Search Results (381)

Background/Objectives: Glycyl-L-histidyl-L-lysine (GHK) and its copper(II) complex GHK-Cu have been studied for matrix remodeling, inflammation, redox regulation, angiogenesis, and tissue repair, yet the literature frequently treats GHK-Cu as a single active ingredient despite formulation-dependent variation in coordination state, speciation, stability, pharmacokinetics, and toxicity. We critically evaluate GHK-Cu simultaneously as a bioactive metallopeptide and as a drug-delivery cargo, with explicit separation of apo-GHK, canonical GHK-Cu, GHK-derived copper peptides, and non-GHK copper-peptide systems. Methods: We conducted a structured systematic evidence-mapping review of PubMed/MEDLINE, Europe PMC, major publisher platforms, ClinicalTrials.gov, backward citation chains, and official European Union, U.S., and ICH regulatory sources from database inception through 12 August 2026. Biological evidence level and chemical/formulation quality were graded independently using an author-defined two-axis framework. Delivery studies were extracted against a fixed matrix comprising formulation, claimed loading, molar copper occupancy, labile copper, species-resolved release, factorial controls, stability/manufacturability, and objective outcome. Quantitative pooling was not performed because active-entity definitions, formulations, doses, models, comparators, and endpoints were not quantitatively commensurable. Results: Preclinical data consistently support effects on matrix remodeling, epithelial repair, inflammatory/redox regulation, and angiogenesis, but the clinical evidence remains sparse and does not meet contemporary active-entity quality standards. Historical cosmetic reports are small or incompletely characterized; a 13-participant post-CO2-laser study was negative on objective endpoints, whereas a 2026 18-participant split-face eyebrow study reported positive cosmetic hair outcomes but did not define GHK-Cu speciation or local exposure. The ongoing phase 2 acute-wound study NCT07437586 remains recruiting and has no efficacy results; its registration cannot be used as evidence of clinical translation. Across delivery studies, particle size, polydispersity, encapsulation efficiency, total peptide/copper content, and bulk release are often reported, whereas molar occupancy, labile copper, and release of intact GHK-Cu versus apo-GHK/free copper are usually not resolved. Conclusions: Translation is limited less by biological plausibility than by pharmaceutical definition and evidence attribution. We define the “active pharmaceutical entity” operationally as the reproducible chemical state intended to mediate pharmacology at administration, not as an established regulatory designation or a claim that one immutable molecular species persists in biological fluids. We further propose, explicitly as an author-derived development framework rather than a consensus standard, a control strategy based on molar occupancy, route-specific labile copper specifications, orthogonal speciation, mechanism-linked potency, species-resolved release, factorial controls, route-specific safety decision thresholds, ICH-aligned stability, and GMP-scalable manufacture. Until these requirements are met and controlled clinical efficacy is demonstrated, GHK-Cu should be regarded as a promising but unproven therapeutic cargo rather than a clinically validated regenerative drug. Full article

Collagen peptides (CPs) possess diverse biological activities, yet their oral efficacy is limited by gastrointestinal degradation and restricted systemic exposure of intact bioactive peptide species. Herein, a stable cholesterol-free nanoliposome system was developed using soybean phospholipids and stigmasterol through high-pressure microfluidization, followed by tangential flow filtration and spray drying to obtain a stable dry formulation. The optimized nanoliposomes exhibited a particle size below 100 nm, high peptide loading, excellent redispersibility, and remarkable physicochemical stability during refrigerated storage and under different pH and thermal conditions. During simulated gastrointestinal digestion, the stigmasterol-stabilized phospholipid bilayer effectively preserved encapsulated CPs throughout the gastric phase while facilitating peptide release under intestinal conditions. Oral administration in rats significantly enhanced collagen peptide bioavailability, increasing the plasma exposure (iAUC_{0–8 h}) of total hydroxyproline by 3.84-fold compared with free CPs. Peptide-bound hydroxyproline exposure increased 9.3-fold and accounted for approximately 94% of total absorbed hydroxyproline. UHPLC–HRMS analysis confirmed substantially enhanced systemic exposure of multiple characteristic hydroxyproline-containing dipeptides and tripeptides following nanoliposomal delivery. These findings indicate that stigmasterol-containing nanoliposomes improve the gastrointestinal stability and systemic delivery performance of collagen peptides, providing a promising strategy for enhancing the oral delivery potential of food-derived bioactive peptides. Full article

