Search Results (1,137)

During gastrointestinal digestion, dietary proteins are hydrolyzed into peptides and free amino acids that modulate enteroendocrine function and satiety-related hormone secretion along the gut–brain axis, thereby contributing to obesity prevention. We investigated whey protein concentrate (WPC) as a source of bioactive peptides and evaluated the effects of its digests on cholecystokinin (CCK) secretion in STC-1 enteroendocrine cells by integrating the standardized INFOGEST in vitro digestion protocol, peptidomics (LC–MS/MS), and in silico bioactivity prediction. In STC-1 cells, the <3 kDa intestinal peptide fraction exhibited the strongest CCK stimulation, positioning these low-molecular-weight peptides as promising bioactive components for satiety modulation and metabolic health applications. Peptidomic analysis of this fraction identified short sequences derived primarily from β-lactoglobulin (β-La) and α-lactalbumin (α-La), enriched in hydrophobic and aromatic residues, including neuropeptide-like sequences containing the Glu–Asn–Ser–Ala–Glu–Pro–Glu (ENSAEPE) motif of β-La f(108–114). In silico bioactivity profiling with MultiPep predicted antihypertensive, angiotensin-converting enzyme (ACE)–inhibitory, antidiabetic, dipeptidyl peptidase-IV (DPP-IV)–inhibitory, antioxidant, antibacterial, and neuropeptide-like activities. Overall, digestion of WPC released low-molecular-weight peptides and amino acids that enhanced CCK secretion in vitro; these findings support their potential use in nutritional strategies to enhance satiety, modulate appetite and energy intake, and improving cardiometabolic health. Full article

Background/Objectives: The objective was to analyze the effects of Dipeptidyl Peptidase-4 (DPP-4) inhibitors on glycemic control, insulin dose, and preservation of β-pancreatic function (C-peptide) in patients with type 1 diabetes mellitus (T1DM). Methods: A systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with a search in the PubMed database. Five randomized clinical trials evaluating the use of different DPP-4 inhibitors in patients with T1DM were selected, measuring parameters including glycated hemoglobin (HbA1c), C-peptide, time in glycemic target/range (TIR), and daily insulin dose. Results: HbA1c showed significant reduction in some studies and no significant alterations in others. TIR increased in one study (~77.87% → ~84.40%). C-peptide showed variable effects across studies. The insulin dose did not show a substantial reduction. Conclusions: DPP-4 inhibitors demonstrated modest benefits for glycemic control and preservation of β-cell function in T1DM, but these effects were inconsistent due to methodological heterogeneity. Standardized studies are needed to define beneficial subgroups and long-term efficacy. Full article

Background: Periodontal disease is prevalent among elite athletes globally, yet its status in Japanese athletes remains unclear. This study assessed periodontal risk in Japanese university athletes and its association with oral health-related quality of life (QOL), sports performance, and immune status. Methods: A cross-sectional study was conducted with 313 university athletes (basketball, volleyball, athletics). Periodontal risk was evaluated using a Trypsin-Like Peptidase activity assay (TLP-AA) kit; a score ≥ 1.5 indicated the presence of Red Complex bacteria (positive risk). Participants completed the Oral Impacts on Daily Performance (OIDP), Oslo Sports Trauma Research Centre (OSTRC) overuse injury, and Immune Status Questionnaires (ISQ). Results: Positive periodontal risk was identified in 25.9% (81/313) of athletes. While overall prevalence was not statistically different from the general population (17.8%), specific associations emerged. Positive risk was significantly associated with “pain related to sports” (OSTRC) overall (p = 0.016) and specifically in males (p = 0.004). Among track and field athletes, positive risk was associated with difficulty “smiling/laughing” (OIDP, p = 0.033) and lower self-rated general health (p = 0.032) and immune functioning (p = 0.047). Conclusions: Periodontal risk is notable in Japanese university athletes and is significantly associated with sports-related pain and specific QOL domains. Regular oral health monitoring may be crucial for maintaining athletic performance and well-being. Full article

