Search Results (736)

Bioactive peptides have significant potential for applications in pharmaceuticals, the food industry, and cosmetics due to their wide spectrum of biological activities. However, their pronounced structural and functional heterogeneity complicates the classification and prediction of biological activity. This study uses data from the PepLab platform, comprising 2748 experimentally confirmed bioactive peptides distributed across 15 functional classes, including ACE inhibitors, antimicrobial, anticancer, antioxidant, toxins, and others. For each peptide, the amino acid sequence and key physicochemical descriptors are provided, calculated via the integrated DMPep module, such as GRAVY index, aliphatic index, isoelectric point, molecular weight, Boman index, and sequence length. The dataset exhibits class imbalance, with class sizes ranging from 14 to 524 peptides. An innovative methodology is proposed, combining descriptive statistical analysis, structural modeling via DEMATEL, and structural equation modeling with neural networks (SEM-NN), where SEM-NN is used to capture complex nonlinear causal relationships between descriptors and functional classes. The results of these dependencies are integrated into a multi-class machine learning model to improve interpretability and predictive performance. Targeted data augmentation was applied to mitigate class imbalance. The developed classifier achieved predictive accuracy of up to 66%, a relatively high value given the complexity of the problem and the limited dataset size. These results confirm that integrating structured dependency modeling with artificial intelligence is an effective approach for functional peptide classification and supports the rational design of novel bioactive molecules. Full article

Pain is a multifactorial phenomenon involving neuronal, immune, and glial components. Annexin A1 (AnxA1), a glucocorticoid-regulated protein with pro-resolving properties, has emerged as a critical modulator of pain. Present in both peripheral and central compartments, AnxA1 acts through the formyl peptide receptor FPR2/ALX to regulate immune responses, modulate nociceptive signaling, and promote tissue homeostasis. Its mimetic peptide, Ac_2–26, has demonstrated robust antinociceptive effects in various pain models, including those induced by inflammation, tissue injury, viral infection, and opioid exposure. AnxA1 modulates cytokine expression, inhibits pro-nociceptive pathways such as TRPV1 and CXCL12/CXCR4, and reprograms macrophages. In the central nervous system, it attenuates neuroinflammation and central sensitization. Notably, AnxA1 can exhibit context-dependent effects, contributing to either the resolution or exacerbation of inflammation. This review examines the molecular mechanisms by which AnxA1 bridges the immune and nervous system pathways, highlighting its therapeutic potential in pain management. Full article

Plant-based bioactive compounds have been recognized as promising alternatives to conventional chemical treatments. Selenium (Se), a trace element, can be incorporated into proteins to enhance the bioactivity of plant-derived peptides. Perilla frutescens seeds are high-protein plants that have shown the ability to absorb Se and biosynthesize selenopeptides. This study examined Se biotransformation during the germination of perilla seeds to synthesize selenoprotein, investigating enzymatic hydrolysis using Alcalase and Flavourzyme as single enzymes, as well as their combinations. The results showed that Alcalase hydrolysates produced Se-peptides with the highest degree of hydrolysis and antioxidant activity. Hydrolysates were purified via ultrafiltration and size-exclusion chromatography, and Se-peptides were characterized by LC-MS/MS. Nine peptides containing Se-binding residues such as cysteine, methionine, and glutamic acid confirmed successful Se incorporation. The Se-peptides demonstrated strong antioxidant activity (ABTS: 66.30%, FRAP: 54.93%), ACE inhibition (83.87%), and cytotoxicity against A549 lung cancer cells (85.88% viability). Compared to non-Se-peptides, Se-enriched peptides showed superior bioactivity, highlighting their potential as functional ingredients in food and pharmaceutical applications. Full article

The design and synthesis of a small library of 2-styrylquinoline derivatives containing a push-pull system, aimed at displacing their fluorescence emission towards the NIR region, is described. We describe here their synthesis, fluorescent characterization and pharmacological evaluation against different amyloid proteins. Their study showed that these compounds are capable to change their spectroscopic properties upon protein interaction, resulting in changes in the absorption and emission wavelengths, together with increased fluorescence intensity. They also showed sensitivity to pH and environment polarity, exhibiting red shifts in lower polarity environments with regard to aqueous media. Inner charge transfer is observed and employed for detecting the interaction of these compounds with protein aggregates. The study of the alterations in the fluorescence intensity allows to calculate the dissociation constant values for the protein-sensor interaction. These spectroscopic results were the basis for the use of these compounds to visualize β-amyloid plates with selectivity over phosphorylated tau in samples of cerebral tissue from deceased Alzheimer patients under fluorescence microscopy, using immunofluorescence techniques. Pharmacological assays showed that the compounds inhibit the aggregation of the Aβ_1–42 and AcPHF6 peptides, representing tau protein. They also showed neuroprotective activity following okadaic acid insult. Full article