Peptidoglycan (PGN) is a mesh like polymer that builds and protects the bacterial cell wall. Across and even within species, PGN varies considerably in structure and composition, and this structural diversity shapes how released fragments are detected by the host. The varied structural features of PGN can also dictate its ability to act as a toxin or danger signal. Traditionally, bacterial cell wall components have been classified as toxic, based on their ability to cause extensive host cell damage, but the specific immune responses triggered by distinct PGN structural motifs when they are released into the extracellular space, and their potential direct role as toxins are not yet fully understood. Emerging evidence suggests that PGN is recognized by the host not only through its canonical di-/tripeptides, but also through novel structural motifs that are sensed by host pattern recognition receptors (PRRs). However, the mechanisms underlying the recognition of these structurally diverse fragments and their role in promoting immune activation, bacterial pathogenesis, and immune evasion remain poorly understood. In this review, we describe how structurally distinct muropeptides are synthesized, processed, and selectively sensed by host PRRs, and how differential immune recognition shapes PRR activation, thereby influencing host–pathogen interactions and infection outcomes. Full article

Myeloperoxidase (MPO) plays a significant role in the development and progression of bronchopulmonary dysplasia (BPD). The neonatal rat model has shown that the tripeptide N-acetyl-lysyltyrosylcysteine amide (KYC) attenuates hyperoxia-induced BPD-like injury, in part by reducing MPO-mediated toxic oxidants and additional cytoprotective mechanisms. However, the rat model does not fully replicate the key characteristics of surfactant deficiency and immature antioxidant capacity in premature human neonates. In contrast, premature rabbit kittens share key features with those of premature human neonates. For this study, premature rabbit kittens delivered at 29 days of gestation (term is 31 days) were exposed to 95% oxygen for 7 days. Hyperoxia caused a BPD-like phenotype characterized by increased MPO-positive inflammatory cell infiltration, elevated MPO expression, alveolar simplification, septal wall thickening, and pulmonary arterial medial wall thickening. Daily intraperitoneal KYC administration attenuated lung inflammatory cell infiltration, reduced MPO expression, improved alveolar morphometric indices, and mitigated pulmonary arterial medial wall thickening compared with phosphate-buffered saline treatment. There were no significant differences in weight changes or survival between the groups. These findings demonstrate that premature rabbit kittens provide a useful developmental model for the evaluation of candidate BPD therapies and reproduce MPO-associated pathological and therapeutic responses previously observed in neonatal rat studies. Full article

The discovery of angiotensin-converting enzyme (ACE)-inhibitory peptides from food protein hydrolysates is commonly guided by empirical fractionation or sequence-based prediction, but few screening rules have been evaluated at the hydrolysate level and independently benchmarked across peptide lengths. Here, we developed a length-aware C-terminal screening rule (Rule 5: P1’ ∈ {W, Y, F, P} and P2’ ∈ {L, I, V, K, R, H}) through an experimentally anchored framework. The rule was derived using 24 stratified protein–protease hydrolysates and showed the strongest associations with ACE inhibition (r = 0.711, p < 0.001) and log₁₀(1/IC₅₀) (r = 0.741, p < 0.001) among five evaluated rules. Independent evaluation in 16 composition-weighted commercial hydrolysates retained predictive utility (r = 0.608 for ACE inhibition and r = 0.581 for log₁₀(1/IC₅₀)). Five peptides—VF, GIF, LP, IP, and VP—were selected because they represented the intersection of in silico cleavage prediction, Rule 5 compliance, and corresponding candidate-associated low-mass MALDI features in the experimentally prepared hydrolysates. All five inhibited ACE (IC₅₀ = 19.50–93.19 µM); VF and GIF showed mixed-type inhibition, whereas LP, IP, and VP showed competitive inhibition. External benchmarking against 1429 quantitative ACE-inhibitory peptides established a defined applicability domain: Rule 5 significantly enriched potent peptides among di- and tripeptides (2–3 residues; median IC₅₀, 28.0 vs. 79.0 µM; p_adj < 0.001, Benjamini–Hochberg-corrected; enrichment factor = 2.5 at IC₅₀ ≤ 1 µM), but enrichment attenuated rapidly as longer sequences were included. Molecular dynamics simulations (200 ns) showed persistent peptide–ACE contact for all five candidates under the simulated conditions. Rule 5 is therefore proposed as a transparent first-pass filter for prioritizing short ACE-inhibitory candidates and protein–protease combinations, rather than as a universal predictor across the full peptide-length spectrum. Full article