Type 2 diabetes mellitus (T2DM) poses a critical global health burden, necessitating safer multi-target therapies. We pioneer the exploration of novel bioactive peptides from Tenebrio molitor larvae—an underexplored, sustainable, and edible insect protein—through proteomics-guided screening and bioassays. Six unique peptides (DK-7, WK-6, GR-7, FK-8, SK-6, and DK-8) demonstrated significant α-glucosidase and dipeptidyl-peptidase IV (DPP-IV) inhibitory effects, and significant glucose consumption enhancement in insulin-resistant HepG2 cells. Molecular docking revealed a binding topology where peptides interacted with α-glucosidase at its active sites (Glu271, Arg643, Arg647, Arg653, Tyr733, Lys765, and Glu767) and with DPP-IV at active residues (Phe357, Tyr547, Trp629, Asp729, and Gln731) through dual hydrogen-bond networks and hydrophobic interactions, establishing a novel inhibition mechanism. We wish to propose that insect-derived biopeptides have potential value as next-generation therapeutics, simultaneously advancing sustainable drug discovery and approximating functional food bioresources to biomedicine. Full article

Dipeptidyl peptidase-4 (DPP-4) is a protease that degrades incretin and inhibits the secretion of insulin. Consequently, DPP-4 inhibition promotes insulin secretion and prevents the onset of type 2 diabetes. Given the growing interest in food-derived DPP-4 inhibitory peptides as potential functional ingredients, buckwheat (Fagopyrum esculentum) represents a promising source; however, few studies have investigated the bioactivity of peptides derived from buckwheat flour hydrolysates. In this study, two DPP-4 inhibitory peptides, Ile-Pro-Trp and Ile-Pro-Leu, were identified through purification of buckwheat flour hydrolysate and liquid chromatography–tandem mass spectrometry analysis. In a rat oral glucose tolerance test (OGTT), a fraction of buckwheat flour hydrolysate, crudely purified by reverse-phase column chromatography, showed a non-significant trend toward reducing increases in blood glucose. To our knowledge, this study is the first to show that Ile-Pro-Trp isolated from food protein hydrolysates exhibits considerable DPP-4 inhibitory activity. Moreover, this is the first study identifying Ile-Pro-Ile as a DPP-4 inhibitor from a plant source. Full article

Fusarium verticillioides (F. verticillioides) is an important fungal pathogen known to infect a variety of economically critical crops, particularly maize, causing substantial yield reductions and economic losses worldwide. In addition to its direct damage to agricultural productivity, F. verticillioides threatens public health by producing/secreting potent compounds, including well-known fumonisins (FUMs), which pose significant health threats to both livestock and humans due to their toxicity and carcinogenicity. However, current knowledge of the materials secreted/produced by F. verticillioides, such as secreted proteins and additional secondary metabolites, remains limited. In the present study, we conducted an integrated secretome analysis of F. verticillioides at the exponential growth stage by using proteomic and metabolomic technologies. The results of the present study showed that proteomic analysis identified 185 proteins, including 138 fungus-specific proteins. GO enrichment of these 138 fungus-specific proteins yielded 24 significant terms spanning carbohydrate/polysaccharide and aminoglycan metabolic/catabolic processes, extracellular and membrane-anchored components, and hydrolase/peptidase activities. Meanwhile, KEGG analysis identified starch and sucrose metabolism as the sole significantly enriched pathway. Metabolomic analysis of medium supernatant showed that a total of 2352 metabolites were identified, with 110 unique to the medium supernatant of the fungal group, including fumonisins (A1, B2, B3, B4), fatty acids, and other bioactive compounds. KEGG pathway enrichment highlighted key metabolic pathways, including the TCA cycle, unsaturated fatty acid biosynthesis, and arachidonic acid metabolism. These findings provide new insights into the pathogenic mechanisms of F. verticillioides, suggesting candidates for virulence-associated functions and metabolic adaptations that potentially contribute to its pathogenicity. Full article

