake, and other peptides with potential antimicrobial effects. DPP-IV-inhibitory peptides (e.g., LDQWLCEKL and VGINYWLAHK) suggest potential for type 2 diabetes management, while ACE inhibitors (such as YLGY and FFVAPFPEVFGK) could support cardiovascular health by reducing hypertension. Antimicrobial peptides such as SDIPNPIGSENSEK and VLNENLLR showed broad spectrum of activity against various harmful microorganisms, positioning Podolica milk as a promising source for natural antimicrobial agents. Additionally, peptides with osteoanabolic, antianxiety, and immunomodulatory properties further highlight the multifaceted health benefits associated with this type of milk. Our findings underline the functional richness of Podolica milk peptides with various bioactivity properties, which could enhance the value of derived dairy products and contribute to sustainable agricultural practices. Future research will aim to explore these bioactivity properties in vivo, establishing a foundation for functional foods and supplements based on Podolica milk. Full article

Dipeptidyl peptidase IV (DPP-IV) is a serine protease whose inhibition has been an object of considerable interest in the context of developing novel treatments for type 2 diabetes mellitus. The development of novel DPP-IV inhibitors from natural or synthetic origin has seen a growing scientific interest in recent years, especially during the SARS-CoV-2 pandemic, when DPP-IV inhibitors were found to be of beneficial therapeutic value for COVID-19 patients. The present manuscript aims to summarize the most recent information on the synthesis of different DPP-IV inhibitors, emphasizing the various heterocyclic scaffolds that can be found in them. Special attention is devoted to DPP-IV inhibitors that are currently in clinical trials. Different synthetic approaches for the construction of DPP-IV inhibitors are discussed, as well as the most recent developments in the field. Full article

Background/Objectives: Type 2 diabetes (T2D) has become a critical global health issue, with an increasing prevalence that contributes to significant morbidity and mortality. Inhibiting dipeptidyl peptidase-IV (DPP4) is a promising strategy for managing T2D. This study aimed to explore the DPP4 inhibitory peptide derived from bitter melon seed protein (BMSP) hydrolysate. Methods: Reversed-phase high-performance liquid chromatography (RP-HPLC) was utilized to fractionate the hydrolysate. Peptide in the highest activity fraction was analyzed using liquid chromatography-mass spectrometry (LC-MS/MS). Peptide synthetic was used for further characterizations, such as bioactivity exploration, inhibition mechanism, molecular docking, and peptide stability against in vitro simulated gastrointestinal (SGI) digestion. Results: The BMSP hydrolysate was digested with gastrointestinal proteases (GP) and assessed for DPP4 inhibitory activity, yielding an IC₅₀ of 1448 ± 105 μg/mL. Following RP-HPLC fractionation, MPHW (MW4) and VPSGAPF (VF7) were identified from fraction F8 with DPP4 IC₅₀ values of 128.0 ± 1.3 µM and 150.6 ± 3.4 µM, respectively. Additionally, MW4 exhibited potential antihypertensive effects through ACE inhibition with an IC₅₀ of 172.2 ± 10.6 µM. The inhibitory kinetics and molecular docking simulations indicated that both MW4 and VF7 were competitive inhibitors of DPP4, while MW4 was also a competitive inhibitor of ACE. Importantly, both peptides remained stable during simulated gastrointestinal digestion, suggesting their resistance to human digestive processes and their capacity to maintain biological activity. Conclusions: The findings suggest that BMSP-GP hydrolysate may have potential in terms of the development of health foods or therapeutic agents. However, in vivo studies are also essential for further confirmation of efficacy. Full article