This study presents a strategy to develop crayfish shell peptides with enhanced antioxidant and angiotensin-I-converting enzyme (ACE) inhibitory properties. Crayfish shell protein hydrolysates (CSPH1–3) with different molecular weights were analyzed. CSPH2 (3–5 kDa) exhibited the strongest antioxidant activities, which could scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) and the 2,2′-azobis(3-ethylbenzothiazoline-6-sulfonic acid) sodium salt (ABTS) radical by (77.40 ± 4.54)% and (91.59 ± 0.30)%, respectively, and ACE inhibition activity of (64.74 ± 0.64)%. CSPH2 was further separated into three fractions, and CSPHF2 showed the maximum biological activity. The sequences of the purified antioxidant peptide (APAPLPPPAP) and ACE inhibitory peptide (QGPDDPLIPIM) were identified by liquid chromatography–tandem mass spectrometry (LC-MS/MS) in CSPHF2. These peptides increased the nitric oxide (NO) concentration and decreased the endothelin-1 (ET-1) content in human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner, while also inhibiting reactive oxygen species (ROS). In addition, CSPH showed protective effects in terms of oxidative damage to HepG2 cells induced by H₂O₂. These findings suggest that crayfish shell peptides have potential applications as ingredients in antihypertensive agents and antioxidants, offering significant health benefits when consumed. Full article

The renin-angiotensin system (RAS) has evolved from being considered solely a peripheral endocrine system for cardiovascular control to being recognized as a complex molecular network with important functions in the central nervous system (CNS) and peripheral nervous system (PNS). Here we examine the organization, mechanisms of action, and clinical implications of cerebral RAS in physiological conditions and in various neurological pathologies. The cerebral RAS operates autonomously, synthesizing its main components locally due to restrictions imposed by the blood–brain barrier. The key elements of the system are (pro)renin; (pro)renin receptor (PRR); angiotensinogen; angiotensin-converting enzyme types 1 and 2 (ACE1 and ACE2); angiotensin I (AngI), angiotensin II (AngII), angiotensin III (AngIII), angiotensin IV (AngIV), angiotensin A (AngA), and angiotensin 1-7 (Ang(1-7)) peptides; RAS-regulating aminopeptidases; and AT1 (AT1R), AT2 (AT2R), AT4 (AT4R/IRAP), and Mas (MasR) receptors. More recently, alamandine and its MrgD receptor have been included. They are distributed in specific brain regions such as the hypothalamus, hippocampus, cerebral cortex, and brainstem. The system is organized into two opposing axes: the classical axis (renin/ACE1/AngII/AT1R) with vasoconstrictive, proinflammatory, and prooxidative effects, and the alternative axes AngII/AT2R, AngIV/AT4R/IRAP, ACE2/Ang(1-7)/MasR and alamandine/MrgD receptor, with vasodilatory, anti-inflammatory, and neuroprotective properties. This functional duality allows us to understand its role in neurological physiopathology. RAS dysregulation is implicated in multiple neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and neuropsychiatric disorders such as depression and anxiety. In brain aging, an imbalance toward hyperactivation of the renin/ACE1/AngII/AT1R axis is observed, contributing to cognitive impairment and neuroinflammation. Epidemiological studies and clinical trials have shown that pharmacological modulation of the RAS using ACE inhibitors (ACEIs) and AT1R antagonists (ARA-II) not only controls blood pressure but also offers neuroprotective benefits, reducing the incidence of cognitive decline and dementia. These effects are attributed to direct mechanisms on the CNS, including reduction of oxidative stress, decreased neuroinflammation, and improved cerebral blood flow. Full article

In this review, our intention was to shed some light on the history of sublingual and buccal delivery over the past 75 years. By searching the query sublingual and buccal, we noticed four steady growth periods in the number of publications between 1950 and 2025. The early phase of sublingual and buccal drug delivery (1950–1982) saw limited attempts to explore this delivery route. The exploratory growth phase (1983–1993) was marked by the use of nitroglycerin to treat angina, calcium channel blockers to treat hypertension, ACE inhibitors to treat heart conditions, the use of opioids in pain management therapy, and peptide and hormonal therapy. The diversification and discovery phase (1994–2009) was marked by the introduction of small molecules for the treatment of opioid use disorder and analgesia, the use of animal models to enhance the pharmacokinetic understanding of the sublingual and buccal route, the use of penetration enhancers, peptide and hormonal therapy, and few marked FDA drug approvals in this area. The innovation and integration phase (2010–2025) was marked by the use of nanoparticles, multilayered mucoadhesive systems, pediatric formulations (fast-dissolving films and tablets), immunotherapy and vaccine delivery, and a broad spectrum of therapeutic agents, such as steroids, antifungals, cannabinoids, antidepressants, antipsychotics, and narcotics (e.g., buprenorphine and apomorphine), novel formulations of fentanyl and diazepam for pain and seizure control, and the introduction of buccal vitamin D3 sprays. Understanding the history of sublingual and buccal delivery demonstrates a growing area of research focused on enhancing mucosal drug delivery for achieving local and systemic therapeutic benefits. 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

