FLASH radiotherapy involves delivering relatively high radiation doses at ultra-high dose rates (UHDRs) that are several orders of magnitude greater than those used in conventional radiotherapy (40 Gy s-1 versus 0.5-5 Gy min-1, respectively). Previous in vivo studies have shown that doses delivered with such UHDRs result in significant tumour killing while having less effect on normal tissues. Most of these in vivo studies were based on the use of charged particles such as electrons and protons. In this study we exposed cells [human epidermal melanocytes (HEM), MM96L melanoma cells, CCD841 colon epithelial cells and CaCo2 colorectal adenocarcinoma cells] grown in vitro to synchrotron-based X-ray beams delivered at either low dose rates or UHDRs to validate the FLASH effect. The FLASH effect that has been reported to occur under hypoxic conditions was also investigated using HEM and MM96L cells. Significant cell killing was observed at 48 h post-irradiation, when the cells were exposed to high dose (≥10 Gy) UHDRs compared with low dose rate beams inboth groups of cells. MM96L melanoma cells were ∼10% less resistant to UHDR than were HEM cells. A similar result was observed in CCD841 and CaCo2 cells. When the hypoxic melanocytes (HEM) were exposed to (≥10 Gy) UHDRs a minimal loss of cell viability was observed; however, when hypoxic MM96L cells were irradiated, significant cell losses were observed. These results show that a FLASH effect is evident in these skin and colon cells. Moreover, when MM96L melanoma cells were pretreated with 1 mM gold nanoparticles and exposed to 10 Gy UHDR X-rays there was a 50% dose enhancement observed where only 15% was observed at low dose rates.

Synthesis of desloratadine analogues as potent antifungal agents: in vitro and in vivo efficacy, and structure-activity relationship studies.

Forsythia suspensa accelerates wound healing by inhibiting neutrophil extracellular traps and activating Wnt/β-catenin via forsythoside A.

Phosphatidylserine-Rich circulating extracellular vesicles activate TAM receptor signaling to promote skin wound repair.

Integrated photoprotection and senescence modulation: A topical formulation counteracts cellular aging in human skin cells.

A single-cell atlas identifies oncogenic transcriptional programs and immune escape mechanisms in CTCL.

Arteriovenous malformations (AVMs) are vascular malformations that can occur in virtually all tissues throughout the body, most commonly in the brain, lungs, and cutaneous tissue. AVM pathophysiology is dynamic and multifactorial with multiple contributing cell types and biological processes. Inflammation and perivascular accumulation of macrophages are well-recognized components of AVM pathophysiology that have been demonstrated for decades in both patient AVM tissue and animal models. Despite the clinical and preclinical data identifying a role for macrophages in AVM pathophysiology, it remains poorly understood how macrophages mechanistically contribute to AVM initiation and progression. Recent single-cell RNA sequencing studies leveraging clinical AVM samples are beginning to shed new light on macrophage diversity in AVM tissue and direct macrophage-mediated effects on endothelial cell signaling pathways. This review will focus on fundamental aspects of AVM pathophysiology, mechanisms of macrophage-mediated vascular remodeling in AVMs, and potential future research directions focused on macrophage-mediated mechanisms in AVM pathophysiology.