Full-length ACTH molecule and ACTH-related hexapeptide H-PKKRRP-OH are demonstrated by the patch-clamp method to decrease the Na_V1.8 channel activation gating system effective charge in the nociceptive neuron membrane, while ACTH-related tetrapeptide Ac-KKRR-NH₂ has no effect. ACTH(1–24), a fully functional ACTH mimetic, and H-PKKRRP-OH show analgesic effects in the formalin test in vivo. All peptides contain the cationic KKRR motif, but only H-PKKRRP-OH and ACTH(1–24) relieve acute pain, targeting the Na_V1.8 channel as a receptor. This seemingly controversial result is explained by application of conformational analysis and blind docking. Though conformational analysis indicates that both H-PKKRRP-OH and Ac-KKRR-NH₂ contain the cationic functional groups at the earlier suggested characteristic distance of 9–12 Å, Ac-KKRR-NH₂ does not interact with the S4_I voltage sensor of the Na_V1.8 channel activation gating system. The docking demonstrates that an extensive network of ligand–receptor ionic and hydrogen bonds involving D151, E157, R218, and R221 VSD_I residues, essential for the analgesic tripeptide Ac-KKK-NH₂ binding, is formed upon the H-PKKRRP-OH binding. Particularly important are the ionic bonds between the H-PKKRRP-OH C-terminal carboxylate anion and the S4_I R218 and R221 guanidinium groups. The described mechanism of Na_V1.8 channel modulation is fundamentally different from the effect of channel blockers. Full article

Collagen, long regarded as the inert structural scaffold of the extracellular matrix, is now recognised as a source of bioactive signaling molecules: enzymatic hydrolysis releases low-molecular-weight bioactive collagen peptides that act systemically. This narrative review synthesises in vitro, animal-model, and veterinary clinical evidence with explicit differentiation of evidence levels; literature was identified through structured searches of PubMed, Web of Science, and Google Scholar, covering peer-reviewed, English-language reports published between 2000 and January 2026, without a formal systematic protocol. Across rodent, porcine, and human pharmacokinetic studies, orally administered collagen hydrolysate is efficiently absorbed, with a fraction reaching the circulation as intact prolyl-hydroxyproline and hydroxyprolyl-glycine through the conserved PEPT1/PEPT2 transporters; reported bioavailability varies with source, dose, and method, so no single value generalises across species. Native collagen and larger collagen fragments engage structure-dependent receptors in vitro (α2β1 integrins, DDR1/DDR2, GPVI, LAIR-1/2) that require triple-helical or Gly-Pro-Hyp presentation, whereas it is not established that the di- and tripeptides that reach the circulation after oral dosing engage them; their systemic actions are partly attributable to intracellular routes, including the Keap1–Nrf2 axis, HDAC/HAT modulation, and glycine-dependent glutathione synthesis. The gut–collagen peptide axis, a model derived from rodent and cell-culture data, links microbial bile acid remodeling and FXR/TGR5 signaling to systemic effects. Current evidence supports validated use in canine and equine osteoarthritis; species-specific bioavailability studies in dogs and cats remain the priority. Full article

