ADENOSINE

Collagen and matrix deposition by fibroblasts is an essential part of wound healing but also contributes to pathologic remodeling of organs leading to substantial morbidity and mortality. Adenosine, a small molecule generated extracellularly from adenine nucleotides as a result of direct stimulation, hypoxia, or injury, acts via a family of classical seven-pass G protein-coupled protein receptors, A2A and A2B, leading to generation of cAMP and activation of downstream targets such as PKA and Epac. These effectors, in turn, lead to fibroblast activation and collagen synthesis. The regulatory actions of these receptors likely involve multiple interconnected pathways, and one of the more interesting aspects of this regulation is opposing effects at different levels of cAMP generated. Additionally, adenosine signaling contributes to fibrosis in organ-specific ways and may have opposite effects in different organs. The development of drugs that selectively target these receptors and their signaling pathways will disrupt the pathogenesis of fibrosis and slow or arrest the progression of the important diseases they underlie.

Wound healing is a dynamic and complex process that involves a well-coordinated, highly regulated series of events including inflammation, tissue formation, revascularization and tissue remodeling. However, this orderly sequence is impaired in certain pathophysiological conditions such as diabetes mellitus, venous insufficiency, chronic glucocorticoid use, aging and malnutrition. Together with proper wound care, promotion of the healing process is the primary objective in the management of chronic poorly healing wounds. Recent studies have demonstrated that A(2A) adenosine receptor agonists promote wound healing in normal and diabetic animals and one such agonist, Sonedenoson, is currently being evaluated as a prospective new therapy of diabetic foot ulcers. We will review the mechanisms by which adenosine receptor activation affects the function of the cells and tissues that participate in wound healing, emphasizing the potential beneficial impact of adenosine receptor agonists in diabetic impaired healing.

Skin aging is a complex biological process. Skin aspect is considered as a sign of well-being and of beauty. In view of this, noninvasive and/or minimally invasive anti-aging strategies were developed. Adenosine, a well-known nucleoside, may play a role in skin rejuvenation. Adenosine receptors belong to the G protein-coupled receptors superfamily and are divided into four subtypes: A 1 , A 2A , A 2B , and A 3 . The adenosine receptors expressed by skin are mainly the A 1 and A 2A subtypes. In the hypodermis, adenosine through the A 1 receptor stimulates lipogenesis and adipogenesis. In the dermis, adenosine through the A 2A receptor subtype stimulates collagen production. Moreover, the nucleoside increases new DNA synthesis and subsequently protein synthesis in dermal cells. Activation of adenosine receptors by interacting with various skin layers may induce a decrease in the amount of wrinkles, roughness, dryness, and laxity. This article has reviewed the mechanisms through which adenosine modulates biological mechanisms in the skin tissues and the effect of preparations containing adenosine or its derivatives on the skin.

Wound healing and tissue repair are critical processes, and adenosine, released from injured or ischemic tissues, plays an important role in promoting wound healing and tissue repair. Recent studies in genetically manipulated mice demonstrate that adenosine receptors are required for appropriate granulation tissue formation and in adequate wound healing. A(2A) and A(2B) adenosine receptors stimulate both of the critical functions in granulation tissue formation (i.e., new matrix production and angiogenesis), and the A(1) adenosine receptor (AR) may also contribute to new vessel formation. The effects of adenosine acting on these receptors is both direct and indirect, as AR activation suppresses antiangiogenic factor production by endothelial cells, promotes endothelial cell proliferation, and stimulates angiogenic factor production by endothelial cells and other cells present in the wound. Similarly, adenosine, acting at its receptors, stimulates collagen matrix formation directly. Like many other biological processes, AR-mediated promotion of tissue repair is critical for appropriate wound healing but may also contribute to pathogenic processes. Excessive tissue repair can lead to problems such as scarring and organ fibrosis and adenosine, and its receptors play a role in pathologic fibrosis as well. Here we review the evidence for the involvement of adenosine and its receptors in wound healing, tissue repair and fibrosis.

