| Background:Diabetic foot Ulcer(DFU)is a common complication of diabetes in clinic.As a typical chronic and intractable ulcer in the field of wound repair,DFU will recurs and will not heal for a long time.Patients with severe ischemia and infection will often experience toe amputation,which may lead to life-threatening sepsis.Western medicine mainly treats the disease by controlling blood sugar,preventing infection,improving circulation,nourishing nerve,changing dressing for wound debridement and so on.Traditional Chinese medicine is effective in the treatment of DFU and shows great advantages in wound treatment.It is often used to improve local circulation,relieve pain,promote angiogenesis and tissue regeneration,and accelerate wound healing.The application of traditional Chinese medicine has greatly reduced the disability and mortality caused by refractory ulcers.Danggui Buxue decoction was first published in Li Dongyuan’s Theory of differentiation of Internal and external injuries during the Jin and Yuan dynasties.It is widely used in various system diseases in clinic.With the deepening of the modernization of traditional Chinese medicine,its role in regulating angiogenesis has been excavated and confirmed.Modern studies have found that Notch signaling pathway regulates all stages of angiogenesis and plays an important role in the structure and function of neovascularization under the continuous regulation of this pathway.However,there are few studies on the effect of Danggui Buxue decoction on angiogenesis in wound repair,and wound angiogenesis has the attribute of "blood" in the theory of qi and blood in traditional Chinese medicine.Therefore,it is proposed that Danggui Buxue decoction can promote the angiogenesis of DFU wound by regulating Notch signal pathway through "tonifying qi and promoting blood",so as to replenish qi and blood,promote muscle and flesh,and then promote wound healing.First of all,through the retrospective analysis of clinical research,the overall clinical syndrome,local wound syndrome,laboratory indicators and major complications of DFU patients.Secondly,through the tools of bibliometrics,we excavate and analyze the research hotspots and trends in the field of angiogenesis of diabetic foot in recent years.Finally,animal experiments were conducted to verify that Danggui Buxue decoction and different proportions of Astragalus and Angelica regulated different targets of Notch pathway to promote DFU angiogenesis,accelerate wound healing,and further explore the modern medical target of "Buqi Shengxue" in regulating wound angiogenesis under the guidance of "Buqi Shengxue" theory.Objective:Through retrospective study and analysis of the influencing factors leading to the incidence and aggravation of DFU,this paper summarizes the TCM syndrome characteristics of DFU patients,analyzes the risk factors of different TCM syndrome types of DFU,and further explores the TCM pathogenesis of DFU,in order to provide reference for individual diagnosis and treatment of TCM syndrome differentiation and treatment of DFU.Through bibliometric methods to evaluate the research hotspots and trends in the field of angiogenesis of diabetic foot in recent years,to provide research basis and ideas for TCM intervention in DFU wound angiogenesis and promote wound healing,and to provide guidance for the modernization of traditional Chinese medicine.Through animal experimental study,to explore the curative effect and mechanism of Danggui Buxue decoction in promoting angiogenesis of DFU wound and promoting wound healing,and to analyze the effectiveness of different proportions of Radix Astragali and Angelica sinensis in intervention of DFU wound angiogenesis,so as to provide modern medical basis for Danggui Buxue decoction in the treatment of DFU wound and modern molecular biological basis for enriching and developing the theory of replenishing qi and promoting blood circulation to regulate wound angiogenesis.Methods:1.Retrospective clinical study:collect the general condition,clinical symptoms and signs,laboratory examination,TCM syndrome differentiation,four diagnostic information and local wound syndrome of DFU patients in our hospital,analyze the influencing factors of DFU incidence and aggravation,summarize the TCM syndrome characteristics of DFU patients,and use statistical methods to analyze the risk factors of DFU patients with different syndrome types.2.Bibliometric analysis:the related literatures about angiogenesis of diabetic foot from the core data set of WebofScience to December 31,2022 were searched.VOSviewer,CiteSpace and R packet "bibliometrix" were used for bibliometric analysis,and the annual publication volume,journals,countries,institutions,authors,and frequency and clustering of keywords in this field