|Year : 2022 | Volume
| Issue : 1 | Page : 10-17
Molecular mechanism of Si-Miao-Yong-An decoction in the treatment of diabetic foot microcirculation and network pharmacology information analysis results
Zhao Wei1, Dong Mingyang2, Pan Dikang3, An Yanbo4, Tong Le5, Yang Zhongkai3, Zhang Jing4, Lv Bonan1, Shi Xiaoming1
1 Department of Vascular Surgery, Hebei General Hospital, Shijiazhuang, China
2 Department of Vascular Surgery, Hebei General Hospital; Graduate School of Hebei Medical University, Shijiazhuang, China
3 North China University of Science And Technology, Tangshan, China
4 Hebei North University, Zhangjiakou, China
5 Wuji County Hospital, Shijiazhuang, Hebei, China
|Date of Submission||18-Nov-2021|
|Date of Decision||02-Jan-2022|
|Date of Acceptance||05-Jan-2022|
|Date of Web Publication||22-Mar-2022|
Dr. Shi Xiaoming
Department of Vascular Surgery, Hebei General Hospital, Shijiazhuang
Source of Support: None, Conflict of Interest: None
OBJECTIVE: This study aims to explore the effect and mechanism of Si-Miao-Yong-An decoction (SMYAD) on diabetic foot by simulating the microenvironment of diabetic foot in vitro, and further verify these results using bioinformatics analysis technology, in order to provide a basis for the treatment of diabetic foot with traditional Chinese medicine.
MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured under hypoxia to simulate the microcirculation of diabetic foot. Then, these were administered with SMYAD for intervention. Afterward, the cell viability was detected by MTT assay, the apoptosis was detected by flow cytometry, and the STAT3 signaling pathway and Bcl-2 and Bax protein expression were detected by Western blot. Next, TCMSP was used to determine the chemical composition and target gene information of the SMYAD, and the GeneCards database was used to search for the disease-related target gene information of diabetic foot. Furthermore, the Venny 2.1 online software was used to screen and obtain the drug–disease common target genes for the SMYAD and diabetic foot. The common target genes were entered into the STRING database for retrieval, in order to construct the network diagram for protein-related action, and the R software was used to analyze the pathway enrichment, in order to explore the mechanism of the SMYAD in the treatment of diabetic foot microcirculation.
RESULTS: Compared with the control group, the SMYAD increased the activity of HUVECs cultured in the hypoxia state but decreased the apoptosis rate. Furthermore, the protein expression of p-STAT3 and Bcl-2 increased, and the protein expression of Bax decreased (P < 0.05). A total of 235 drug-related target genes were found by screening, and 4553 target genes related to diabetic foot were obtained. The Venny software analysis revealed that there were 171 drug–disease interaction target genes. The STRING database and the GO and KEGG functional enrichment analysis revealed that STAT3, AKT, MAPK, and other proteins were involved, and that these may be correlated to the mechanism of the SMYAD in the treatment of diabetic foot microcirculation.
CONCLUSION: SMYAD can affect the expression of Bcl-2 and Bax genes by regulating the activity of the STAT3 signaling pathway, playing a role in the treatment of diabetic foot.
