Geng Xiaoyu, Wang Ying, Li Huan, Song Liang, Luo Chen, Gu Xiaojie, Zhong Haixin, Chen Huilin, Chen Xinzhu, Wang Jianwei, Pan Zheng
College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China.
Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Chongqing, China.
Chin Med. 2024 Mar 22;19(1):53. doi: 10.1186/s13020-024-00921-1.
Lamiophlomis rotata (Benth.) Kudo (L. rotata), the oral Traditional Tibetan herbal medicine, is adopted for treating knife and gun wounds for a long time. As previously demonstrated, total iridoid glycoside extract of L. rotata (IGLR) induced polarization of M2 macrophage to speed up wound healing. In diabetic wounds, high levels inflammatory and chemotactic factors are usually related to high reactive oxygen species (ROS) levels. As a ROS target gene, nuclear factor erythroid 2-related factor 2 (NRF2), influences the differentiation of monocytes to M1/M2 macrophages. Fortunately, iridoid glycosides are naturally occurring active compounds that can be used as the oxygen radical scavenger. Nevertheless, the influence of IGLR in diabetic wound healing and its associated mechanism is largely unclear.
With macrophages and dermal fibroblasts in vitro, as well as a thickness excision model of db/db mouse in vivo, the role of IGLR in diabetic wound healing and the probable mechanism of the action were investigated.
Our results showed that IGLR suppressed oxidative distress and inflammation partly through the NRF2/cyclooxygenase2 (COX2) signaling pathway in vitro. The intercellular communication between macrophages and dermal fibroblasts was investigated by the conditioned medium (CM) of IGLR treatment cells. The CM increased the transcription and translation of collagen I (COL1A1) and alpha smooth muscle actin (α-SMA) within fibroblasts. With diabetic wound mice, the data demonstrated IGLR activated the NRF2/KEAP1 signaling and the downstream targets of the pathway, inhibited COX2/PEG2 signaling and decreased the interaction inflammatory targets of the axis, like interleukin-1beta (IL-1β), interleukin 6 (IL-6), apoptosis-associated speck-like protein (ASC), cysteinyl aspartate specific proteinase1 (caspase1) and NOD-like receptor-containing protein 3 (NLRP3).In addition, the deposition of COL1A1, and the level of α-SMA, and Transforming growth factor-β1 (TGF-β1) obviously elevated, whereas that of pro-inflammatory factors reduced in the diabetic wound tissue with IGLR treatment.
IGLR suppressed oxidative distress and inflammation mainly through NRF2/COX2 axis, thus promoting paracrine and accelerating wound healing in diabetes mice.
藏药独一味长期以来被用于治疗刀伤和枪伤。如先前所示，独一味总环烯醚萜苷提取物（IGLR）可诱导M2巨噬细胞极化以加速伤口愈合。在糖尿病伤口中，高水平的炎症和趋化因子通常与高活性氧（ROS）水平相关。作为一个ROS靶基因，核因子红细胞2相关因子2（NRF2）影响单核细胞向M1/M2巨噬细胞的分化。幸运的是，环烯醚萜苷是天然存在的活性化合物，可作为氧自由基清除剂。然而，IGLR对糖尿病伤口愈合的影响及其相关机制在很大程度上尚不清楚。
利用体外巨噬细胞和真皮成纤维细胞，以及体内db/db小鼠的厚度切除模型，研究IGLR在糖尿病伤口愈合中的作用及其可能的作用机制。
我们的结果表明，IGLR在体外部分通过NRF2/环氧化酶2（COX2）信号通路抑制氧化应激和炎症。通过IGLR处理细胞的条件培养基（CM）研究巨噬细胞与真皮成纤维细胞之间的细胞间通讯。CM增加了成纤维细胞内I型胶原（COL1A1）和α平滑肌肌动蛋白（α-SMA）的转录和翻译。对于糖尿病伤口小鼠，数据表明IGLR激活了NRF2/KEAP1信号通路及其下游靶点，抑制了COX2/PEG2信号通路，并减少了该轴的相互作用炎症靶点，如白细胞介素-1β（IL-1β）、白细胞介素6（IL-6）、凋亡相关斑点样蛋白（ASC）、半胱天冬酶1（caspase1）和含NOD样受体蛋白3（NLRP3）。此外，在接受IGLR治疗的糖尿病伤口组织中，COL1A1的沉积、α-SMA和转化生长因子-β1（TGF-β1）的水平明显升高，而促炎因子的水平降低。
IGLR主要通过NRF2/COX2轴抑制氧化应激和炎症，从而促进旁分泌并加速糖尿病小鼠的伤口愈合。
