ABSTRACT Progressive neuronal death caused by oxidative stress, aberrant protein aggregation, cholinergic deficits, neuroinflammation, and dysbiosis of the gut‐brain axis are attributes of neurodegenerative disorders (NDs), which include Alzheimer's and Parkinson's diseases. The investigation of novel Phyto therapeutics is prompted by the fact that conventional therapies only provide symptomatic relief without altering the disease. The aim of this study is to evaluate plant‐derived bioactive peptides critically for their dualistic neuroprotective versus neuro‐destructive potential in NDs, clarifying the underlying molecular mechanisms and translational barriers. The systematic review process followed the PRISMA 2020 guidelines to ensure transparency and reproducibility. A review of literature in Medline, EMBASE, PubMed, Scopus, and ScienceDirect was carried out from 2006 to 2026. Procedures for peptide isolation and purification, sequence activity relationship analyses, in vitro/in vivo functional tests (ROS scavenging, cholinesterase inhibition, tau phosphorylation, Aβ fibrillogenesis, cytokine profiling, microbiota modulation), and toxicological evaluations were all included in the inclusion criteria. Neuroprotective peptides activate the Nrf2/HO‐1 antioxidant cascade, inhibit GSK‐3β/JNK ‐mediated tau hyperphosphorylation, impede Aβ aggregation, suppress acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) activity, upregulate neurotrophins (BDNF, NGF), and restore microbial homeostasis via short‐chain fatty acid modulation by increasing Bifidobacterium/Lactobacillus abundance and decreasing inflammatory Firmicutes. Immunomodulatory sequences fine‐tune microglial clearance. Inspite of their size and polarity, several plant peptides can traverse the BBB primarily through receptor‐ and adsorptive‐mediated transcytosis, enabling central delivery. Conversely, cyclotides and thionins exhibit dose‐dependent hemolysis, cardiotoxicity, and immunogenic risk. Despite screening similar phytochemical motifs such as cationicity, hydrophobic residues, and ß‐sheet propensity protective peptides prevent aggregation and misfolding, while destructive peptides exploit same features to induce membrane disruption and cytotoxicity. Major challenges include scalable purification, gastrointestinal stability, and immunogenicity. Integrative strategies computational docking, targeted nanoencapsulation and peptide cyclization are imperative to enhance bioavailability, target specificity, and safety, thereby accelerating the translation of plant peptides into precision Phyto therapeutics for neurodegenerative diseases.
ABSTRACT To compare the repair effects of elastin peptides (EPs) from different tissue and recombinant sources on ultraviolet B (UVB)‐induced photoaging damage in human dermal fibroblasts (HDFs), four EP preparations were evaluated: bovine ligament‐derived elastin peptide (BL), bovine cardiovascular tissue‐derived elastin peptide (BC), bonito‐derived elastin peptide (Bon), and recombinant human elastin peptide (RH). These preparations represented two bovine tissue‐derived EPs, one marine‐derived EP, and one recombinant human EP. Their regulatory effects on extracellular matrix (ECM) degradation, inflammatory responses, and antioxidant‐related indicators were systematically evaluated. The molecular weight distribution and amino acid composition of the four EPs were first characterized by gel permeation chromatography (GPC) and amino acid analysis. Subsequently, the UVB irradiation dose and working concentrations of EPs were determined using the Cell Counting Kit‐8 (CCK‐8) assay. The expression levels of matrix metalloproteinase‐1 (MMP‐1), matrix metalloproteinase‐12 (MMP‐12), type I collagen (COL I), elastin (ELN), tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and related genes were evaluated by enzyme‐linked immunosorbent assay (ELISA) and quantitative real‐time polymerase chain reaction (qPCR). The results demonstrated significant differences in molecular weight distribution and amino acid composition among the four EPs. RH exhibited the most concentrated molecular weight distribution, whereas Bon showed a relatively higher proportion of medium‐molecular‐weight fractions. BL and BC displayed relatively similar overall amino acid compositions. Functional evaluation further revealed distinct anti‐photoaging characteristics among the four EPs. BL showed the most pronounced inhibitory effects on MMP‐12 and TNF‐α expression, BC exhibited the strongest effects in suppressing MMP‐1 expression and enhancing antioxidant‐related gene expression, Bon demonstrated the greatest restorative effects on COL I and collagen type I alpha 1 chain ( COL1A1 ) mRNA expression, and RH showed the most prominent effects in promoting ELN recovery and suppressing IL‐6 expression. Collectively, EPs from different tissue and recombinant sources exhibited distinct functional preferences in the UVB‐induced HDF photoaging model, which may be associated with their molecular weight distribution and amino acid composition characteristics. This study provides an experimental basis for the precise development and differential application of elastin peptide materials.