Skin aging stems from intrinsic decline and external stressors that induce oxidative stress and mitochondrial damage, ultimately lowering cellular energy production and slowing epidermal turnover to cause wrinkles, dryness, and pigment imbalances. While disodium adenosine monophosphate (AMP2Na) is hypothesized to enhance cellular adenosine triphosphate production and restore epidermal metabolism, its broader anti-aging effects have remained underexplored. To address this, a multi-tiered study integrating in vitro, ex vivo, and clinical investigations was conducted. Specifically, a 12-week exploratory clinical trial involving female participants with facial hyperpigmentation (n = 23), alongside a short-term forearm study (n = 22), suggested that the AMP2Na-containing product could reduce wrinkles and hyperpigmentation while safely improving hydration, barrier function, skin lifting, and epidermal turnover with high participant satisfaction. Mechanistically, in vitro assays on human dermal fibroblasts showed that the formulation restored antioxidant enzyme activity and mitigated senescence. Ex vivo UVB-irradiated skin explant models corroborated these findings by revealing reduced melanin levels, preserved collagen and elastin networks, and an upregulation of key structural and barrier-related proteins. Ultimately, by potentially supporting epidermal turnover and restoring barrier function through this biomimetic mechanism, the AMP2Na-containing product might offer a promising option for alleviating wrinkles, dryness, and hyperpigmentation. Future randomized, vehicle-controlled clinical trials and comprehensive laboratory studies are warranted to validate its true potential in skin rejuvenation.

The Gi protein-associated A3 adenosine receptor (A3AR) is over-expressed in inflammatory cells, and this high expression is also reflected in the peripheral blood mononuclear cells of patients with autoimmune inflammatory diseases such as rheumatoid arthritis, psoriasis, and Crohn's disease. CF101, a selective agonist with high affinity to the A3AR, is known to induce robust anti-inflammatory effect in experimental animal models of adjuvant-, collagen-, and tropomyosin-induced arthritis. The effect is mediated via a definitive molecular mechanism entailing deregulation of the nuclear factor-κB (NF-κB) and the Wnt signal transduction pathways resulting in apoptosis of inflammatory cells. CF101 was found to be safe and well tolerated in all preclinical, phase I, and phase II human clinical studies. In two phase II clinical studies where CF101 was administered to rheumatoid arthritis (RA) patients as a stand-alone drug, a significant anti-rheumatic effect and a direct significant correlation were found between receptor expression at baseline and patients' response to the drug, suggesting that A3AR may be utilized as a predictive biomarker. The A3AR is a promising therapeutic target in rheumatoid arthritis and can be used also as a biological marker to predict patients' response to CF101. This is a unique type of a personalized medicine approach which may pave the way for a safe and efficacious treatment for this patient population.

Adenosine is a ubiquitous molecule with key regulatory and cytoprotective mechanisms at times of metabolic imbalance in the body. Among a plethora of physiological actions, adenosine has an important role in attenuating ischaemia-reperfusion injury and modulating the ensuing fibrosis and tissue remodeling following myocardial damage. Adenosine exerts these actions through interaction with four adenosine G protein-coupled receptors expressed in the heart. The adenosine A 2B receptor (A 2B AR) is the most abundant adenosine receptor (AR) in cardiac fibroblasts and is largely responsible for the influence of adenosine on cardiac fibrosis. In vitro and in vivo studies demonstrate that acute A 2B AR stimulation can decrease fibrosis through the inhibition of fibroblast proliferation and reduction in collagen synthesis. However, in contrast, there is also evidence that chronic A 2B AR antagonism reduces tissue fibrosis. This review explores the opposing pro- and anti-fibrotic activity attributed to the activation of cardiac ARs and investigates the therapeutic potential of targeting ARs for the treatment of cardiac fibrosis.

Olfactory receptors (ORs) are increasingly being recognized for their ectopic functions beyond olfaction, including roles in skin. Keratinocytes, the predominant cell type in the epidermis, not only provide structural integrity but also regulate inflammatory responses through activation of the nuclear factor kappa B (NF-κB) signaling pathway, which controls the expression of pro-inflammatory cytokines such as interleukin-1 beta (IL-1β), IL-6, and IL-8. In this study, we investigated the role of ectopically expressed ORs in keratinocyte inflammation. The five most highly expressed ORs at the mRNA level were identified, and their potential ligands were screened using an in silico molecular modeling approach, followed by in vitro validation with cyclic adenosine monophosphate-response element (CRE) reporter assays. We found that two odorants, α-ionone and methyl eugenol, functionally activated OR7D2-and OR10A4-associated signaling, respectively. To determine whether these ligands modulate inflammatory responses, NF-κB transcriptional activity was assessed after ligand treatment. OR7D2 activation by α-ionone significantly suppressed NF-κB activity, reducing expression of IL-1β and IL-6 at both mRNA and protein levels. In contrast, OR10A4 activation by methyl eugenol enhanced NF-κB activity and upregulated these cytokines. These findings suggest that ectopic OR-associated signaling may contribute to the regulation of inflammatory mediator expression in keratinocytes and provide a mechanistic basis for future studies on odorant-OR interactions in inflammatory skin responses.