Scarring remains an inevitable consequence of adult wound healing, often accompanied by functional, aesthetic, and psychological burdens. In contrast, fetal wound healing follows a fundamentally different trajectory, characterized by minimal inflammation, abundant hyaluronic acid, elevated type III collagen, and balanced matrix remodeling, culminating in regeneration without scar formation. This regenerative capacity is largely absent in adult tissues, which is the main incentive for understanding the pathophysiology of scarless healing phenotype to replicate such outcomes in adult tissues. The human amniotic membrane (hAM), as an embryogenic derivative, shares many structural and biochemical properties with fetal cutaneous tissue, positioning it as a promising biological tool to bridge adult wound healing toward a scarless, fetal-like outcome. hAM contains a rich milieu of growth factors, anti-inflammatory cytokines, and extracellular matrix components that support epithelialization, angiogenesis regulation, fibroblast modulation, and myofibroblast suppression. These effects are mediated through modulation of key signaling pathways including TGF-β/SMAD, PI3K/AKT, Wnt/β-catenin, and MAPK cascades; each central to the orchestration of fibrosis and regeneration. Furthermore, hAM's angio-modulatory behavior, antioxidant capacity, and context-dependent immune regulation contribute to a healing microenvironment that more closely mimics fetal conditions. In this review, we highlight the unique biology of fetal scarless healing which can be harnessed through the use of amniotic membrane-based therapies in adults. We highlight how the properties of hAM can help shift adult wound healing toward a more regenerative, less fibrotic outcome. We also examine different ways hAM is processed and applied in clinical settings and processing effects on anti-scar characteristic of hAM and discuss the main challenges that still need to be addressed, such as product standardization and optimizing treatment protocols, in a biomimetic way from scarless wound healing in embryo. Altogether, application of hAM presents a compelling and biologically sound approach to promote scarless wound healing in adult patients, a longstanding goal in regenerative medicine.

Abstract Introduction and aims Skin being the largest organ in the body has three layers: epidermis, dermis and hypodermis. The epidermal layer itself has multiple layers with self-renewal capabilities. Malignant transformation of keratinocyte carcinoma occurs owing to failure in the completion of differentiation programme, which can lead to dysplastic epithelium and precancerous cells in skin. E74-like factor (ELF)5 is a member of the E26 transformation-specific (ETS) family of transcription factors, predominantly expressed in some epithelial tissues including skin and is known to have an antitumorigenic role in other epithelial tissues. We have shown that ELF5 is essential for normal keratinocytes proliferation, differentiation and stem/progenitor maintenance in mouse skin and loss of ELF5 in human immortalized keratinocytes can lead to tumorigenesis. Further analysis is required to clearly define the role of ELF5 in malignant keratinocyte development. Methods Our investigations provide novel approach into the role of ELF5 in keratinocytes activities and its malignant transformation. Using cancer cell lines such as SCC-13, A431 and SCC-9, we transduced cells lentiviral particles (ELF5 control and ELF5 overexpression) with subsequent Fluorescence-activated cell sorting live cell sorting, followed by transcriptomic (RNA sequencing analysis) and proteomic analyses (quantitative polymerase chain reaction, Western blot analysis) and functional studies (migration transwell assay, soft agar and three-dimensional colony-forming assay) in vitro. Results Our findings suggest that overexpression of ELF5 is instrumental in reducing migrations and inhibiting skin tumorigenesis, thus representing a potential target for future therapeutic interventions in malignant. Conclusions Our data demonstrate an important understanding of ELF5 as a crucial regulator of keratinocyte malignant transformation and will provide better understanding of the novel transcriptional regulator in skin in many areas of research, including stem cell and cancer biology.

Despite advancements in burn care, older burn patients continue to experience disproportionately high mortality. Impaired wound healing is a major prognostic indicator of burn patient survival, yet the mechanisms underlying delayed repair in older adults remain poorly understood. Cellular senescence, a hallmark of aging, contributes to tissue dysfunction and impaired regeneration, making it a potential mediator of age-associated deficits in burn wound healing. Here, we investigated the role of cellular senescence in post-burn wound repair using a validated adult and aged murine full-thickness scald burn model and evaluated whether senolytic treatment with Dasatinib and Quercetin improves healing outcomes in aged mice. Thermal injury increased senescence-associated features in burn wounds, including SA-β-Gal-positive skin cells, and was associated with reduced myofibroblast-associated marker expression, increased extracellular matrix-degrading components, and delayed wound healing in aged mice. In contrast, senolytic treatment in aged burn mice reduced cellular senescence, demonstrated by a 4.4-fold decrease in SA-β-Gal-positive skin cells to baseline levels, increased α-SMA and Col1a1 expression, and improved macroscopic burn wound healing. Together, these findings suggest that cellular senescence is associated with impaired skin repair after burn injury and that senescence-targeting therapies may represent a potential strategy to improve wound healing outcomes in older burn patients.

