Inflammation, in conjunction with leukocytes, plays a key role in most acute kidney injury (AKI). Non-resolving renal inflammation leads to chronic fibrosis and renal failure. Resolvin D series (RvDs) and E series (RvEs), protectins, and maresins (MaRs) are endogenous omega-3 fatty acid-derived lipid mediators (LMs) that potently promote inflammation resolution by shortening neutrophil life span and promoting macrophage (Mf) non-phelogistic phagocytosis of apoptotic cells and the subsequent exit of Mfs from inflammatory tissue. 14S,21R-dihydroxy docosahexaenoic acid (14S,21R-diHDHA), a Mf-produced autacrine, reprograms Mfs to rescue vascular endothelia. RvD1, RvE1, or 14S,21R-diHDHA also switches Mfs to the phenotype that produces pro-resolving interleukin-10. RvDs or protectin/neuroprotectin D1 (PD1/NPD1) inhibits neutrophil infiltration into injured kidneys, blocks toll-like receptor -mediated inflammatory activation of Mfs and mitigates renal functions. RvDs also repress renal interstitial fibrosis, and PD1 promotes renoprotective heme-oxygenase-1 expression. These findings provide novel approaches for targeting inflammation resolution and LMs or modulation of LM-associated pathways for developing better clinical treatments for AKI.

Third-degree burn injuries pose a significant health threat. Safer, easier-to-use, and more effective techniques are urgently needed for their treatment. We hypothesized that covalently bonded conjugates of fatty acids and tripeptides can form wound-compatible hydrogels that can accelerate healing. We first designed conjugated structures as fatty acid–aminoacid1–amonoacid2–aspartate amphiphiles (Cn acid–AA1–AA2–D), which were potentially capable of self-assembling into hydrogels according to the structure and properties of each moiety. We then generated 14 novel conjugates based on this design by using two Fmoc/tBu solid-phase peptide synthesis techniques; we verified their structures and purities through liquid chromatography with tandem mass spectrometry and nuclear magnetic resonance spectroscopy. Of them, 13 conjugates formed hydrogels at low concentrations (≥0.25% w/v), but C8 acid-ILD-NH₂ showed the best hydrogelation and was investigated further. Scanning electron microscopy revealed that C8 acid-ILD-NH₂ formed fibrous network structures and rapidly formed hydrogels that were stable in phosphate-buffered saline (pH 2–8, 37 °C), a typical pathophysiological condition. Injection and rheological studies revealed that the hydrogels manifested important wound treatment properties, including injectability, shear thinning, rapid re-gelation, and wound-compatible mechanics (e.g., moduli G″ and G′, ~0.5–15 kPa). The C8 acid-ILD-NH₂(2) hydrogel markedly accelerated the healing of third-degree burn wounds on C57BL/6J mice. Taken together, our findings demonstrated the potential of the Cn fatty acid–AA1–AA2–D molecular template to form hydrogels capable of promoting the wound healing of third-degree burns.

Royal jelly and medical grade honey are traditionally used in treating wounds and infections, although their effectiveness is often variable and insufficient. To overcome their limitations, we created novel amphiphiles by modifying the main reparative and antimicrobial components, queen bee acid (hda) and 10-hydroxyl-decanoic acid (hdaa), through peptide bonding with specific tripeptides. Our molecular design incorporated amphiphile targets as being biocompatible in wound healing, biodegradable, non-toxic, hydrogelable, prohealing, and antimicrobial. The amphiphilic molecules were designed in a hda(hdaa)-aa1-aa2-aa3 structural model with rational selection criteria for each moiety, prepared via Rink/Fmoc-tBu-based solid-phase peptide synthesis, and structurally verified by NMR and LC–MS/MS. We tested several amphiphiles among those containing moieties of hda or hdaa and isoleucine–leucine–aspartate (ILD-amidated) or IL-lysine (ILK-NH₂). These tests were conducted to evaluate their prohealing and antimicrobial hydrogel properties. Our observation of their hydrogelation and hydrogel-rheology showed that they can form hydrogels with stable elastic moduli and injectable shear-thinning properties, which are suitable for cell and tissue repair and regeneration. Our disc-diffusion assay demonstrated that hdaa-ILK-NH₂ markedly inhibited Staphylococcus aureus. Future research is needed to comprehensively evaluate the prohealing and antimicrobial properties of these novel molecules modified from hda and hdaa with tripeptides.

