Byun Kyung-A, Park Hyun Jun, Oh Seyeon, Son Kuk Hui, Byun Kyunghee
Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea.
LIBON Inc., Incheon 22006, Republic of Korea.
Int J Mol Sci. 2025 Sep 7;26(17):8720. doi: 10.3390/ijms26178720.
Polynucleotide (PN), a high-molecular-weight DNA fragment derived from salmon and other fish sources, shows promising anti-aging and regenerative effects on the skin. This study investigated how PN enhances collagen synthesis, focusing on its effect on phosphoenolpyruvate carboxykinase 1 (PCK1) in senescent macrophages and its downstream effects on fibroblasts. Using in vitro senescent cell models and in vivo aged animal models, PN significantly upregulated the adenosine 2A receptor (A2AR), adenylate cyclase (AC), cyclic AMP (cAMP), protein kinase A (PKA), and cAMP response element-binding protein (CREB) in senescent macrophages. This led to increased PCK1 expression, which reduced oxidative stress and promoted M2 macrophage polarization, associated with elevated levels of interleukin-10 and tumor growth factor-β. Conditioned media from PN-treated macrophages enhanced SMAD family member 2 and signal transducer and activator of transcription 3 phosphorylation in senescent fibroblasts, increasing collagen I and III synthesis and reducing nuclear factor-κB activity. In vivo, PN administration elevated expression of the A2AR/AC/PKA/CREB/PCK1 pathway, reduced oxidative stress, increased M2 macrophage markers, and significantly improved collagen density and skin elasticity over time. Use of a PCK1 inhibitor attenuated these effects, highlighting the pivotal role of PCK1. Overall, PN modulates macrophage-fibroblast interactions via the CREB/PCK1 axis, enhancing collagen synthesis and counteracting age-related skin changes. PN has emerged as a promising therapeutic agent for skin rejuvenation by targeting cellular senescence and promoting extracellular matrix restoration.
多核苷酸（PN）是一种源自鲑鱼和其他鱼类的高分子量DNA片段，对皮肤显示出有前景的抗老化和再生作用。本研究调查了PN如何增强胶原蛋白合成，重点关注其对衰老巨噬细胞中磷酸烯醇丙酮酸羧激酶1（PCK1）的作用及其对成纤维细胞的下游影响。使用体外衰老细胞模型和体内衰老动物模型，PN显著上调衰老巨噬细胞中的腺苷2A受体（A2AR）、腺苷酸环化酶（AC）、环磷酸腺苷（cAMP）、蛋白激酶A（PKA）和cAMP反应元件结合蛋白（CREB）。这导致PCK1表达增加，从而降低氧化应激并促进M2巨噬细胞极化，这与白细胞介素-10和肿瘤生长因子-β水平升高相关。来自PN处理的巨噬细胞的条件培养基增强了衰老成纤维细胞中SMAD家族成员2以及信号转导和转录激活因子3的磷酸化，增加了I型和III型胶原蛋白的合成并降低了核因子-κB活性。在体内，随着时间的推移，PN给药提高了A2AR/AC/PKA/CREB/PCK1途径的表达，降低了氧化应激，增加了M2巨噬细胞标志物，并显著改善了胶原蛋白密度和皮肤弹性。使用PCK1抑制剂减弱了这些作用，突出了PCK1的关键作用。总体而言，PN通过CREB/PCK1轴调节巨噬细胞-成纤维细胞相互作用，增强胶原蛋白合成并对抗与年龄相关的皮肤变化。PN已成为一种有前景的治疗剂，通过靶向细胞衰老和促进细胞外基质恢复来实现皮肤年轻化。