Background and Objectives: Dichrostachys glomerata and Cissus quadrangularis, two species traditionally used in Cameroon, are recognized for their weight-reducing potential. This study examined the effects of standardized extracts of these botanicals on glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 (DPP-4), and key metabolic outcomes in individuals with excess body weight. Materials and Methods: In this 16-week, randomized, double-blind, placebo-controlled trial, 248 adults (126 women and 122 men; mean age 41.3 ± 0.3 years; BMI 25–34.9 kg/m²) were assigned to receive 400 mg D. glomerata extract (DGE), 300 mg C. quadrangularis extract (CQE), semaglutide (dose-escalated from 3 mg to 14 mg), or placebo, administered once daily. These are all standard clinical regimens. Primary assessments included changes in GLP-1 levels and DPP-4 activity. Secondary evaluations included body composition, caloric intake, satiety response, fasting glucose levels, and lipid profiles. Results: Participants receiving DGE or CQE displayed notable elevations in circulating GLP-1 (+38.6 pg/mL and +42.2 pg/mL, respectively; p < 0.01) and significant reductions in DPP-4 activity (−15.3% and −17.8%; p < 0.01) compared with placebo. Both extracts produced substantial improvements in body weight (−5.2% and −5.8%), body fat (−10.3% and −10.9%), energy intake (−16.2% and −17.5%), and satiety (+25.6% and +27.4%) (p < 0.01). Significant changes in fasting glucose and serum lipid levels were also observed (p < 0.05). These responses are comparable to those of semaglutide. Moreover, GLP-1 increments showed strong negative correlations with body fat percentage (r = −0.91 to −0.92; p < 0.001) and DPP-4 activity (r = −0.97 to −0.98; p < 0.001). Conclusions: Supplementation with D. glomerata and C. quadrangularis extracts enhanced GLP-1 secretion and reduced DPP-4 activity, yielding significant benefits for body composition and metabolic parameters. These findings indicate that both botanicals are promising natural agents for managing obesity through incretin-based mechanisms. Full article

Kallikrein-related peptidases (KLKs) are hallmarks of higher vertebrates, in particular of mammals. While the 15 human KLKs occur in nearly all tissues and body fluids and participate in many physiological processes, they are also involved in severe diseases. Among them are prostate, ovarian and breast cancer, as well as inherited skin and neurological disorders. Thus, KLKs have become targets for inhibitory compounds in academic and commercial research. The most prominent clinical biomarker and anti-cancer target for various approaches is PSA/KLK3. Already in the distant past, natural crude extracts were the source of medicine, while purified natural compounds and their derivatives are still the basis of about 50% of all pharmaceuticals. Nevertheless, structure-based rational design and high-throughput screening of natural and synthetic compound libraries are highly effective approaches for discovering lead compounds in the development of new drugs. Recently, computer-aided virtual or in silico screening has become a rapid method for such discoveries when combined with in vitro assays using protein targets or tests in cell cultures. To date, the successful implementation of artificial intelligence (AI) in the biosciences has significantly contributed to drug discovery. Our review focuses on state-of-the-art strategies and techniques in the context of KLK targets. Full article

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) promotes insulin secretion, lowers blood glucose levels, and is increasingly linked to bone remodeling. Native GIP is quickly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), whereas (D-Ala²)GIP is a novel GIP analog engineered to resist DPP-4 degradation. Tumor necrosis factor-alpha (TNF-α), a key proinflammatory cytokine, promotes osteoclastogenesis and is notably upregulated during orthodontic tooth movement (OTM). This study aimed to evaluate the effects of (D-Ala²)GIP on TNF-α-induced osteoclast formation and bone resorption in vivo, as well as on OTM and related root resorption. Mice received daily supracalvarial injections of TNF-α with or without (D-Ala²)GIP for 5 days. The (D-Ala²)GIP-treated group showed significantly reduced osteoclast formation, bone resorption, and expression of osteoclastic markers TRAP and cathepsin K, compared to the group that received TNF-α alone. OTM was induced in mice by applying a nickel-titanium closed-coil spring, and mice were treated with either phosphate-buffered saline (PBS) or (D-Ala²)GIP every 2 days. After 12 days, the (D-Ala²)GIP-treated group showed significantly reduced tooth movement and fewer osteoclasts and odontoclasts on the compression side compared to the PBS control. These findings suggest that (D-Ala²)GIP inhibits OTM, potentially by suppressing TNF-α-driven osteoclastogenesis and bone resorption. Full article