Coffee silverskin (CS), a by-product generated during coffee roasting, contains high levels of xylan hemicellulose and protein, making it a promising substrate for functional ingredient production. This study developed an integrated bioprocess to simultaneously produce bioactive peptides and xylooligosaccharides (CS-XOS) from CS. Conventional alkaline extraction (CAE) under optimized conditions (1.0 M NaOH, 90 °C, 30 min) yielded 80.64 mg of protein per gram of CS and rendered the solid residue suitable for XOS production. Enzymatic hydrolysis of the extracted protein using protease_SE5 generated low-molecular-weight peptides (0.302 ± 0.01 mg/mL), including FLGY, FYDTYY, and FDYGKY. These peptides were non-toxic, exhibited in vitro antioxidant activity (0–50%), and showed ACE-inhibitory activities of 60%, 26%, and 79%, and DPP-IV-inhibitory activities of 19%, 18%, and 0%, respectively. Concurrently, the alkaline-treated CS solid residue (ACSS) was hydrolyzed using recombinant endo-xylanase, yielding 52.5 ± 0.08 mg of CS-XOS per gram of ACSS. The CS-XOS exhibited prebiotic effects by enhancing the growth of probiotic lactic acid bacteria (μ_max 0.100–0.122 h⁻¹), comparable to commercial XOS. This integrated bioprocess eliminates the need for separate processing lines, enhances resource efficiency, and provides a sustainable strategy for valorizing agro-industrial waste. The co-produced peptides and CS-XOS offer significant potential as functional food ingredients and nutraceuticals. Full article

Hypertension is a major pathogenic contributor to cardiovascular diseases, primarily mediated through activation of the angiotensin-converting enzyme (ACE) system. Food-derived ACE-inhibitory peptides represent a promising alternative to synthetic drugs due to their favorable safety profile and minimal side effects. ACE-inhibitory peptides have been extensively identified from various foods, with their antihypertensive activity and molecular mechanisms comprehensively characterized through in vitro and in vivo studies. ACE-inhibitory peptides can be prepared by methods such as natural extraction, enzymatic hydrolysis, and fermentation. The production process significantly modulates structural characteristics of the polypeptides including peptide chain length, amino acid composition, and sequence, consequently determining their functional activity. To comprehensively elucidate the gastrointestinal stability and mechanisms action of ACE-inhibitory peptides, integrated experimental approaches combining both in vitro and in vivo methodologies are essential. This review systematically examines current advances in food-derived ACE-inhibitory peptides in terms of sources, production, structure, in vivo and in vitro activities, and bioavailability. Full article

Background: The candidate therapeutic peptide TnP demonstrates broad, system-level regulatory capacity, revealed through integrated network analysis from transcriptomic data in zebrafish. Our study primarily identifies TnP as a multifaceted modulator of drug metabolism, wound healing, proteolytic activity, and pigmentation pathways. Results: Transcriptomic profiling of TnP-treated larvae following tail fin amputation revealed 558 differentially expressed genes (DEGs), categorized into four functional networks: (1) drug-metabolizing enzymes (cyp3a65, cyp1a) and transporters (SLC/ABC families), where TnP alters xenobiotic processing through Phase I/II modulation; (2) cellular trafficking and immune regulation, with upregulated myosin genes (myhb/mylz3) enhancing wound repair and tlr5-cdc42 signaling fine-tuning inflammation; (3) proteolytic cascades (c6ast4, prss1) coupled to autophagy (ulk1a, atg2a) and metabolic rewiring (g6pca.1-tg axis); and (4) melanogenesis-circadian networks (pmela/dct-fbxl3l) linked to ubiquitin-mediated protein turnover. Key findings highlight TnP’s unique coordination of rapid (protease activation) and sustained (metabolic adaptation) responses, enabled by short network path lengths (1.6–2.1 edges). Hub genes, such as nr1i2 (pxr), ppara, and bcl6aa/b, mediate crosstalk between these systems, while potential risks—including muscle hypercontractility (myhb overexpression) or cardiovascular effects (ace2-ppp3ccb)—underscore the need for targeted delivery. The zebrafish model validated TnP-conserved mechanisms with human relevance, particularly in drug metabolism and tissue repair. TnP’s ability to synchronize extracellular matrix remodeling, immune resolution, and metabolic homeostasis supports its development for the treatment of fibrosis, metabolic disorders, and inflammatory conditions. Conclusions: Future work should focus on optimizing tissue-specific delivery and assessing genetic variability to advance clinical translation. This system-level analysis positions TnP as a model example for next-generation multi-pathway therapeutics. Full article

