20(S)-Protopanaxadiol enhances angiogenesis via HIF-1α-mediated VEGF secretion by activating p70S6 kinase and benefits wound healing in genetically diabetic mice.
Zhang Er-Yun,Gao Bo,Shi Hai-Lian,Huang Ling-Fang,Yang Li,Wu Xiao-Jun,Wang Zheng-Tao
Experimental & molecular medicine
Impaired angiogenesis is one of the crucial factors that impede the wound healing process in diabetic foot ulcers (DFUs). In this study, we found that 20(S)-protopanaxadiol (PPD), an aglycone of ginsenosides in Panax notoginseng, stimulated angiogenesis and benefited wound healing in genetically diabetic mice. In HUVECs, PPD promoted cell proliferation, tube formation and VEGF secretion accompanied by increased nuclear translocalization of HIF-1α, which led to elevated VEGF mRNA expression. PPD activated both PI3K/Akt/mTOR and Raf/MEK/ERK signaling pathways in HUVECs, which were abrogated by LY294002 and PD98059. Furthermore, these two pathways had crosstalk through p70S6K, as LY294002, PD98059 and p70S6K siRNA abolished the angiogenic responses of PPD. In the excisional wound splinting model established in db/db diabetic mice, PPD (0.6, 6 and 60 mg ml) accelerated wound closure, which was reflected by a significantly reduced wound area and epithelial gaps, as well as elevated VEGF expression and capillary formation. In addition, PPD activated PI3K/Akt/ERK signaling pathways, as well as enhanced p70S6K activity and HIF-1α synthesis in the wounds. Overall, our results revealed that PPD stimulated angiogenesis via HIF-1α-mediated VEGF expression by activating p70S6K through PI3K/Akt/mTOR and Raf/MEK/ERK signaling cascades, which suggests that the compound has potential use in wound healing therapy in patients suffering from DFUs.
10.1038/emm.2017.151
Exosomes Derived from Human Endothelial Progenitor Cells Accelerate Cutaneous Wound Healing by Promoting Angiogenesis Through Erk1/2 Signaling.
Zhang Jieyuan,Chen Chunyuan,Hu Bin,Niu Xin,Liu Xiaolin,Zhang Guowei,Zhang Changqing,Li Qing,Wang Yang
International journal of biological sciences
Chronic skin wounds represent one of the most common and disabling complications of diabetes. Endothelial progenitor cells (EPCs) are precursors of endothelial cells and can enhance diabetic wound repair by facilitating neovascularization. Recent studies indicate that the transplanted cells exert therapeutic effects primarily via a paracrine mechanism and exosomes are an important paracrine factor that can be directly used as therapeutic agents for regenerative medicine. However, application of exosomes in diabetic wound repair has been rarely reported. In this study, we demonstrated that the exosomes derived from human umbilical cord blood-derived EPCs (EPC-Exos) possessed robust pro-angiogenic and wound healing effects in streptozotocin-induced diabetic rats. By using a series of in vitro functional assays, we found that EPC-Exos could be incorporated into endothelial cells and significantly enhance endothelial cells' proliferation, migration, and angiogenic tubule formation. Moreover, microarray analyses indicated that exosomes treatment markedly altered the expression of a class of genes involved in Erk1/2 signaling pathway. It was further confirmed with functional study that this signaling process was the critical mediator during the exosomes-induced angiogenic responses of endothelial cells. Therefore, EPC-Exos are able to stimulate angiogenic activities of endothelial cells by activating Erk1/2 signaling, which finally facilitates cutaneous wound repair and regeneration.
10.7150/ijbs.15514
Adipose-derived stem cells promote diabetic wound healing via the recruitment and differentiation of endothelial progenitor cells into endothelial cells mediated by the VEGF-PLCγ-ERK pathway.
Chen Lang,Zheng Qian,Liu Yingping,Li Linling,Chen Xianzhuo,Wang Lan,Wang Lei
Archives of biochemistry and biophysics
Adipose-derived stem cell (ADSC) therapy is a promising treatment strategy for wound healing; however, the mechanism underlying this effect remains unclear. In the present study, we aimed to explore the influence of ADSC-derived VEGF on diabetic wounds and its role in modulating endothelial progenitor cells. The effect of ADSCs and ADSC-derived VEGF in vivo was investigated using a diabetic wound healing model, and inflammatory factors, such as IL-6, IL-10, and TNF-α, were detected. RT-qPCR and western blot analysis were used to detect the expression of downstream targets. In addition, the role of ADSC-derived VEGF in modulating endothelial progenitor cells (EPCs) was investigated using EdU assay, CD-31 immunofluorescence, and Transwell assay in vitro. The results show that ADSCs accelerated diabetic wound tissue closure and decreased the expression of inflammatory factors, such as IL-6, IL-10, and TNF-α. Further molecular mechanism studies indicated that coculturing EPCs with ADSC--conditioned medium enhanced the proliferation, mobilization and differentiation of EPCs into endothelial cells. This enhancement was inhibited when the expression of the VEGF downstream signal molecules VEGFR2, PLCγ, and ERK1/ERK2 was blocked, indicating that ADSCs might accelerate diabetic wound healing through the recruitment and differentiation of EPCs mediated by VEGF. Overall, the results of the study revealed that ADSCs could promote diabetic wound healing through the recruitment and differentiation of EPCs via angiogenesis effects regulated by the VEGF-PLCγ-ERK1/ERK2 pathway and suppression of the inflammatory response. In addition, it will be helpful to establish further understanding of ADSC therapy for clinical application.
10.1016/j.abb.2020.108531
The signaling pathways of traditional Chinese medicine in promoting diabetic wound healing.