were statistically analyzed.Animal experiment:the rat model of DFU wound was established,and the representative prescription "Danggui Buxue decoction" and its different proportion of Radix angelicae Sinensis were selected to intervene.By observing the general condition of rats and wound healing,HE staining was used to observe inflammatory cells,fibroblasts and sweat glands in dermis,and immunohistochemical staining was used to determine the optical density of positive expression of VEGF and FN.Western blot detection of Notchl,D114 and Jaggedl protein expression in Notch pathway in wound tissue.Results:1.With the increase of age,the Wanger grade of DFU patients also increased gradually.The prevalence rate of male DFU patients was about twice that of female patients,and the age of onset was significantly lower than that of female patients.The lower extremities and feet of DFU patients were often accompanied by abnormal sensation,skin temperature,skin color,humidity,edema and dorsalis pedis artery pulsation.The lower limbs felt intermittent claudication,numbness,burning and rest pain.The skin temperature is often decreased,and the skin color is often red,swollen and dark red;often accompanied by edema of the knee joint and foot and dry and chapped skin,and the Yang pulse weakens or even disappears.Foot fungal infection and callus in foot compression area often exist in patients with DFU,which are the main risk factors for the occurrence of DFU.DFU wounds are often characterized by a small amount of pus,yellow and white color,filthy texture and smelly smell;wounds are mostly covered by carrion and closely attached;granulation is thick and dark red,less epithelium.Specific to different TCM syndrome types,DFU patients in different syndrome types of pus quantity,color and smell,the number of carrion,wound epithelium distribution in different TCM syndrome types in the distribution of statistical differences.The increased risk of DFU in diabetic patients with diabetic nephropathy and retinopathy suggests that microvascular complications represented by diabetic nephropathy and retinopathy are one of the important causes of DFU,and long-term poor blood glucose control is still an important factor in the occurrence of DFU.Blood coagulation,inflammatory indexes and renal function reflect the progress and prognosis of DFU to some extent.The frequency of different TCM syndrome types of DFU is related to many factors such as lower limb and foot syndrome,wound syndrome and laboratory index.Through the correlation between routine objective index and TCM syndrome type of DFU patients,the relevant objective index is used as an auxiliary basis for syndrome differentiation and treatment of DFU patients,which is conducive to the further integration and development of integrated traditional Chinese and western medicine in the treatment of DFU.2.The number of related literatures in the field of angiogenesis of diabetic foot is increasing year by year from 2019 to 2022,and the number of related literatures has increased rapidly in the last four years(2019-2022),which indicates that the research of angiogenesis in diabetic foot is in an explosive period.more and more scholars begin to pay attention to it.Research institutions in China and the United States have an absolute advantage in the literature on angiogenesis of diabetic foot.The research on angiogenesis of diabetic foot is mainly published in basic research and clinical research related journals,which indicates that the current related research has entered the clinical verification from the basic research stage.In recent years,the key words focused on angiogenesis in DFU include vascular endothelial growth factor,inflammation,chronic wound,mesenchymal stem cells,hydrogel,exocrine,hypoxia inducible factor and hyperbaric oxygen.3.In the ulcer model of diabetic rats,the expression of Notchl and Jaggedl protein in Notch signal pathway was inhibited,while the expression of DLL4 protein was up-regulated,VEGF and FN expression was decreased,wound angiogenesis was difficult and healing time was prolonged,which may be one of the mechanisms of DFU wound angiogenesis difficulty.On the 28th day after intragastric administration of Danggui Buxue decoction,it was found that Notchl and Jagged1 protein were up-regulated and DLL4 protein was down-regulated in DFU rats compared with model group.Immunohisto-chemistry showed that the expression of VEGF and FN in wound tissue of DFU rats was higher than that of model group.It is suggested that Danggui Buxue decoction can inhibit the expression of DLL4 in Notch signal pathway,up-regulate Notchl and Jaggedl,promote wound angiogenesis and accelerate wound healing.The classic Astragalus and Angelica 5:1 ratio of Danggui Buxue decoction has obvious advantages