Background/Objective: Ultraviolet A and B (UVAB) radiation is a major environmental factor that induces DNA damage and upregulates programmed death-ligand 1 (PD-L1) expression in skin cells, thereby contributing to immune evasion and impaired tissue repair. This study evaluated the protective effects of two purified compounds, Cinnamtannin B1 (CTB-1) and Cinnamtannin D1 (CTD-1), as well as cinnamon extract, in UVAB-irradiated human keratinocyte HaCaT cells. Methods: HaCaT cells were exposed to low (20 kJ/m2 UVA, 1.3 kJ/m2 UVB), medium (30 kJ/m2 UVA, 2 kJ/m2 UVB), and high (40 kJ/m2 UVA, 2.7 kJ/m2 UVB) UVAB doses of UVAB radiation. Dose-dependent effects of CTB-1 and CTD-1 (0, 5, 10, 25, and 50 µg/ mL) and cinnamon extract (0, 5, 10, 50, and 100 µg/mL), as well as time-dependent effects (12, 24, and 72 h), were evaluated by measuring PD-L1 expression, cell viability, and DNA damage. Results: CTD-1 was the most effective compound, significantly reducing UVAB-induced PD-L1 expression and DNA double-strand breaks without compromising cell viability. CTB-1 also demonstrated protective effects at specific doses and time points; however, higher concentrations reduced cell viability. Cinnamon extract was protective at low concentrations but cytotoxic at higher doses. Conclusions: CTD-1, CTB-1, and cinnamon extract attenuated UVAB-induced cellular damage in HaCaT cells, with CTD-1 demonstrating the most favorable protective profile. These findings support the potential of cinnamon-derived compounds as therapeutic candidates for preventing UVAB-induced skin damage and immune dysregulation.

Early post-op ambulation benefits burn survivors by expediting return to functional independence, preventing bedrest complications, and shortening hospital admissions. Despite published practice guidelines supporting early ambulation, significant variability in practice continues among burn centers, ranging between 0-14 days post-op. A 3-year retrospective review was completed of this 15 bed, adult verified burn center, to identify 149 patients who underwent split thickness skin graft (STSG) placement and/or Autologous Skin Cell Suspension (ASCS) application to their lower extremities (LE). Patients unable to ambulate at baseline or died during admission were excluded. LE involvement ranged from 1-28% TBSA (Median: 5%). Autograft placement included 83% meshed (1:1-3:1) STSG (n=125), 14.8% ASCS (n=22), and 1.3% sheet STSG (n=2). Grafts crossed joints on 119 patients including the knee (n=58), ankle (n=57), and foot (n=41). Initial ambulation occurred between POD 1-3 (Avg 1.05) with gait distance ranging from 2 to 1,500 ft (Avg 125.4 ft). Twelve patients experienced minor graft loss, which healed conservatively. Additional analysis compared patients with and without graft loss. There was no significance associated between initial POD ambulation and graft loss. However, graft loss was significantly association with history of stroke (p=0.006), renal disorder (p =0.012), and previous amputation (p = 0.006). These findings suggest that, within a structured protocol, early ambulation as soon as POD 1 may be safely implemented without increased graft loss risk. Incorporating standardized mobility protocols, including use of compression and individualized clinical assessment, may help reduce practice variability and support earlier functional recovery in burn survivors.