Infected skin defects persist in a pathological state characterized by dysregulation of the immune microenvironment and impaired bioenergetics, requiring coordinated treatment strategies to remold them. Currently developing therapies with coordinated effects are often hampered by incomplete targets, high complexity, and limited clinical performance, underscoring the need for minimalist yet effective strategies that integrate both targets. Here, we address this challenge by designing a two-component system, the polyphosphate-gallic acid (polyP-GA) complex, with high biocompatibility and adaptability to different material forms ( e.g. , solution, spray, hydrogel, and paste). Based on the mutually complementary and enhanced effects of the two constituents, the polyP-GA complex markedly inhibits bacterial infection, reduces reactive oxygen species (ROS) accumulation, and suppresses inflammation evidenced by facilitated macrophage polarization toward the reparative M2 phenotype and broad related anti-inflammatory transcriptional effects. Concurrently, the polyP-GA complex restores mitochondrial function and elevates intracellular adenosine triphosphate (ATP) levels, thereby activating pathways essential for fibroblast migration and angiogenesis. In a mouse model of infected skin defects, application of the polyP-GA complex (in the form of hydrogel and spray sequentially) significantly accelerated wound closure, enhanced collagen deposition and neovascularization, and promoted functional tissue remodeling. This work demonstrates that the minimalist therapeutic design, built on the synergistic pairing of biocompatible but otherwise subtherapeutic agents polyP and GA, can effectively break the cycle of infection-driven regenerative arrest, achieving high performance in promoting the healing of infected skin defects.

Polydeoxyribonucleotide (PDRN) has been shown to have consistent regenerative and anti-inflammatory properties in a wide range of applications. Selective activation of the A2A receptor (A2AR) and induction of the phosphate scavenger system constitute its primary actions, which overlap the mechanism of skin regeneration after a surgical procedure; thus, PDRN can potentially be added to the post-surgical aesthetic surgery protocol of laser resurfacing, chemical peeling, microneedling, and radiofrequency. Literature search was conducted in the PubMed/MEDLINE (Medical Literature Analysis and Retrieval System Online), Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) databases with the following keywords: polydeoxyribonucleotide (PDRN) or polynucleotide, wound repair, aesthetic recovery, erythema, scar, lasers, and skin regeneration. No stipulated date limit was applied. Interventional and observational human studies, any available relevant preclinical evidence, and published systematic reviews were included. The studies were chosen based on their applicability to the biological processes of PDRN and their clinical application in skin repair situations that can be implemented in aesthetic practice. Narrative synthesis was used for thematic analysis. The pro-resolving immune reaction of PDRN works through a two-pronged mechanism: balancing the pro-inflammatory cytokine A2AR-mediated action (tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1 beta) and vascular endothelial growth factor-mediated nucleotide provisioning to growing keratinocytes and fibroblasts. There is human clinical evidence (including randomized controlled trials (RCTs), comparative cohort studies, and split-face trials) that PDRN enhances the period of re-epithelialization, erythema, scarring, and melanogenesis, which are the direct clinical outcomes with respect to post-procedural aesthetic recovery. PDRN has also shown non-inferior short-term cosmetic results compared to hyaluronic acid filler, with indications of greater biostimulatory stability. The adverse event profile in all published studies is invariably positive. The limitations of the technique, however, are a lack of RCTs (with human aesthetic cohorts), small sample sizes, variability in formulations, and a lack of long-term follow-up. Thus, the findings discussed in the current paper make PDRN an appealing and bio-plausible clinical partner in enhancing post-surgical recovery of patients undergoing aesthetic surgery. The available mechanistic and translational evidence establishes a credible biological basis for integrating PDRN into post-procedural care. On the basis of this evidence, its use may be considered a reasonable adjunct in clinical practice, subject to individual patient assessment and institutional protocol.