ABSTRACT Phenylalanyl‐Tyrosine (Phe‐Tyr) dipeptide has attracted attention as a bioactive peptide due to its possible therapeutic properties. In this study, the anti‐cancer potential of Phe‐Tyr was investigated using integrated computational and experimental methods. Molecular docking analysis was performed against five important cancer‐related targets, including Epidermal Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), Phosphoinositide 3‐kinase (PI3K), Protein Kinase B (Akt1), and Mechanistic Target of Rapamycin (mTOR). The peptide exhibited favorable binding affinities toward all receptors, with docking energies ranging from −7.5 to −8.9 kcal/mol, while the strongest interaction was observed with Akt1 (−8.9 kcal/mol). To further evaluate complex stability, molecular dynamics simulations of the Phe‐Tyr complexes were performed for 100 ns, confirming stable ligand–protein interactions under dynamic conditions. In addition, in silico predictions of biological activity, toxicity, adverse effects, and cytochrome P450 interactions indicated favorable pharmacological and safety characteristics. The anti‐cancer activity of Phe‐Tyr was further evaluated experimentally on A549 cells using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay, while apoptotic cell death was assessed by flow cytometry using Annexin V–fluorescein isothiocyanate/propidium iodide double staining. Overall, these findings suggest that Phe‐Tyr may serve as a promising peptide‐based anti‐cancer candidate, although further experimental studies are required to validate its therapeutic potential.
ABSTRACT Histidine (His)‐containing β‐sheet assemblies are promising pH‐responsive nanomaterials that function in mildly acidic biological environments. Although these assemblies have been extensively studied, it remains unclear how the number and positioning of His residues in β‐sheet‐forming sequences define the pH range for β‐sheet formation and nanofiber assembly and how they regulate pH‐triggered structural transitions in pre‐formed nanofibers. Here, we designed five FVIFLD‐based β‐sheet‐forming peptide–oligo(ethylene glycol) (OEG) conjugates by systematically varying the number and positioning of His residues. Circular dichroism measurements over pH 3.9–9.0 showed that four conjugates exhibited a characteristic three‐region pH dependence, displaying random coil‐like signatures at high and low pH and β‐sheet‐like signatures within an intermediate pH range, whereas one conjugate remained random coil‐like across the entire pH range. Notably, even with the same total number of His residues, the pH region favorable for β‐sheet formation shifted depending on their positioning. Transmission electron microscopy confirmed nanofiber formation within the β‐sheet‐forming pH range. In addition, pre‐formed nanofibers underwent a decrease in β‐sheet order and shifted toward random coil‐like conformations upon acidification to mildly acidic pH. The midpoint pH for acid‐triggered destabilization of pre‐formed nanofibers (pH D50 ) was not determined solely by the total number of His residues but was also influenced by their positioning within the sequence, and it did not necessarily correlate with the midpoint pH for assembly (pH A50 ). Together, these results provide a practical reference for designing His‐mediated pH‐responsive β‐sheet assemblies.
ABSTRACT Oral delivery of peptide therapeutics remains a major challenge due to extensive enzymatic degradation, mucus entrapment, limited epithelial permeability, active efflux, and hepatic first‐pass metabolism, all of which restrict systemic exposure. Recent advances in nanocarrier engineering and AI‐driven design are beginning to overcome these barriers through synergistic innovations in medicinal chemistry, formulation science, and clinically validated enhancer platforms. Mechanistic insights into gastrointestinal physiology have enabled the rational development of technologies such as SNAC and TPE, supporting gastric or intestinal transcellular uptake and establishing the first clinically approved oral peptide formulations. Parallel progress in peptide engineering including cyclization, D‐amino acid substitution, lipidation, and transporter‐targeted conjugation enhances proteolytic stability and epithelial interaction, while next‐generation polymer–lipid hybrids, mucus‐penetrating carriers, bile‐acid–guided systems, and stimuli‐responsive biomaterials provide tunable protection and controlled release across the GI tract. Device‐assisted platforms such as LUMI, SOMA, and RaniPill further expand this toolkit by bypassing epithelial barriers altogether. These technological gains intersect with sustainable manufacturing and green bioprocessing considerations essential for scalable clinical translation, along with persistent global health challenges in LMIC settings. Collectively, these developments highlight a decisive shift toward clinically viable, patient‐centric oral peptide therapeutics and outline a forward SDG‐aligned trajectory in which computational design, eco‐efficient production, and advanced biomaterial systems converge to enable reliable systemic and local delivery via the oral route.