This study evaluates a nanostructured lipid carrier (NLC) formulation incorporating taperebá (Spondias mombin L.) peel extract and natural deep eutectic solvents (NaDES) as a sustainable antioxidant and anti-inflammatory platform for skin health. The peel extract, rich in polyphenols and carotenoids, was combined with NaDES-based lipids to improve stability and biocompatibility. The NLC-TAP-NaDES demonstrated an average particle size of approximately 150 nm. Human keratinocytes (HaCat) and melanocytes (SH-4) were used to assess cytotoxicity, oxidative stress, and cytokine modulation. NLC-TAP-NaDES showed low toxicity, preserved cell morphology, and significantly reduced superoxide and hydroxyl radicals under hydrogen peroxide stress. The formulation also modulated key cytokines: TNF-α increased under basal conditions, supporting angiogenesis, while IL-6 and IFN-γ were downregulated in keratinocytes, suggesting balanced inflammation and improved barrier function. These findings indicate that NLC-TAP-NaDES provides oxidative protection and modulates inflammatory signaling in skin cells, supporting its potential as a sustainable platform for cosmetic and dermatological applications derived from agricultural byproducts.

The rise of antimicrobial resistance (AMR) has created an urgent need for alternative therapies, particularly against biofilm-driven polymicrobial wound infections. Although green-synthesized nanoparticles have emerged as promising candidates, many studies lack rigorous validation of their quantum properties, fail to clarify mechanisms of action, and omit essential cytotoxicity profiling in human cells. To synthesize silver (Ag), copper (Cu), and zinc oxide (ZnO) quantum dots (QDs) using Quercus brantii acorn extract, confirm quantum confinement effects, and evaluate their antimicrobial efficacy, mechanistic basis, and biosafety in a clinically relevant murine wound model. QDs were synthesized via a standardized hydrothermal approach. Quantum confinement was verified using photoluminescence (PL) spectroscopy and Tauc plot analysis. Antimicrobial activity was tested against multidrug-resistant (MDR) clinical isolates of Pseudomonasaeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii, and Klebsiella pneumoniae. To differentiate oxidative stress from chemical artifacts, we employed non-thiol reactive oxygen species (ROS) scavengers (Trolox, Mannitol) and electron paramagnetic resonance (EPR). Cytotoxicity was assessed in human keratinocytes (HaCaT) and dermal fibroblasts (HDF). In vivo efficacy was evaluated in a murine excisional wound model infected with a polymicrobial consortium, tracking pathogen-specific clearance. Hydrogel rheology and stability were also characterized. Monodispersed, crystalline QDs with evidence consistent with quantum confinement were obtained (Ag-QDs: 7.2 ± 1.5nm; apparent bandgap: 2.85eV). Ag-QDs showed strong antimicrobial activity (MIC: 4.5-18.1µg/mL) and biofilm inhibition (up to 85% at ½×MIC). Mechanistic experiments, including EPR and ROS-scavenger assays, supported ROS-associated oxidative stress as a major contributor to bacterial killing under the tested conditions. Ag-QDs exhibited bactericidal activity at concentrations that were non-toxic to human skin cells in the employed assay (Selectivity Index for MRSA: 18.9). In vivo, topical application of an Ag-QD hydrogel (shear-thinning) accelerated wound closure to 95.3% by Day 14 (comparable to uninfected controls) and reduced the total bacterial burden by 4.2 log₁₀ CFU/g; all four pathogens were below the detection limit at the study endpoint. No overt systemic toxicity was observed based on the assessed biomarkers. Resistance development in serial passage assays was limited (2-fold MIC increase after 30 passages), noting that longer-term polymicrobial studies are required to fully evaluate resistance evolution. Q. brantii-mediated Ag-QDs are a promising green-synthesized nanomaterial with physicochemical characteristics consistent with quantum-dot behavior and notable antimicrobial and antibiofilm activity against MDR polymicrobial communities. In a preclinical murine wound model, topical Ag-QD hydrogel treatment was associated with accelerated wound closure and marked reductions in bacterial burden, alongside a favorable preliminary biosafety profile based on the endpoints assessed. Further studies are warranted to validate efficacy in clinically relevant chronic wound settings (e.g., diabetic models), to expand long-term toxicology, and to clarify resistance evolution and mechanistic pathways in polymicrobial systems.