Leprosy presents a broad clinical–immunological spectrum, whose heterogeneity challenges early diagnosis and disease stratification. Metabolomic approaches have emerged as promising tools for identifying potential biomarkers associated with the disease’s pathophysiology. This study aimed to investigate metabolic profiles associated with the different clinical forms of leprosy using untargeted metabolomics in formalin-fixed paraffin-embedded (FFPE) tissue samples. A retrospective cross-sectional study was conducted with 55 patients classified according to the Ridley–Jopling spectrum. Metabolites were extracted from FFPE skin biopsies and analyzed by liquid chromatography–mass spectrometry (LC-MS). From 908 metabolites initially detected, 27 were retained after frequency filtering. Six metabolites ultimately met the criteria of one-way analysis of variance (ANOVA, p < 0.05) and fold-change (FC ≥ 2.0) for differential expression, while N-stearoyl tryptophan was identified as an additional candidate metabolite based on its contribution to multivariate group discrimination. These included 11-hydroperoxy-H4-neuroprostane, which showed a specific association with bacterial load, and the Gly-Pro-Lys tripeptide, which correlated with markers of infection progression. Metabolomics applied to FFPE samples proved feasible for discriminating the clinical spectrum of leprosy and annotating signatures associated with immune response. This approach represents an innovative strategy for exploratory biomarker discovery using archived histopathological samples in translational research. Full article

The tripeptide glutathione (GSH) is the most abundant cellular non-enzymatic antioxidant. The GSH system plays a crucial role in antioxidant defense against oxidative stress and in supporting cellular redox homeostasis, regulating the reduction of lipid peroxides, and protecting cells from ferroptosis depending on the GSH level, which is maintained in a state of dynamic equilibrium not only by the activities of GSH synthesis enzymes, transporters of GSH precursor amino acids, and GSH transporters, but also by the actions of GSH-related enzymes. Some GSH-related enzymes are key enzymes with antioxidant functions such as glutathione peroxidases (GPxs), especially GPx4, and glutathione S-transferases (GSTs), which use GSH as a co-substrate for the reduction of hydroperoxides to alcohols, whereas glutathione-specific gamma-glutamyl cyclotransferase 1 (ChaC1) degrades intracellular GSH, so they can correspondingly lead to suppression or induction of ferroptosis. Ferroptosis is characterized by a buildup of lipid peroxides due to excessive lipid peroxidation and iron accumulation, which results from redox imbalance between ferroptosis’s drivers and defense systems, including impaired cellular antioxidant systems, particularly disruptions of GSH metabolism. It appears pertinent to assess the influence on ferroptosis regulation by GSH-dependent enzymes that utilize the GSH pool in diverse ways. This review offers an updated exploration of the roles of GPx4, ChaC1, and GSTs in redox regulation of ferroptosis in cancer cells, with a focus on both the regulation of each enzyme’s activity and their possible interactions, considering the impact on the risk of ferroptosis induction. Full article

Spinal cord injury (SCI) is a devastating neurological disorder. The development of effective therapies to ameliorate the consequences of SCI represents a major challenge and a central priority of international biomedical research. The stromal vascular fraction (SVF) derived from adipose tissue possesses considerable functional potential. SVF is a heterogeneous mixture of cells that act synergistically. However, after local transplantation, SVF is rapidly cleared via the bloodstream, and its poor survival severely compromises therapeutic efficacy. To overcome this limitation, we employed a self-assembling peptide nanohydrogel HGF-RADA16-IKVAV (where HGF denotes the tripeptide histidine–glycine–phenylalanine) as a scaffold to enhance SVF retention and efficacy in a rat model of SCI. Implantation of SVF and HGF into the injured spinal cord demonstrated that this combined therapy significantly modulated the inflammatory response, increased neuronal survival, and promoted a denser network of axon tracts. Consequently, the SVF-encapsulated HGF hydrogel resulted in superior restoration of limb movement and reduced neuropathic pain. Proteomic analysis confirmed that the combined treatment shifted the injury-induced molecular landscape, particularly in immune and inflammatory pathways. Collectively, these findings demonstrate that this combinatorial strategy represents an effective therapeutic paradigm for SCI. Full article