Spurred by the enormous therapeutic success of glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP1-RAs) against diabetes and obesity, glucagon family receptor pharmacology has garnered a tremendous amount of interest. Glucagon family receptors, e.g., the glucagon receptor itself (GCGR), the GLP-1R, and the glucose-dependent insulinotropic peptide receptor (GIPR), belong to the incretin receptor superfamily, i.e., receptors that increase blood glucose-dependent insulin secretion. All incretin receptors are class B1 G protein-coupled receptors (GPCRs), coupling to the G_s type of heterotrimeric G proteins which activates adenylyl cyclase (AC) to produce cyclic adenosine monophosphate (cAMP). Most GPCRs undergo desensitization, i.e., uncouple from G proteins and internalize, thanks to interactions with the βarrestins (arrestin-2 and -3). Since the βarrestins can also mediate their own G protein-independent signaling, any given GPCR can theoretically signal (predominantly) either via G proteins or βarrestins, i.e., be a G protein- or βarrestin-“biased” receptor, depending on the bound ligand. A plethora of experimental evidence suggests that the GLP-1R does not undergo desensitization in physiologically relevant tissues in vivo, but rather, it produces robust and prolonged cAMP signals. A particular property of constant cycling between the cell membrane and caveolae/lipid rafts of the GLP-1R may underlie its lack of desensitization. In contrast, GIPR signaling is extensively mediated by βarrestins and the GIPR undergoes significant desensitization, internalization, and downregulation, which may explain why both agonists and antagonists of the GIPR exert the same physiological effects. Here, we discuss this evidence and make a case for the GLP-1R being a phenotypically or functionally G_s-selective receptor. We also discuss the implications of this for the development of GLP-1R poly-ligands, which are increasingly pursued for the treatment of obesity and other diseases. Full article

In order to innovatively develop high-activity ACE inhibitory peptides from edible fungi, the conditions for a double-enzymatic hydrolysis preparation of ACE inhibitory peptides from Flammulina velutipes were optimized by response surface methodology. After purification by macroporous resin, gel chromatography, and RP-HPLC, a crude peptide fraction was obtained; its ACE inhibition rate was 85.73 ± 0.95% (IC₅₀ = 0.83 ± 0.09 mg/mL). Based on LC-MS/MS sequencing, the four novel peptides, namely, FAGGP, FDGY, FHPGY, and WADP, were screened by computer analysis and molecular docking technology. The four peptides exhibited a binding energy between −9.4 and −10.3 kcal/mol, and formed hydrogen bonds with Tyr523, Ala354, and Glu384 in the S1 pocket, Tyr520 and His353 in the S2 pocket, and His383 in the HEXXH zinc-coordinating motif of ACE, indicating their good affinity with the ACE active site. The IC₅₀ values of the four ACE inhibitory peptides were 29.17, 91.55, 14.79, and 41.27 μM, respectively, suggesting that these peptides could potentially contribute to the development of new antihypertensive products. Full article

Background: The amylin receptor is a receptor for the peptide hormone amylin, and its activation is known to reduce body weight. The amylin receptor functions as a heterodimer complex that consists of the calcitonin receptor for peptide hormone calcitonin and an accessary protein. Although the structural information of amylin receptors is currently available, receptor–ligand binding studies that support the peptide binding mode for amylin receptors remain incomplete. Methods: Here, we introduced mutagenesis to the amylin receptor 1 extracellular domain and examined mutational effects on peptide binding affinity. We focused on several residues mainly from the peptide-binding pocket (D97, D101, E123, N124, and N135 of the calcitonin receptor). Two well-known peptide ligands for amylin receptors were used for this study: a salmon calcitonin fragment and an antagonist amylin analog AC413 fragment with Y25P mutation. Results: Among the introduced mutations, D101A and N135A mutations abolished peptide ligand binding, suggesting that these residues are critical for peptide interaction. The N124A mutation also significantly decreased the peptide binding affinity by more than 8-fold. Intriguingly, the N124D mutation restored the decreased affinity of the salmon calcitonin fragment, while it failed to restore the decreased affinity of the AC413 fragment. Structural analyses suggested that there was a potential role of salmon calcitonin serine 29 in the interaction with aspartate of the N124D mutation. Conclusions: This study validates the critical residues of the amylin receptor 1 extracellular domain for the interaction with C-terminal fragments of peptide ligands. This study also suggests that modulating receptor–ligand interaction is feasible by the modification of receptor amino acids near an interacting peptide ligand. Full article