Peptidases constitute at least 2% of genes in living organisms and participate in nearly all physiological processes across life forms. Conversely, peptidase inhibitors are essential for regulating proteolytic activity and have been widely applied. Combining high-throughput sequencing of novel peptidase inhibitor sources with molecular modeling and drug design currently represents an efficient strategy for developing new molecules. Venomous spiders harbor a wide array of peptidase inhibitors in both their venom and digestive system. However, biochemical and transcriptomic investigations of non-venomous spiders (Uloboridae) remain recent and scarce. Here, transcriptomic and biochemical analyses of the Uloboridae spider Zosis geniculata’s digestive midgut diverticula (MD) revealed that this species exhibited a digestive enzyme profile similar to that of other spiders. Furthermore, the MD transcriptome identified 19 peptidase inhibitors belonging to six inhibitor families. Serine peptidase inhibitors were the most abundant and diverse, while metallopeptidases represented the main proteolytic enzymes, suggesting that these inhibitors may have evolved to counteract prey-derived peptidases. Inhibitory assays using trypsin from potential insect prey confirmed this activity. The diversity and abundance of these molecules highlight Uloboridae spiders as promising novel sources of proteolytic inhibitors. Full article

Background/Objectives: Diabetes mellitus (DM) represents a major global public health challenge and is consistently associated with an increased risk of atrial fibrillation (AF). Despite extensive epidemiological evidence linking the two conditions, the underlying mechanisms and the influence of glucose-lowering therapies on AF susceptibility remain incompletely defined. This review aims to summarize the current knowledge on the pathophysiological pathways linking DM and AF and to assess the impact of commonly used antidiabetic therapies on arrhythmic risk. We conducted a narrative review of epidemiological studies, mechanistic research, and cardiovascular outcome trials that evaluate the association between DM and AF. We included data addressing structural, electrical, autonomic, metabolic, and inflammatory mechanisms of AF in diabetes, as well as clinical evidence regarding the impact of metformin, insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium–glucose cotransporter-2 (SGLT-2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists on AF incidence or recurrence. Results: DM promotes AF development through multiple complementary mechanisms, including atrial fibrosis, electrical conduction abnormalities, autonomic dysfunction, inflammation, glycemic fluctuations, oxidative stress, and expansion of epicardial adipose tissue. These changes create a vulnerable atrial substrate that facilitates both initiation and maintenance of AF. Evidence from recent trials indicates that the arrhythmic effects of glucose-lowering therapies are heterogeneous. Metformin and SGLT-2 inhibitors appear to offer favorable or neutral effects on AF risk. GLP-1 receptor agonists provide substantial cardiovascular benefits, although their specific impact on AF remains under investigation. Insulin therapy has been linked to a higher AF risk, whereas DPP-4 inhibitors show an overall neutral effect with inconsistent findings across studies. Conclusions: AF in patients with DM results from complex interactions between metabolic disturbances, structural remodeling, and inflammatory activation. Although several antidiabetic drugs appear to have potential antiarrhythmic effects, further dedicated research is needed to clarify their role in AF prevention and management. Full article

Extracellular vesicles (EVs) are promising therapeutic agents due to their role in intercellular communication. This study examined the protective effects of milk-derived EVs (mEVs) on bovine oviductal epithelial cells (BOECs) under cobalt chloride (CoCl₂)-induced oxidative stress (OS), comparing EVs stored at −80 °C or lyophilized. mEVs and algae-derived EVs (aEVs; negative control) were isolated via tangential flow filtration and applied at 10⁷, 10⁹, and 10¹¹ particles/mL in three treatment strategies: pre-treatment, co-incubation, and post-treatment. mEVs specifically enhanced cell viability in all protocols except for post-treatment, where only 10⁷ particles/mL was effective; meanwhile, storage method did not affect EV activity. Enzyme digestion suggested that internal EV cargos are potentially the dominant contributors to the protective response compared to surface-associated molecules. mEVs reduced the expression of the OS markers DDIT4 and HIF1A while promoting cell migration more effectively than aEVs. Pathway enrichment analysis of previously reported mEV miRNAs indicated regulation of cytokine production and glucocorticoid responses, potentially contributing to OS defense. mEV protein cargo analysis showed pathways primarily linked to peptidase and vesicle-related functions, suggesting that protein cargo may also contribute to the observed protective effects. Overall, mEVs protect BOECs against CoCl₂-induced OS and maintain bioactivity after lyophilization. Full article