Neuropathic pain affects over 20 million people in the United States, and painful diabetic neuropathy (PDN), a common complication of diabetes, is among its most prevalent and treatment-resistant forms. Although PDN is characterized by nociceptor dysfunction, the upstream peripheral mechanisms remain incompletely understood. While dorsal root ganglion (DRG) nociceptor hyperexcitability is a hallmark of PDN, emerging evidence suggests that nonneuronal skin cells may modulate nociceptor function. Here, we investigated whether epidermal Langerhans cells (LCs) contribute to neuropathic pain in PDN through neuroimmune signaling. Using a clinically relevant high-fat diet (HFD) mouse model, transgenic LC ablation, behavioral assays, human skin biopsies, and single-cell RNA seq of epidermis and DRG, we found that LC density increased in male diabetic mice in parallel with mechanical allodynia. In skin samples of people with PDN, LCs exhibited increased volume and dendritic complexity correlating with diabetes duration. Genetic depletion of LCs prevented mechanical allodynia and spontaneous pain-like behavior in male, but not female, HFD mice, revealing a sex-dependent contribution. Single-cell and interactome analyses identified male-specific inflammatory LC programs, including upregulation of chemokine signaling pathways. Consistently, LC secretome profiling showed increased CCL2 release, and local CCR2 blockade reversed allodynia. These findings identify epidermal LCs as peripheral regulators of PDN pain and highlight sex-dependent chemokine-mediated neuron-immune communication at the skin-nerve interface.

Anchusa species have traditionally been used to treat arthritis, gout, rheumatism, and skin wounds. Cisplatin (Cis) is a widely used chemotherapy drug associated with serious adverse effects. The study aimed to evaluate the potential synergistic anticancer effects of Anchusa azurea methanol extract (AAME) in combination with cisplatin against bone, skin, and oral cancer cell lines. This study involved a comprehensive metabolomic profiling of AAME, alongside cytotoxicity assays, cell cycle analysis, autophagy assessment, and evaluation of IL-17 and TNF-α pathway-related protein expression. AAME inhibited the proliferation of MG63 and HNO97 cancer cells while sparing HSF normal cells. AAME and Cis displayed synergistic effects (combination index < 1), especially in HNO97 cells. Treatments led to a synergistic decrease in TNF-α, p/t-JNK, IL-17, pNFκB/tNFκB, TRAF6, pMAPK/tMAPK ratios, and AP1 expression, also increased Casp3 and Casp8 levels, cell cycle arrest, and enhanced autophagy. The TPC and TFC of AAME are 5.46 mgGAE/gE and 0.13 mgRE/gE respectively, reflecting on its radical scavenging activity (EC50 209.67 µg/mL). HRLC-MS/MS leading to the annotation of 50 metabolites, including phenolics and flavonoid derivatives, notably with a prevalence of rosmarinic acid, quercetin, and kaempferol. In network pharmacology, the 90 genes are common between AAME constituents and oral cancer. A. azurea enhances cisplatin's anticancer effects by modulating IL-17, TNF-α, and apoptotic pathways, offering a promising adjuvant therapeutic strategy. Further in vivo investigations are warranted to validate the observed in vitro synergistic anticancer effects of A. azurea in combination with Cis.