Zhou Xin,Guo Yanling,Yang Kun,Liu Peng,Wang Jun
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:The diabetic wound is one of the common chronic complications of diabetes, which seriously affects patients' quality of life and even causes disability and death. Traditional Chinese medicine (TCM) is a unique and precious resource in China, which has a good curative effect and safety. At present, it has been found that Chinese herbal compounds and effective active ingredients can effectively promote diabetic wound healing, and its mechanism needs to be further studied. Signaling pathways are involved in the pathogenesis and progression of diabetic wounds, which is one of the main targets for the pathologic mechanism of diabetic wounds and the pharmacological research of therapeutic drugs. AIM OF THE REVIEW:This study has been carried out to reveal the classical signaling pathways and potential targets by the action of TCM on diabetic wound healing and provides evidence for its clinical efficacy. MATERIALS AND METHODS:"diabetic wound", "diabetic foot ulcer", "traditional Chinese medicine", "natural plant" and "medicinal plant", were selected as the main keywords, and various online search engines, such as PubMed, Web of Science, CNKI and other publication resources, were used for searching literature. RESULTS:The results showed that TCM could regulate the signaling pathways to promote diabetic wound healing, such as Wnt, Nrf2/ARE, MAPK, PI3K/Akt, NF-κB, Notch, TGF-β/Smad, HIF-1α/VEGF, which maintaining inflammatory interaction balance, inhibiting oxidative stress and regulating abnormal glucose metabolism. CONCLUSION:The effect of TCM on diabetic wound healing was reflected in multiple levels and multiple pathways. It is envisaged to carry out further research from precision-targeted therapy, provide ideas for screening the core target of TCM in treating diabetic wounds and create modern innovative drugs based on this target.
10.1016/j.jep.2021.114662
Propranolol regulates ERK1/2 signaling pathway and promotes chronic wound healing in diabetic rats.
Chang X,Li S,Xue X-D,Chang F
European review for medical and pharmacological sciences
OBJECTIVE:This study aimed to investigate if propranolol could regulate ERK1/2 signaling pathway and promote chronic wound healing in diabetic rats. MATERIALS AND METHODS:Twenty-two rats were used to establish a diabetic chronic wound animal model. They were randomly separated into two groups: the propranolol group and the control group. The propranolol group was treated with propranolol ointment and the control group was treated with propranolol matrix cream to cover the wound surface. The expression of the p-ERK1/2 protein was detected by the Western Blot. RT-qPCR was used to detect the expression of VEGF. The concentrations of IL-6 and TNF-α were detected by ELISA. RESULTS:The body weight of rats was significantly reduced after type 2 diabetes mellitus modeling. The healing rate of rats in the control group was significantly lower than that in the propranolol group (p<0.05). There was a significant increase in the expression of the p-ERK1/2 protein in the wound tissue of the propranolol group compared with that in the control group, except for the 11th day (p<0.05). The relative expression of Vascular Endothelial Growth Factor (VEGF) in the propranolol group was significantly higher than that in the control group on the 2nd day (p<0.05), while the relative expression of VEGF in the propranolol group was significantly increased on the 11th day after modeling (p<0.05). On the 20th day, the expressions of IL-6 and TNF-α in the propranolol group were significantly higher than those in the control group, and there were significant differences (p<0.05). It was found that the IL-6 and TNF-α expressions in the propranolol group reached the peak on the 11th day and then gradually decreased (p<0.05). CONCLUSIONS:The results indicated that propranolol can accelerate the healing of diabetic wounds by regulating the expression of VEGF by phosphorylation of ERK1/2 protein, thus promoting chronic wound healing in diabetes.
10.26355/eurrev_201905_17962
Kanglexin accelerates diabetic wound healing by promoting angiogenesis via FGFR1/ERK signaling.
Zhao Yixiu,Wang Xinhui,Yang Shuang,Song Xia,Sun Na,Chen Chao,Zhang Yannan,Yao Dahong,Huang Jian,Wang Jinhui,Zhang Yan,Yang Baofeng
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Diabetic foot is one of the main causes of non-traumatic amputation. However, there is still lack of effective drugs to treat diabetic foot in clinical practice. Kanglexin (KLX) is a new anthraquinone compound with cardiovascular protective effects. Here we report that KLX accelerates diabetic wound healing by promoting angiogenesis via FGFR1/ERK signaling. Firstly, KM mice were injected (ip) with streptozocin to establish type 1 diabetic model. The full thickness wound with the diameter of 5 mm was prepared on the back of each mice. The wounds were treated with KLX once a day for 14 consecutive days. Results showed that KLX significantly accelerated the closure of diabetic wounds. Pathological studies of skin tissues around the wounds showed that KLX promoted the formation of granulation tissue and new blood vessels, increased collagen deposition and reduced inflammatory cell infiltration. Besides, KLX significantly alleviated advanced glycation end products (AGEs) - induced abnormal proliferation, migration and tubule formation of human umbilical vein endothelial cells (HUVECs), and up-regulated phospho-ERK1/2 both in the diabetic wound tissue and AGEs - treated HUVECs. Moreover, molecular docking results indicated that KLX had the potential to bind with FGF receptor 1 (FGFR1), and subsequent experiments confirmed that FGFR1 inhibitor PD173074 reversed the effect of KLX on promoting the phosphorylation of ERK1/2 and angiogenesis, suggesting that KLX promoted angiogenesis through FGFR1/ERK signaling. In conclusion, our study provides a new effective compound for treating diabetic wounds. More importantly, KLX has the potential to be developed as a topical drug to promote diabetic wound healing.
10.1016/j.biopha.2020.110933