Glaucoma is a neurodegenerative disease characterized by progressive degeneration of optic nerve axons and loss of retinal ganglion cells (RGCs). Although elevated intraocular pressure (IOP) is a major risk factor, many patients develop glaucoma with normal IOP, highlighting the need for neuroprotective therapies. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, has shown beneficial effects in diabetes-induced retinal neurodegeneration. This study aimed to evaluate whether sitagliptin eye drops, previously effective in diabetes-induced retinal neurodegeneration, could prevent corticosteroid-induced glaucoma. Glaucoma was induced in mice by periocular injection of dexamethasone (DEX) once weekly for five weeks. Sitagliptin or vehicle eye drops were administered from day 14 to 35. Untreated mice served as controls. DEX treatment caused significant loss of RGC bodies and optic nerve axons compared to controls, which was prevented by sitagliptin eye drops (p < 0.001), without affecting IOP. Sitagliptin also inhibited DEX-induced activation of macroglia and microglia and prevented oligodendrocyte loss. Furthermore, it suppressed overexpression of galectin-3 and gamma-synuclein in the optic nerve head (ONH) (p < 0.001), key mediators of inflammation and apoptosis. Sitagliptin eye drops exert a potent neuroprotective effect against corticosteroid-induced glaucoma, supporting their potential as a novel therapeutic strategy for glaucoma. Full article

This study investigated the potential of scale-up mango leaf extract (MLE) as a treatment for diabetes, a global public health concern. MLE was prepared by boiling in water, yielding 12.07% (w/w), with a bioactive mangiferin content of 165.67 ± 10.88 μg/g in the crude powder. Mechanistically, MLE demonstrated a hypoglycemic effect by stimulating glucagon-like peptide-1 (GLP-1) secretion in NCI-H716 L-cells. This occurred through activation of the MAPK signaling pathway, evidenced by increased p-ERK1/2, p-p38, and p-c-Jun expression, and the Wnt signaling pathway, shown by increased β-catenin and decreased GSK-3β and Axin1 expression, consistent with molecular docking. In a type 2 diabetic rat model, MLE administration (40 mg/kg) significantly reduced metabolic parameters, including fasting blood glucose (FBG), body weight, cholesterol (CHOL), triglycerides (TGs), and HbA1c. Notably, MLE lowered serum insulin and the HOMA-IR index, and reduced serum dipeptidyl peptidase-IV (DPP-IV) levels, resulting in increased serum GLP-1, comparable to the drug sitagliptin. These findings suggest that MLE has great potential to lower blood glucose by inducing GLP-1 secretion via MAPKs and Wnt signaling pathways, positioning it as a promising candidate for alternative diabetes treatment or development as a dietary supplement. Full article

Celiac disease (CD) is an autoimmune disorder triggered by pepsin-resistant, gluten-derived immunogenic peptides (GIPs) in genetically predisposed individuals. Enzyme therapy targeting GIPs has been suggested as a complementary practice to a gluten-free diet to help reduce the symptoms of CD. Here, we present the crystal structure of RmuAP1, a pepsin-like aspartic protease from Rhodotorula mucilaginosa, which effectively degrades the toxic 33-mer and 26-mer GIPs under postprandial gastric conditions (pH 3.0–6.0). RmuAP1 has a canonical fold characteristic of the aspartic protease subfamily A1; however, it features a distinct flap and a flexible loop structure. Compared to pepsin, RmuAP1 accommodates the tetrapeptides PQQP and PQPQ, motifs frequently repeated on GIPs, via an adaptable binding cleft. Molecular dynamics (MD) simulations have shown that RmuAP1 stably engages these ligands, maintaining both the catalytic water in position and a closed flap conformation, primarily through ligand-induced remodeling of the S1′ pocket. In contrast, pepsin neither binds these ligands effectively nor achieves a catalytically competent conformation. Structural comparisons and dihedral analysis further support an induced-fit mechanism underlying RmuAP1’s pocket remodeling. Together, this study clarifies the structural basis for RmuAP1 to hydrolyze GIPs, emphasizing the potential of RmuAP1 as a platform for developing enhanced oral peptidase for CD patients through protein engineering approaches. Full article