ABSTRACT
As one of the classic prescriptions of traditional Chinese medicine， Didangtang is an effective prescription for breaking and expelling blood stasis. It was considered that Didangtang damage the healthy qi and contained toxic Chinese medicinal materials such as leeches and gadflies， and thus it was rarely used. However， as the attention to classic prescriptions increases， Didangtang has been widely used in clinical practice and demonstrated definite efficacy in treating diabetes mellitus and its complications， malignant tumors， Alzheimer's disease， stroke， renal diseases， cardiovascular diseases， peripheral vascular diseases， gynecological disease， and male diseases according to the disease location， pathogenesis， symptoms， and pharmacological effects. Didangtang has the effects of mitigating insulin resistance， improving microvascular and peripheral vascular circulation， delaying diabetic macrovascular lesions， preventing vascular fibrosis， improving immunity， inhibiting tumor growth， protecting the brain tissue， nerve cells， vascular endothelial function， and kidney， reducing inflammation， and delaying aging. This paper summarizes the clinical application of Didangtang and initially explores the underlying mechanism.
ABSTRACT
ObjectiveTo explore the mechanism of Didangtang （DDT） against the inflammatory cascade triggered by foam cell pyroptosis in high-glucose environment. MethodOxidized low density lipoprotein （ox-LDL， 100 mg·L-1） was used to induce pyroptosis of foam cells. The control group （5.5 mmol·L-1 glucose）， foam cell group （100 mg·L-1 ox-LDL）， high-glucose group （33.3 mmol·L-1 glucose）， DDT group （10% DDT-containing serum）， and NOD-like receptor family pyrin domain-containing 3 （NLRP3） inhibitor group （MCC950， 10 nmmol·L-1） were designed. The cell membrane damage was observed by lactate dehydrogenase （LDH） release assay. The expression of cysteinyl aspartate-specific proteinase-1 （Caspase-1） was detected by immunofluorescence method， and expression of key proteins NLRP3， Caspase-1， gastermin D （GSDMD）， interleukin-1β （IL-1β）， and interleukin-18 （IL-18） in the pyroptosis pathway was determined by Western blot. The release of IL-18 and IL-1β， monocyte chemoattractant protein-1 （MCP-1）， and tumor necrosis factor α （TNF-α） in cell supernatant was measured by enzyme-linked immunosorbent assay （ELISA）. ResultThe expression of NLRP3， Caspase-1， and GSDMD was up-regulated （P<0.01） and the release of IL-1β， IL-18， MCP-1， IL-1α， and TNF-α was increased （P<0.01） in foam cell group compared with those in the control group. The expression of NLRP3， Caspase-1， and GSDMD was higher （P<0.01） and the release of inflammatory factors was more （P<0.01） in the high-glucose group than in the foam cell group. DDT and MCC950 can inhibit expression of NLRP3， Caspase-1， GSDMD and reduce the release of IL-1β， IL-18， MCP-1， IL-1α， and TNF-α. ConclusionDDT can suppress the pyroptosis of foam cells induced by NLRP3/Caspase-1 pathway in high-glucose environment and thereby alleviate the inflammatory cascade.