Psoriasis is a common chronic inflammatory skin disease characterized by epidermal hyperproliferation and immune dysregulation. However, local metabolic interactions remain incompletely understood, and biomarkers for disease activity and treatment response are still lacking. Current approaches such as skin biopsies or tape stripping are disruptive to the skin barrier and may cause scarring, limiting their repeated use. In contrast, microdialysis enables minimally invasive sampling of soluble mediators from intact skin. We applied untargeted proteomic and metabolomic profiling of skin microdialysates from lesional and nonlesional sites in patients with psoriasis and healthy controls to explore local pathophysiology and evaluate this technique's potential for monitoring disease severity and treatment response. Principal component analysis revealed distinct molecular signatures in psoriatic lesions, with separation by disease severity, resulting from elevated proinflammatory proteins (SERPINB3/4, FABP5), purine and pyrimidine metabolites (adenosine-5-monophosphate, 5'-cytidine monophosphate) and polyamines (spermidine and spermine). Pathway analysis confirmed upregulated nucleotide metabolism and polyamine biosynthesis alongside reduced histidine metabolism, consistent with hyperproliferation, immune activation, and barrier disruption. Importantly, lesional metabolomic profiles normalized in patients responding to systemic therapy, highlighting the utility of microdialysate profiling for tracking therapeutic efficacy. This study establishes microdialysate proteometabolomics as a minimally invasive platform for mechanistic studies, biomarker discovery, and personalized monitoring in psoriasis.

Staphylococcus epidermidis ( S. epidermidis ) is a common opportunistic pathogen in clinical settings. The widespread misuse of antibiotics has led to a continuous increase in its antimicrobial resistance, greatly complicating treatment. Drug repurposing, characterized by low cost, high safety, and short development cycles, represents an effective strategy for combating drug-resistant bacterial infections. This study aims to investigate the antibacterial activity of the antiparasitic drug resorantel against S. epidermidis and to preliminarily elucidate its antibacterial mechanism. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of resorantel against S. epidermidis were determined using the broth microdilution method. Disk diffusion assays, 2, 3-Bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilid (XTT) assays, and time‑kill curves were employed to evaluate the susceptibility of S. epidermidis to resorantel. Serial induction experiments were conducted to assess the potential for resistance development. Crystal violet staining and XTT assays were used to evaluate the inhibitory and eradication effects of resorantel on biofilms. The checkerboard microdilution method was performed to investigate the combined effects of rafoxanide with conventional antibiotics. Antibacterial mechanisms were preliminarily explored by assessing membrane permeability, proton motive force, intracellular adenosine triphosphate (ATP) levels, and propidium iodide staining. Finally, a murine skin abscess model was established to evaluate the in vivo antibacterial activity of resorantel. The MIC and MBC of resorantel against S. epidermidis were 2 μg/mL and 16 μg/mL, respectively. Disk diffusion assays demonstrated a pronounced antibacterial effect of resorantel against S. epidermidis . XTT assay results demonstrated that resorantel significantly reduced the viability of S. epidermidis ( P <0.05). Time‑kill curve analysis indicated that even 1/4×MIC of resorantel effectively inhibited bacterial proliferation. After continuous exposure for 15 d, S. epidermidis did not develop resistance to resorantel. Crystal violet staining and XTT staining both revealed that 1 μg/mL resorantel significantly inhibited biofilm formation, while 2 μg/mL resorantel significantly reduced preformed biofilms (all P <0.05). Resorantel altered the proton motive force, inhibited intracellular ATP synthesis, and disrupted bacterial cell membrane integrity. In the murine skin abscess model, resorantel treatment significantly reduced the bacterial burden within abscess tissues (all P <0.05). Resorantel exhibits both in vitro and in vivo antibacterial activity against S. epidermidis . Its antibacterial mechanism involves disruption of bacterial membrane integrity and proton motive force, as well as inhibition of intracellular ATP synthesis. 目的 : 表皮葡萄球菌是临床常见的机会致病菌，抗生素滥用致其耐药性不断攀升，治疗难度显著加大。药物再利用具有成本低、安全性高、周期短等优势，是应对耐药菌感染的有效策略。本研究旨在探究抗寄生虫药物雷琐太尔对表皮葡萄球菌的抗菌活性，并初步阐明其作用机制。 方法 : 采用微量肉汤稀释