Atopic dermatitis (AD) is a chronic skin disorder driven by Th2 immune dysregulation, persistent inflammation, and epidermal barrier defects. Oxidative stress acts as a major upstream factor in this process, amplifying inflammatory signals and worsening disease severity. While current treatments relieve acute symptoms, long-term application is often constrained by side effects and poor barrier restoration, pointing to a need for safer, multifaceted alternatives. Here, we formulated a complex of Torilis japonica extract (TJE) and GHK-Cu (Glycyl-L-histidyl-L-lysine copper(II)) complex and examined its anti-atopic and skin-regenerative properties using a TNF-α (Tumor necrosis factor-α)/IFN-γ (Interferon-γ)-stimulated HaCaT cell model. TJE decreased the expression of AD-related chemokines (TARC(Thymus and activation-regulated chemokine (CCL17)) and CTACK(Cutaneous T-cell-attracting chemokine (CCL27)) as well as IgE production, confirming the suppression of Th2-driven inflammation. An optimized 6:4 ratio (TJE:GHK-Cu) yielded the highest efficacy compared to individual treatments, indicating a synergistic interaction. TJE–GHK-Cu complex suppressed the transcription of key Th2 cytokines (IL-4, IL-5, IL-10, and IL-13) and promoted keratinocyte migration during wound healing assays. The formulation also displayed strong radical scavenging activity without compromising cell viability. These results demonstrate that the TJE–GHK-Cu complex provides simultaneous anti-inflammatory, antioxidant, and regenerative benefits, presenting a formulation warranting further investigation for managing AD. Full article

Sponge spicules have emerged as promising biomaterial scaffolds due to their biocompatibility and unique structural properties; however, achieving stable and bioactive functionalization remains a key challenge. The tripeptide GHK is known to promote collagen synthesis and wound repair, yet its therapeutic efficacy is often limited by rapid diffusion and instability. Here, we report ALTUM, a thiol-functionalized sponge spicule composite in which GHK is covalently conjugated via disulfide linkage to enable controlled and redox-responsive peptide delivery. ALTUM exhibited sustained GHK retention under physiological and storage conditions, while exposure to reduced glutathione (GSH) selectively accelerated peptide release through disulfide bond cleavage. This dual release behavior—long-term stability combined with reduction-triggered activation—distinguishes ALTUM from conventional delivery systems. The composite also demonstrated structural stability under thermal, cyclic, and photostability conditions. In an artificial human skin model, ALTUM enhanced dermal penetration of GHK and significantly increased collagen deposition in the dermal layer, demonstrating its capacity to promote collagen production within deeper skin tissue, compared to simple spicule–peptide mixtures. ALTUM was fabricated at an optimized spicule-to-peptide ratio of 3% (w/w), preserving the needle-shaped spicule morphology after surface modification. In vitro, ALTUM exhibited a sustained release profile, with GHK release markedly accelerated in the presence of 10 mM glutathione (GSH) compared with non-reductive conditions, reaching approximately 60% cumulative release over 35 days. In the bioprinted artificial human skin model, ALTUM delivered 9.72 ng/cm² of GHK, more than five-fold higher than the physical mixture of spicules and free GHK (1.9 ng/cm²), and significantly increased type I collagen expression in human dermal fibroblasts. Mechanistically, ALTUM-mediated delivery was associated with increased TGF-β expression and engagement of the SMAD signaling pathway, as indicated by increased phosphorylation of SMAD2/3, consistent with involvement of the TGF-β–SMAD axis in the observed collagen induction. Collectively, these findings establish ALTUM as a structurally stable, redox-responsive dermal delivery platform that enhances collagen synthesis and skin regeneration. Full article