In our method for synthesizing potent anticancer derivatives against both liver and breast tumors, a series of novel azo dispersion dyes was produced by coupling salicylaldehyde with diazonium ions derived from aryl amines to evaluate their anticancer efficacy while ensuring high safety for human normal cells. The diazenyl thiosemicarbazones (3a-f), resulting from the reaction of 5-arylazo-2-hydroxybenzaldehyde (1a-f) with thiosemicarbazide, subsequently reacted with ethyl chloroacetate to yield a series of diazenyl-4-thiazolidinones (4a-f). The chemical structures of these derivatives were well-characterized utilizing numerous analytical approaches, including FT-IR, 13C-NMR, 1H-NMR, and UV-Visible spectroscopy. Furthermore, the synthesized derivatives were assessed for their anticancer activity against HepG2 (liver cancer) and MDA-MB-231 (breast cancer) cell lines, compared to normal HSF cells. The synthesized compounds exhibited anticancer activity while maintaining high safety for normal cells. Compounds 3f, 4d, and 4f demonstrated significant cytotoxic efficacy against HepG2 cells, with selectivity index (SI) values of 109.47, 116.63, and 116.48, respectively. Additionally, the SI of the same compounds 3f (78.18), 4d (48.91), and 4f (71.82) displayed the highest cytotoxic property against MDA-MB-231 cells. Remarkably, neither of the tested azo compounds (3f and 4f) caused any detectable damage to normal skin cells. The findings of the molecular docking investigation were consistent with the biological assessments. The new synthesized diazenyl thiosemicarbazones have demonstrated potent anticancer activity. This is due to the presence of electron-donating groups at the para position of the diazo ring. The positive charge generated in this cationic form facilitates their adhesion to the negatively charged surfaces of the cell membrane of the treated cancer cells and enhances their permeability. However, some limitations of this study warrant further examination, such as the lack of a comprehensive pharmacokinetic analysis and long-term safety assessments. Furthermore, the pharmacokinetics and immunogenicity of the newly synthesized derivatives have not been studied. Furthermore, further research is needed to explore the effects of the synthetic derivatives in various animal models. These features should be investigated in future studies to clearly clarify the therapeutic potential and systemic performance of the synthesized derivatives. This study suggests that compounds 3f and 4f are very selective anticancer agents. in silico ADMET investigation exposed the superior pharmacokinetic properties of the newly synthesized derivatives and can serve to offer valuable insight for developing an effective cancer therapy.

Gallic acid, a catechin polyphenol in tea, completely inhibited angiogenesis in assays of human tissue at 10-3 M. Psoriasis is a skin disease caused by excessive secretion of angiogenenic factors by keratinocytes and stromal skin cells. In a double-blind pilot study, six subjects with bilateral plaque psoriasis were treated with 10-2 M gallic acid in a cream base or with a cream base placebo over 8 weeks, four times a day, and treatments were randomly assigned to either the left or the right side. The gallic acid cream was well tolerated, but it did not reduce the psoriasis more than the placebo. One subject wanted to extend treatment for an additional 8 weeks. At the end of 16 weeks, the subject had complete resolution of the psoriatic plaque treated with gallic acid cream. In contrast, the plaque treated with placebo cream was not reduced and stayed equivalent to week six. Gallic acid is inexpensive and does not cause side effects. A longer trial evaluating 10-2 M gallic acid cream for the treatment of psoriasis seems indicated.

The impact of avobenzone and oxybenzone on fibroblast and keratinocyte membranes. Searching for the role of lipids in the effect of UV filters on skin cells.

Chronic pruritus is a debilitating symptom accompanying numerous inflammatory skin diseases and remains a major therapeutic challenge. Neurogenic inflammation plays a central role in its pathogenesis, with the tachykinin substance P acting as a key mediator at the interface of the nervous system, immune cells, and cutaneous tissues. While substantial research has focused on substance P signaling via the neurokinin-1 receptor, clinical trials targeting this pathway have yielded inconsistent results, suggesting an incomplete understanding of substance P-mediated mechanisms in pruritic disorders. This review broadens the current perspective by highlighting the importance of substance P metabolism and the biological activity of its metabolites in pruritus-related diseases. Many C-terminal substance P metabolites retain neurokinin 1-receptor affinity but induce biased intracellular signaling. In contrast, N-terminal metabolites can activate alternative receptors such as mas-related G protein-coupled receptor X2, promoting mast cell degranulation, neurogenic inflammation, and itch, or exert counter-regulatory effects via yet unidentified targets. Importantly, the expression and activity of substance P-degrading proteases are altered in pruritic skin diseases, shifting the balance toward biologically active, pruritogenic metabolites. In conclusion, substance P, its metabolites, receptor isoforms, and metabolizing enzymes form a complex regulatory network that fine-tunes itch, pain, and inflammatory signaling. A deeper understanding of this interplay may explain the limited efficacy of current therapeutic approaches and might offer novel targeted treatment strategies in chronic pruritus.