Nitrogen mustard (HN2) is a highly reactive bifunctional alkylating agent that causes severe skin injury. To define its impact on keratinocyte bioenergetics and stress responses, we examined mitochondrial function, metabolism, and cell death signaling in human HaCaT cells. Seahorse analysis showed that HN2 caused time- and concentration-dependent suppression of oxidative phosphorylation, including reductions in basal, adenosine 5'-triphosphate-linked, and maximal oxygen consumption. Glycolytic activity was similarly impaired, with decreased extracellular acidification, reduced glucose-stimulated glycolysis, and loss of glycolytic capacity and reserve, indicating broad metabolic dysfunction. HN2-induced bioenergetic impairment triggered rapid nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulation of antioxidant and mitochondrial regulatory genes (HO-1, NQO1, GSTA4, and PGC1α). In parallel, HN2 activated multiple programmed cell death pathways, including apoptosis, autophagy, and ferroptosis, as evidenced by corresponding alterations in Bax, Bcl-xL, LC3-II, SQSTM1/p62, caspase-2, caspase-9, GPx4, TFRC, and ACSL4. Cell cycle analysis identified cells in G2/M as particularly susceptible to HN2, which exhibited enhanced apoptotic signaling. N -acetylcysteine attenuated Nrf2 activation, preserved mitochondrial and glycolytic function, and reduced activation of cell death pathways, demonstrating a central role for oxidative and electrophilic stress in HN2 toxicity. These findings reveal a novel mechanism by which HN2 disrupts keratinocyte bioenergetics to drive stress-dependent cell death and highlight antioxidant intervention as a potential strategy to mitigate HN2-induced skin injury.

Melanoma is a highly aggressive skin malignancy characterized by early metastasis, marked therapeutic resistance, and poor clinical outcomes in advanced disease. Increasing evidence indicates that immune dysregulation within the tumor microenvironment (TME) is a central determinant of melanoma progression, metastatic dissemination, and treatment failure. The melanoma immune microenvironment is shaped by complex interactions among tumor-associated macrophages, tumor-infiltrating lymphocytes, regulatory T cells, myeloid-derived suppressor cells, stromal cells, endothelial cells, and extracellular matrix components, together with hypoxia and acidosis, all of which cooperatively drive immune evasion, chronic inflammation, angiogenesis, and resistance to therapy. Mechanistically, cancer-associated fibroblasts promote immune tolerance by secreting CXCL12 and CCL17, thereby recruiting regulatory T cells and reinforcing a suppressive stromal niche; melanoma-derived factors and metabolic perturbations reprogram tumor-associated macrophages toward a pro-tumoral phenotype through lipid metabolic remodeling, endoplasmic reticulum stress, and immunosuppressive mediator production; and hypoxic stress amplifies CD39/CD73-dependent adenosine generation, which suppresses dendritic cell maturation and cytotoxic T-cell activity while facilitating immune escape. These immunosuppressive networks not only impair effective antitumor immune surveillance but also limit the long-term efficacy of immune checkpoint blockade and other systemic treatments. This review summarizes the immunopathological mechanisms underlying melanoma progression within the immune microenvironment and highlights emerging therapeutic strategies targeting immune and stromal crosstalk, providing a valuable theoretical basis for understanding melanoma immune escape and an important reference for the development of more effective and durable immunotherapeutic interventions.

UVB induces an epidermal damage response, including keratinocyte hyperplasia, immune cell infiltration, and the recruitment of follicular melanocyte stem cells to the interfollicular epidermis. In this study, we establish the oncofetal chromatin remodeling factor Hmga2 (high mobility group AT-hook 2) as a regulator of these phenotypes through a cAMP-driven process. In this study, we identify somatic tissue expression of Hmga2 in the basal layer of hyperplastic UVB-exposed keratinocytes. Loss of Hmga2 results in the near absence of epidermal hyperplasia, cutaneous neutrophil infiltration, and melanocyte stem cell migration to the interfollicular epidermis. RNA sequencing of UVB-exposed keratinocytes from wild-type and Hmga2 loss-of-function models reveals increased expression of Adora1 (adenosine A1 receptor), a negative regulator of cAMP. Administration of the cAMP pathway activator forskolin to Hmga2 -/- animals is sufficient to rescue melanocyte stem cell migration, thus highlighting the Hmga2-cAMP axis as a regulator in the cutaneous UVB response.