Background/Objectives: Glutathione (GSH) is a fundamental tripeptide essential for maintaining cellular redox homeostasis, detoxification, and immune regulation. While GSH is synthesized endogenously, its levels typically decline with age, potentially increasing susceptibility to oxidative stress-related conditions. This review aims to discuss the benefits of GSH for the body and clarify the distinctions between dietary intake, endogenous synthesis, and supplementation as strategies for maintaining optimal GSH levels. Results: All studies show that GSH is a powerful antioxidant that plays a crucial role in maintaining various physiological processes in the body. It offers several benefits, primarily through its antioxidant properties and involvement in detoxification and immune regulation. This effect has potential implications for various health conditions associated with oxidative stress and inflammation, including neurodegenerative diseases, cardiovascular diseases, and metabolic disorders. Whether through diet or supplementation, ensuring adequate GSH levels can have profound benefits on longevity, immunity, and overall well-being. There are many foods known to contain GSH, and there are also many GSH supplements available on the market, but precursor-based supplements and compounds that activate GSH synthesis pathways show stronger and more consistent increases in human GSH. A diet rich in protein (for amino acids) and phytochemical-dense plants can support this, while targeted precursors (e.g., glycine, γ-glutamylcysteine) and Nrf2-activating foods or agents provide the most robust increases shown so far. Such supplementation can be beneficial, and it is most effective when combined with a diet rich in sulfur-containing foods and other nutrients that support GSH synthesis. Full article

Soil salinity as a major abiotic stressor has significantly affected crop production worldwide. However, plants have developed complex signaling networks that enable them to adapt and cope with such environmental shifts. Recent research has demonstrated the involvement of hydrogen sulfide (H₂S) in signaling cascades that link plant development with stress tolerance management. Similarly, glutathione (GSH), a non-enzyme antioxidant, and a vital tripeptide, has been found to protect plants from oxidative damage and regulate metabolic functions under abiotic stress. As a potential scavenger of ROS, GSH maintains cellular redox homeostasis through the ascorbate-GSH cycle and acts as a signaling molecule for the sulfur-status of plants. This review focusses on: (i) revisiting the concept and current status of soil salinity; (ii) highlighting its impact at cellular and whole-plant levels; (iii) elucidating the role of a H₂S and GSH in plant salt stress tolerance; and (iv) exploring the potential interactive roles of H₂S and GSH in mitigating salinity impacts. This review will provide valuable insights into the complex network involving H₂S and GSH, suggesting pathways for developing climate-resilient crops. Full article

With natural gas demand growing rapidly in this century, solidified natural gas technology holds great potential for strengthening energy resilience and delivering secure global gas supply. However, this technology is still impeded by insufficient gas uptake capacity and sluggish hydrate formation rate. Environmentally benign peptides have recently emerged as a novel class of green hydrate promoters. Different from single amino acids, peptides exhibit significant structural diversity owing to their varying sequences and combinations of their constituent amino acid monomers, showing great potential in hydrate-based applications. In this work, a unique tripeptide promoter, L-glutathione reduced (GSH), was employed, and the thermodynamic influence factors in methane hydrate formation were systematically investigated. Furthermore, as a highly hydrophilic amino acid, L-arginine was chosen for a comparative kinetic investigation with extremely hydrophilic GSH. The results revealed that experimental pressure showed a strong effect on the methane uptake rate, while it presented little influence on final methane storage capacity. The initial temperature greatly affected the average induction time, the rate of hydrate growth, and the yields of hydrates promoted by GSH. Increasing temperature resulted in a significant reduction in both the hydrate formation rate and methane uptake at 3 h. Therefore, in the GSH-promoted hydrate formation process, suitable pressure and temperature should be carefully chosen for desirable hydrate performance. Furthermore, the initial 15 min hydrate formation rate of 0.3 wt% L-arginine is 52.4% lower than that of 0.3 wt% GSH. The final methane uptake of 0.3 wt% arginine is substantially smaller than that of 0.3 wt% GSH. Although both GSH and arginine exhibit strong hydrophilic properties, the tripeptide GSH is more effective than the amino acid arginine in enhancing methane hydrate formation. The insights gained from this work offer a theoretical foundation for the application of peptide-based promoters in solidified natural gas technology. Full article