Keywords: Diabetic foot, microcirculation, network pharmacological informatics analysis, Si-Miao-Yong-An decoction, STAT3 signaling pathway
|How to cite this article:|
Wei Z, Mingyang D, Dikang P, Yanbo A, Le T, Zhongkai Y, Jing Z, Bonan L, Xiaoming S. Molecular mechanism of Si-Miao-Yong-An decoction in the treatment of diabetic foot microcirculation and network pharmacology information analysis results. Vasc Invest Ther 2022;5:10-7
|How to cite this URL:|
Wei Z, Mingyang D, Dikang P, Yanbo A, Le T, Zhongkai Y, Jing Z, Bonan L, Xiaoming S. Molecular mechanism of Si-Miao-Yong-An decoction in the treatment of diabetic foot microcirculation and network pharmacology information analysis results. Vasc Invest Ther [serial online] 2022 [cited 2022 May 24];5:10-7. Available from: https://www.vitonline.org/text.asp?2022/5/1/10/340414
| Introduction|| |
In recent years, the incidence rate of diabetic complications has been increasing with the morbidity of diabetes. Diabetic foot is the most common terminal point of diabetic complications, and its incidence risk can reach as high as 25%. Since diabetic foot ulcer is difficult to heal, this brings great pain to patients. Furthermore, limb necrosis may occur, and amputation is often required. It has been reported that the 5-year and 10-year survival rate for diabetic foot after amputation is 40% and 24%, respectively. A large amputation would increase the mortality rate, reduce the quality of life of patients, and even endanger their lives. Microcirculation disorder of diabetic foot is the main cause of diabetic foot. This can cause an arteriovenous short circuit at the end of the lower limb, which would cause substance exchange disorder. At present, the main treatment measures for microcirculation of diabetic foot include controlling the primary disease, actively changing medicine, promoting blood circulation, expanding blood vessels, and the operation of lower extremity blood vessels. However, the effect cannot reach a satisfactory level, and the survival rate after treatment is worse than that of tumor patients. Therefore, the treatment of diabetic foot microcirculation remains as a great challenge. Traditional Chinese medicine has played an important role in the treatment of various peripheral vascular diseases. The Si-Miao-Yong-An decoction (SMYAD), as one of the traditional prescriptions in China, mainly consists of honeysuckle, Scrophularia, Angelica, and liquorice. Among these, the main medicine, honeysuckle, is mainly used for clearing away the heat and detoxification. This is supplemented by Radix Scrophulariae purging fire and detoxification, with Angelica sinensis for promoting blood circulation and removing blood stasis, allowing the licorice and honeysuckle flower to strengthen the function of clearing away the heat and detoxification for the treatment of gangrene. This prescription has the effect of improving blood circulation, and has been mostly used in the treatment of arteriosclerosis obliterans and thromboangiitis obliterans in clinical practice. It has been reported that the SMYAD can improve cardiac function by inhibiting platelet aggregation., Furthermore, it has also been reported that the SMYAD has a good effect in the treatment of diabetic retinopathy., However, the specific mechanism of the SMYAD in the treatment of diabetic foot remains unclear. It known endothelial cell apoptosis is the basis of microcirculation lesions. Fadini et al. reported that compared with the normal control group, circulating endothelial progenitor cells and endothelial cells in diabetic patients decreased by 33% and 40%, respectively. This study provides a theoretical basis for the clinical application of the SMYAD in the treatment of diabetic foot microcirculation. A cell experiment was performed to simulate the microcirculation of diabetic foot,, which verifies the effect of the SMYAD in improving the microcirculation of diabetic foot, and analyze the possible mechanism of the SMYAD in the treatment of diabetic foot microcirculation through network pharmacological information technology, providing a basis for the treatment of diabetic foot microcirculation.
| Materials and Methods|| |
Verification of the mechanism of the Si-Miao-Yong-An decoction on diabetic foot in vitro
Cell line culture and grouping
The human umbilical vein endothelial cell (HUVEC) was purchased from the Shanghai Cell Resource Center of Chinese Academy of Sciences, and was maintained, resuscitated, and cultured in the Scientific Research Center of CAS. These cells were divided into two groups: normal oxygen concentration culture group (control group) and hypoxia concentration culture group (hypoxia group). The vascular microenvironment of diabetic foot was simulated under hypoxia condition. The specific culture conditions were shown in the previous research report of our group.
The MTT method was used to detect the cell activity
HUVECs in the logarithmic growth phase were inoculated into a 96-well plate, trypsin digestion was adjusted to the cell density of 5 × 104 cells/ml, 200 μL of cell suspension was added into each well, and the culture was continued for 24 h. After cells adhered to the wall, these cells were treated according to the experimental design. After 24 h of treatment, each well was added with 20 μl of MTT at 5 g/L. After 4 h of culture, the culture medium was discarded. After adding 150 μl of dimethyl sulfoxide, the 96-well plate was placed in a cell oscillator, and vibrated for 15 min. The optical density (OD) of each well was measured at 490 nm by an enzyme-labeled instrument. The relative activity of cells was represented by the ratio of the OD value of cells in each group to the blank control group (only Phosphate buffered solution (PBS)). The HUVECs were divided into two groups: normal group and hypoxia group. Cells in the hypoxia group were intervened, and further divided into two subgroups: SMYAD alcohol extract group (treated with ethanol extract of 10 mg/ml for 24 h) and control group (treated with PBS of equal amount). The preparation method for the alcohol extract of the SMYAD is shown in a reference, and the experiment was repeated for three times.