in up-regulating the expression of VEGF and FN and wound healing compared with the other two groups;and through the observation of wound histopathology,it is found that the ratio of Radix Astragali and Angelica at 5:1 can improve the inflammatory response of DFU wound,promote the functional proliferation and migration of fibroblasts and skin appendage regeneration,and promote the re-epithelialization of DFU wound.Through the detection of proteins related to Notch1-Dll4/Jagged1 signal pathway,we found that the increase of the proportion of astragalus in Danggui Buxue decoction was positively correlated with the expression of Notchl and Jaggedl protein,and negatively correlated with DLL4 protein.Conclusion:1.With the increase of age,the Wanger grade of DFU patients is aggravated,and the incidence of male is twice as high as that of female.It is often accompanied by intermittent claudication,numbness,burning and rest pain of lower extremities,decreased skin temperature,redness,swelling and dark redness of skin,edema of knee joint and foot,dry and chapped skin,weakening or even disappearance of Yangyang pulse.There are significant differences in the quantity,color and smell of pus,the amount of carrion and the amount of wound epithelium in different TCM syndrome types of DFU.Diabetic patients with diabetic nephropathy and retinopathy have an increased risk of DFU.Long-term poor blood glucose control is still an important factor in the occurrence of DFU.Blood coagulation,inflammatory indexes and renal function reflect the progress and prognosis of DFU to some extent.The frequency of different TCM syndrome types is related to many factors,such as lower limb and foot syndrome,wound syndrome,laboratory index and so on.2.In recent years,the quantity and quality of related literature published abroad have improved rapidly,and the research of angiogenesis in diabetic foot wounds has been paid more and more attention by scholars all over the world,but the depth and quality of domestic articles need to be improved.According to the development direction of this field in the future,on the one hand,the study of the mechanism of angiogenesis in various stages of wound healing of diabetic foot will help scholars to analyze the causes of abnormal angiogenesis in diabetic foot wound.Compared with traditional drugs,many kinds of cell therapy and exocrine therapy based on mesenchymal stem cells have great advantages in the treatment of diabetic foot wounds.therefore,the study of cell therapy and exocrine therapy strategy has important application value for the accurate treatment of diabetic foot wound angiogenesis in the future.On the other hand,in the field of wound repair,the integration of new interdisciplinary technologies will be the future development trend.3.Notch1-Dll4/Jagged1 signal pathway may be one of the important signal pathways in the process of intervention of Danggui Buxue decoction and different combinations of Radix Astragali and Angelica sinensis on the angiogenesis of DFU wound.Through animal experiments,it was found that Danggui Buxue decoction could promote the regular arrangement of fibroblasts,angiogenesis,regeneration of skin appendages such as sebaceous glands and hair follicles during DFU wound repair,up-regulate the expression of VEGF and FN in wound tissue,up-regulate Notchl and Jaggedl protein and down-regulate DLL4 protein in Notch pathway in wound tissue,promote wound angiogenesis and accelerate wound healing.In addition,the proportion of Radix Astragali and Angelica sinensis in Danggui Buxue decoction was further adjusted and divided into 1:1,1:5 and 5:1 groups.It was found that the proportion of Astragalus and Angelica at 5:1 had more advantages than the other two groups in improving DFU wound inflammation,promoting fibroblast functional proliferation and migration and skin appendage regeneration,up-regulation of wound VEGF and FN expression and wound healing.Through the detection of proteins related to Notch pathway,it was found that the increase of the proportion of astragalus was positively correlated with the expression of Notchl and Jaggedl protein,and negatively correlated with DLL4 protein.Based on the traditional Chinese medicine theory of Danggui Buxue decoction,it is speculated that when the TCM theory of tonifying qi and invigorating blood guides the treatment of wound angiogenesis,the modern medical target of its effect of "tonifying qi" may be Notchl and Jaggedl proteins in Notch signal pathway.The target of its "blood generating" effect may be D114 protein,and the modern mechanism of invigorating qi and promoting blood circulation to promote wound healing may be to regulate different targets in the Notch pathway to promote angiogenesis and accelerate wound healing. |
PDF Full Text Request