(1) Background: Impeded resolution of inflammation contributes substantially to the pathogenesis of Alzheimer’s disease (AD); consequently, resolving inflammation is pivotal to the amelioration of AD pathology. This can potentially be achieved by the treatment with specialized pro-resolving lipid mediators (SPMs), which should resolve neuroinflammation in brains. (2) Methods: Here, we report the histological effects of long-term treatment with an SPM, maresin-like 1 (MarL1), on AD pathogenesis in a transgenic 5xFAD mouse model. (3) Results: MarL1 treatment reduced Aβ overload, curbed the loss of neurons in brains especially cholinergic neurons associated with cleaved-caspase-3-associated apoptotic degeneration, reduced microgliosis and the pro-inflammatory M1 polarization of microglia, curbed the AD-associated decline in anti-inflammatory Iba1⁺Arg-1⁺-M2 microglia, inhibited phenotypic switching to pro-inflammatory N1 neutrophils, promoted the blood–brain barrier-associated tight-junction protein claudin-5 and decreased neutrophil leakage in 5xFAD brains, and induced the switch of neutrophils toward the inflammation-resolving N2 phenotype. (4) Conclusions: Long-term administration of MarL1 mitigates AD-related neuropathogenesis in brains by curbing neuroinflammation and neurodegeneration, based on the histological results. These findings provide preclinical leads and mechanistic insights for the development of MarL1 into an effective modality to ameliorate AD pathogenesis.

Biofilm-associated bacterial infections are the major reason for treatment failure in many diseases including burn trauma infections. Uncontrolled inflammation induced by bacteria leads to materiality, tissue damage, and chronic diseases. Specialized proresolving mediators (SPMs), including maresin-like lipid mediators (MarLs), are enzymatically biosynthesized from omega-3 essential long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), by macrophages and other leukocytes. SPMs exhibit strong inflammation-resolving activities, especially inflammation provoked by bacterial infection. In this study, we explored the potential direct inhibitory activities of three MarLs on Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa and Escherichia coli) bacteria in their biofilms that are leading bacteria in burn trauma-related infections. We also examined the effects of MarLs on the bactericidal activities of a typical broad-spectrum antibiotic, carbenicillin (carb), on these bacteria in their preformed biofilms. The results revealed that MarLs combined with carbenicillin can inhibit the survival of Gram-positive and Gram-negative bacteria in their biofilms although MarLs alone did not exhibit bactericidal activity. Thus, our findings suggest that the combination of MarLs and carbenicillin can lower the antibiotic requirements to kill the bacteria in preformed biofilms.

Pro-regenerative lipid mediator 1 (PreM1) is a specialized pro-resolving lipid mediator that promotes wound healing and regenerative functions of mesenchymal stem cells (MSCs), endothelial cells, and macrophages. The healing of third-degree (3°) burns and regenerative functions of MSCs are enhanced by ACgel1, an arginine-and-chitosan-based protein-mimic hybrid hydrogel. Adipose-tissue derived microvascular fragments (MVFs) are native vascularization units and a rich source of MSCs, endothelial cells, and perivascular cells for tissue regeneration. Here we describe an innovative PreM1-MVFs-ACgel1 construct that incorporated PreM1 and MVFs into ACgel1 via optimal design and fabrication. This construct delivered PreM1 to 3°-burn wounds at least up to 7 days-post-burn (dpb), and scaffolded and delivered MVFs. PreM1-MVFs-ACgel1 promoted the healing of 3°-burns in mice, including vascularization and collagen formation. The re-epithelization and closure of 3° burn wounds were promoted by ACgel1, MVFs, PreM1, MVFs-ACgel1, PreM1-ACgel1, or PreM1-MVFs-ACgel1 at certain time-point(s), while PreM1-MVFs-ACgel1 was most effective with 97% closure and 4.69% relative epithelial gap at 13 dpb compared to saline control. The PreM1-ACgel1 and MVFs-ACgel1 also promoted blood vessel regeneration of 3°-burns although PreM1-MVFs-ACgel1 is significantly more effective. These PreM1- and/or MVF-functionalized ACgel1 have nonexistent or minimal graft-donor requirements and are promising adjuvant therapeutic candidates for treating deep burns.