Flow cytometry was used to detect the apoptosis rate
Cells in the ethanol extract group with the SMYAD and the control group were taken and centrifuged at 670.8 × g (2000 rpm) for 5 min after trypsin digestion, and 105 cells were collected after discarding the supernatant and rinsing with PBS. Then, 5 μl of Annexin V-TITC and 10 μl of PI were added. After allowing this to stand in the dark for 15 min, the apoptosis was detected on the machine (Thermo Fisher, Attune NxT type). The experiment was repeated for three times.
Western blot was used to detect the expression of each target protein
Hypoxia-inducible factor 1 α (HIF-1α), p-STAT3, STAT3, Bcl-2, Bax, and β-actin were products obtained from Sigma. The total protein was extracted and quantified. Then, 50 μg of the samples were taken for detection. The sodium dodecyl sulfonate-polyacrylamide gel electrophoresis separated the different molecular weight protein components, and transferred these into the polyvinylidene fluoride membrane. After the skim milk powder was sealed, the diluted primary and secondary antibodies were respectively added. Then, chemiluminescence was used to induce the target protein color. The ratio of the OD value for each target protein to the OD value for the internal reference protein was used to represent the relative expression intensity of the protein.
Statistical analysis software SPSS 22.0 was used to process the data from the cell experiment. The data were expressed as mean ± standard deviation. Group comparison t-test was used for comparisons between the two groups, and one-way ANOVA was used for comparisons of more than three groups. The difference was statistically significant (P < 0.05).
Screening and analysis of target genes related to the Si-Miao-Yong-An decoction and diabetic foot
First, in the TCMSP database (http://tcmspw.com/tcmsp.php), an objective search was conducted for the chemical constituents and target gene information of the four drugs of the SMYAD, including Angelica sinensis, honeysuckle, Scrophularia, and Glycyrrhiza. The names of the target genes were revised and unified by the UniProt database. Then, GeneCards database (https://www.genecards.org/) was used. The keyword “diabetic foot” was searched to obtain the target genes of the disease. Then, the target genes of the SMYAD and diabetic foot were entered on the Venny 2.1 online software mapping tool platform, and the Venny Image was drawn.
Bioinformatics analysis process of the data
Using the Cytoscape 3.7.1 software, the network diagram for the drug–target gene interaction was constructed. The common target genes of drugs and diseases were entered into the STRING database for retrieval, and the protein–protein interaction network for the protein interaction was constructed by selecting a high confidence of <0.9, and ranking according to the correlation degree among proteins. The R software was used to install the Bioconductor software package, and analyze the functional enrichment of the GO and KEGG of the key target genes (P < 0.05, Q < 0.05).
| Results|| |
Comparison of human umbilical vein endothelial cell activity between the control group and the hypoxia group
The MTT results revealed that the activity of HUVECs in the control group (1.12 ± 0.11) was significantly higher than that in the hypoxia group (0.56 ± 0.08) (t = 10.085, P < 0.001) [Figure 1].
|Figure 1: The cell activity of human umbilical vein endothelial cells in the normal and hypoxia groups (MTT results). Note: Compared with the control human umbilical vein endothelial cell group, P < 0.001|
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The protein expression levels of hypoxia-inducible factor 1 α, p-STAT3, STAT3, Bcl-2, and Bax in human umbilical vein endothelial cells in the control group and the hypoxia group
The Western blot results revealed that the HIF-1α and Bax protein levels in the normal group were lower than those in the hypoxia group, while the protein expression levels of p-STAT3 and Bcl-2 in the normal group were significantly higher than those in the hypoxia group (P < 0.05) [Figure 2].
|Figure 2: The protein expression of human umbilical vein endothelial cells in the control and hypoxia groups (Western blot results). Note: (a) (1) The human umbilical vein endothelial cells in the control group; (2) The human umbilical vein endothelial cells in the hypoxia group; (b) Compared with the normal human umbilical vein endothelial cell group, P < 0.05|
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Comparison of the activity of hypoxic human umbilical vein endothelial cells between the two groups
The MTT results revealed that the activity of HUVECs in the SMYAD group (treated with the SMYAD) was significantly higher than that in the hypoxia control group (0.24 ± 0.08) (t = 10.085, P < 0.001) [Figure 3].
