ABSTRACT
BACKGROUND: Diabetic foot ulcers (DFU), as severe complications of diabetes mellitus (DM), significantly compromise patient health and carry risks of amputation and mortality. AIM: To offer new insights into the occurrence and development of DFU, focusing on the therapeutic mechanisms of X-Paste (XP) of wound healing in diabetic mice. METHODS: Employing traditional Chinese medicine ointment preparation methods, XP combines various medicinal ingredients. High-performance liquid chromatography (HPLC) identified XP's main components. Using streptozotocin (STZ)-induced diabetic, we aimed to investigate whether XP participated in the process of diabetic wound healing. RNA-sequencing analyzed gene expression differences between XP-treated and control groups. Molecular docking clarified XP's treatment mechanisms for diabetic wound healing. Human umbilical vein endothelial cells (HUVECs) were used to investigate the effects of Andrographolide (Andro) on cell viability, reactive oxygen species generation, apoptosis, proliferation, and metastasis in vitro following exposure to high glucose (HG), while NF-E2-related factor-2 (Nrf2) knockdown elucidated Andro's molecular mechanisms. RESULTS: XP notably enhanced wound healing in mice, expediting the healing process. RNA-sequencing revealed Nrf2 upregulation in DM tissues following XP treatment. HPLC identified 21 primary XP components, with Andro exhibiting strong Nrf2 binding. Andro mitigated HG-induced HUVECs proliferation, metastasis, angiogenic injury, and inflammation inhibition. Andro alleviates HG-induced HUVECs damage through Nrf2/HO-1 pathway activation, with Nrf2 knockdown reducing Andro's proliferative and endothelial protective effects. CONCLUSION: XP significantly promotes wound healing in STZ-induced diabetic models. As XP's key component, Andro activates the Nrf2/HO-1 signaling pathway, enhancing cell proliferation, tubule formation, and inflammation reduction.
ABSTRACT
BACKGROUND: Diabetic skin ulcers, a significant global healthcare burden, are mainly caused by the inhibition of cell proliferation and impaired angiogenesis. XB130 is an adaptor protein that regulates cell proliferation and migration. However, the role of XB130 in the development of diabetic skin ulcers remains unclear. AIM: To investigate whether XB130 can regulate the inhibition of proliferation and vascular damage induced by high glucose. Additionally, we aim to determine whether XB130 is involved in the healing process of diabetic skin ulcers, along with its molecular mechanisms. METHODS: We conducted RNA-sequencing analysis to identify the key genes involved in diabetic skin ulcers. We investigated the effects of XB130 on wound healing using histological analyses. In addition, we used reverse transcription-quantitative polymerase chain reaction, Western blot, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, immunofluorescence, wound healing, and tubule formation experiments to investigate their effects on cellular processes in human umbilical vein endothelial cells (HUVECs) stimulated with high glucose. Finally, we performed functional analysis to elucidate the molecular mechanisms underlying diabetic skin ulcers. RESULTS: RNA-sequencing analysis showed that the expression of XB130 was up-regulated in the tissues of diabetic skin ulcers. Knockdown of XB130 promoted the healing of skin wounds in mice, leading to an accelerated wound healing process and shortened wound healing time. At the cellular level, knockdown of XB130 alleviated high glucose-induced inhibition of cell proliferation and angiogenic impairment in HUVECs. Inhibition of the PI3K/Akt pathway removed the proliferative effects and endothelial protection mediated by XB130. CONCLUSION: The findings of this study indicated that the expression of XB130 is up-regulated in high glucose-stimulated diabetic skin ulcers and HUVECs. Knockdown of XB130 promotes cell proliferation and angiogenesis via the PI3K/Akt signalling pathway, which accelerates the healing of diabetic skin ulcers.