|Figure 3: The cell activity of hypoxia human umbilical vein endothelial cells (MTT results) in the SMYAD group and control group. Note: Compared with the control group, P < 0.001|
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The effect of the Si-Miao-Yong-An decoction group and control group for the apoptosis of hypoxia human umbilical vein endothelial cells
The flow cytometry results revealed that the apoptosis rate of HUVECs in the SMYAD group was significantly lower than that in the hypoxia control group (72.873% ± 5.803%) (t = −5.213, P = 0.006) [Figure 4].
|Figure 4: (a) The apoptosis of human umbilical vein endothelial cells in the SMYAD group and control group (flow cytometry results). (b) Compared with the control group, P < 0.01|
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The effects of the Si-Miao-Yong-An decoction group and control group on the hypoxia-inducible factor 1 α, p-STAT3, STAT3, Bcl-2, and Bax protein expression in hypoxia HUVECs
The Western blot results revealed that the HIF-1α and Bax protein levels of HUVECs in the SMYAD group were lower than those in the control group, while the protein expression levels of p-STAT3 and Bcl-2 were significantly higher than those in the control group (P < 0.01) [Figure 5].
|Figure 5: The protein expression of hypoxia human umbilical vein endothelial cells in the SMYAD group and control group (Western blot results). Note: (a) (1) Human umbilical vein endothelial cells in the Si-Miao-Yong-An decoction group; (b) Human umbilical vein endothelial cells in the control group|
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The screening results for target genes related to the Si-Miao-Yong-An decoction and diabetic foot
The chemical constituents and target genes for the four drugs of the SMYAD were searched in the TCMSP database, and the information was corrected through the UniProt database. The results revealed that 235 target genes were correlated to the action of the SMYAD. Furthermore, 4553 disease target genes were obtained by searching the GeneCards database with the keyword “diabetic foot.” By entering these target genes into the Venny 2.1 software, 171 drug–disease common target genes were identified [Figure 6]. Using the Cytoscape 3.7.1 software, the interaction network diagram for the “drug target gene” was constructed [Figure 7].
|Figure 6: The Venny Image for the Si-Miao-Yong-An decoction and diabetic foot common target gene. Note: The blue part represents the disease target gene, the red part represents the drug target gene, and the overlapping part represents the drug-disease common target gene|
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|Figure 7: The interaction of related target genes for the Si-Miao-Yong-An decoction. Note: Green represents licorice, yellow represents Scrophularia, red represents common target gene, blue represents honeysuckle, and purple represents the multiple drugs|
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Network diagram for the interaction between Si-Miao-Yong-An decoction and diabetic foot common target gene proteins
The common target gene was entered into the STRING database, for the protein interaction was analyzed [Figure 8]a. Each edge represents the interaction between protein and protein. The more the lines, the greater the correlation. The further analysis revealed that STAT3, AKT1, MAPK1, MAPK3, JUN, HSP90, RELA, MAKA8, epidermal growth factor receptor (EGFR), interleukin-6 (IL-6), and other related proteins were the main target proteins [Figure 8]b (barplot.tiff).
|Figure 8: (a) The protein-protein interaction diagram for the interaction between the Si-Miao-Yong-An decoction and diabetic foot common target gene proteins. (b) The barplot plot of the protein-protein interaction diagram for the Si-Miao-Yong-An decoction and diabetic foot common target gene protein interaction. Note: This figure shows the top 30 target proteins. The longer the band, the greater the effect of the protein|
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Pathway enrichment analysis of the Si-Miao-Yong-An decoction and diabetic foot common target gene protein
The R software was used to analyze the functional enrichment of the GO and KEGG. The common target gene was analyzed by the GO after running in the R language. Three parts, namely, biological process, cellular component, and molecular function, were selected [Figure 9]. After running the common target gene in the R language, 163 KEGG pathways were obtained [ Figure10]a. The related target genes and pathways were entered into the Cytoscape 3.7.1 software to construct the KEGG relationship network [Figure 10]b
|Figure 9: The pathway enrichment analysis for the Si-Miao-Yong-An decoction and diabetic foot common target gene proteins (the GO results). Note: BP: Biological process; CC: Cellular component; MF: Molecular function|
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|Figure 10: The pathway enrichment analysis for the Si-Miao-Yong-An decoction and diabetic foot common target gene proteins (The KEGG results). Note: (a) The KEGG functional enrichment bar graph (showing the top 20 results; P represents the significance of enrichment, and the red color represents a higher significance); (b) The KEGG relationship network diagram constructed by the Cytoscape 3.7.1 software (red represents the pathway, green represents the related target genes; the larger the color area, the more important the related pathways are, and the more important the related target genes are)|
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| Discussion|| |
Diabetic foot is one of the main complications of diabetes. Due to the damage of microcirculation in diabetic patients, diabetic foot ulcers are difficult to heal. Nearly half of diabetic foot ulcers would be infected with secondary infection, and amputation mostly starts from the formation of infection, which brings great pain to patients. Furthermore, this can even be life-threatening in severe cases. In the present study, the investigators simulated the microenvironment of diabetic foot vascular endothelial cells to prepare the HUVEC model of hypoxic culture. The results revealed that under hypoxia, the activity of HUVECs decreased. Furthermore, the protein expression of HIF-1α and Bax was higher than that in the normal group, while the protein expression of p-STAT3 and Bcl-2 was lower than that in the normal group. These results indicate that the activity of the STAT signaling pathway decreases under hypoxia, which leads to the decrease in Bcl-2 expression, thereby leading to the inhibition of apoptosis, while the expression of Bax, which can promote apoptosis, increases. These results suggest that the apoptosis of vascular endothelial cells is enhanced under hypoxia, which leads to the aggravation of the disease. The investigator used the SMYAD to intervene the hypoxia-treated HUVECs. The results revealed that as the activity of HUVECs increased, the apoptosis rate decreased, the protein expression of p-STAT3 and Bcl-2 increased, and the protein expression of Bax decreased. This indicates that regulating the STAT pathway and affecting the cell apoptosis is one of the important mechanisms of the SMYAD. However, the specific mechanism needs to be further investigated.
In the present study, the molecular mechanism of the SMYAD in the treatment of diabetic foot was discussed through bioinformatics analysis technology. Bioinformatics is a comprehensive subject that analyzes the biological functions of drugs and molecules in recent years, including biology, computer science, information engineering, mathematics, and statistics. In the present study, based on the TCMSP and GeneCards database, the main components of the SMYAD and diabetic foot-related target genes were searched and mined. A total of 171 drug–disease common target genes of the SMYAD and diabetic foot were screened using the Venny 2.1 software. The results revealed that STAT3, AKT1, MAPK1, MAPK3, JUN, HSP90, RELA, MAPK8, EGFR, IL-6, and other related proteins may be the main target proteins of the SMYAD in the treatment of diabetic foot. The STAT3 protein, as a signaling pathway, has been proven to be closely correlated to apoptosis-related proteins and the treatment of diabetic foot microcirculation. Combined with the specific action mechanism of these proteins,,,,,,,,,,, it was also found that mapk3, Jun, EGFR, and other related proteins can also regulate the expression of apoptosis-related proteins, and regulate IL-6 and other related inflammatory factors, thereby affecting the treatment of diabetic foot. The results of the cell experiment were further verified by bioinformatics analysis.
| Conclusion|| |
In conclusion, the present study analyzed the mechanism of the SMYAD in the treatment of diabetic foot microcirculation through in vitro experiments, and further verified the cell experiment through the results of the bioinformatics analysis. It was found that the SMYAD could affect the expression of Bcl-2 and Bax genes by regulating the activity of the STAT3 signaling pathway, thereby playing a role in the treatment of diabetic foot. However, the present study is still in the primary stage, and the specific in-depth mechanism needs to be further analyzed.
All authors would like to express our sincere thanks to the Department of Vascular Surgery, Hebei General Hospital, and Graduate School of Hebei Medical University for supporting this study. We also thank Mr. Wen for her assistance in the experimental process.
Financial support and sponsorship
This work is financially supported by the research project of traditional Chinese medicine of Hebei Provincial Bureau of traditional Chinese medicine in 2017 (Code: 2017173).
Conflicts of interest
There are no conflicts of interest.
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