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Objective:To investigate the effects of different doses of Didangtang on myocardial inflammatory lesions in diabetic mice. Method:Sixty C57BL/6J mice were randomly divided into normal group （<italic>n</italic>=10） and model group （<italic>n</italic>=50）. The diabetic mice in the model group were established by intraperitoneal injection of high-fat diet combined with streptozotocin （STZ）. After model reproducing， the mice were fed with high-fat diet. After 8 weeks， the cardiac function of the mice was detected by using an ultrasound imaging platform. If the cardiac function decreased， the diabetic cardiomyopathy mice were modeled successfully. The nonmodel mice were eliminated， and finally 40 model mice were modeled. The rats in the model group were randomly divided into model group， low， medium and high dose of Didangtang group（1.5，3，6 g·kg<sup>-1</sup>） and simvastatin group（0.001 5 g·kg<sup>-1</sup>） according to heart function， with 8 rats in each group. The cardiac function of mice was detected by ultrasound imaging platform， fiber bragg grating（FBG）， triglyceride（TG） and total cholesterol（TC） were detected by automatic biochemical analyzer， hematoxylin-eosin （HE） staining was used to observe the pathological changes of myocardium， and the levels of NOD-like receptor3（NLRP3）， thiomdoxin interaction protein（TXNIP）， cysteinyl aspartate specific proteinase-1（Caspase-1） and Interleukin-1<italic>β</italic>（IL-1<italic>β</italic>） in myocardial tissue， as well as the content of reactive oxygen species（ROS） were detected by Western blot. Result:Compared with the normal control group， the levels of FBG， TC and TG in the model group significantly increased （<italic>P</italic><0.01）； the values of EF and FS significantly decreased （<italic>P</italic><0.01）； the expression of ROS significantly increased （<italic>P</italic><0.05）， and the expressions of NLRP3， TXNIP， Caspase-1 and IL-1<italic>β</italic> in the myocardial tissue significantly increased （<italic>P</italic><0.05）. Compared with the model group， the levels of FBG， TC and TG in the middle and high dose groups of Didangtang and simvastatin groups significantly decreased （<italic>P</italic><0.05）； the EF and FS in each dose group and simvastatin group improved （<italic>P</italic><0.05）， and the change in the middle dose group was more obvious （<italic>P</italic><0.05）. HE staining showed that Didangtang could improve the pathological changes of myocardial tissue in mice， the ROS expression levels of mice in each dose group of Didangtang and simvastatin group significantly reduced， especially in the middle dose group， the expression levels of NLRP3， TXNIP， Caspase-1 and IL-1<italic>β</italic> in each dose group significantly decreased， and the effect of middle dose of Didangtang on reducing expressions of NLRP3， TXNIP and Caspase-1 in myocardial tissue was more obvious， the effect of high dose of Didangtang on reducing the expression of IL-1<italic>β</italic> in myocardial tissue was more obvious. Conclusion:Didangtang can improve myocardial inflammatory lesions in diabetic cardiomyopathy mice by inhibiting the activation of NLRP3 inflammasome.
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Objective:To observe the clinical efficacy of Didangtang combined with gemcitabine chemotherapy in postoperative patients with non-muscle invasive bladder ctraditional chinese medicineancer （NMIBC）. Method:A total of 100 patients with NMIBC in Jiangsu Provincial Second Chinese Medicine Hospital and Jiangsu Province Hospital of Chinese Medicine from January 2015 to September 2020 were randomly divided into control group and treatment group. 50 cases in the treatment group received Didangtang combined with intravesical infusion of gemcitabine， and 50 cases in the control group received placebo combined with intravesical infusion of gemcitabine. Before and after the treatment cycle， the blood biochemistry， immune cell subsets（CD3<sup>+</sup>，CD4<sup>+</sup> and CD4<sup>+</sup>/CD8<sup>+</sup>） were detected to assess the safety and immune function changes in treatment group. Quality of life scale for patients with bladder cancer prepared by European Organization for the Research and Treatment of Cancer （EORTC QLQ-C30） and Specificity scale for patients with superficial bladder cancer （EORTC QLQ-BLS24） were scored to assess the changes in physical， role， emotional and social functioning of the patients， symptomatic conditions such as fatigue， pain， nausea and vomiting， shortness of breath， insomnia， loss of appetite， diarrhea and constipation， as well as bladder cancer-specific symptoms such as treatment-generated problems， future concerns， bowel symptoms and urinary tract symptoms. Result:There were no differences in terms of age， sex， disease duration and tumor states. During the treatment period， both groups had no recurrence or adverse events. The traditional Chinese medicine（TCM） efficacy in the treatment group was significantly better than that in the control group（<italic>χ<sup>2</sup></italic><sup> </sup>= 7.23，<italic>P </italic>= 0.02）. After treatment， the number of CD3<sup>+</sup>，CD4<sup>+</sup> ，CD8<sup>+</sup> cells and the CD4<sup>+</sup>/CD8<sup>+</sup> ratio in the treatment group were significantly higher than those in control group（<italic>P</italic><0.05）. Both groups showed significant improvements in the domains of role functioning， social functioning， and general health after treatment （<italic>P</italic><0.05）. In addition， fatigue， diarrhea， constipation， intestinal symptoms， and urinary tract symptoms in the treatment group were significantly better than those in the control group after treatment （<italic>P</italic><0.05）. Conclusion:Didangtang can reduce adverse clinical symptoms during postoperative gemcitabine infusion chemotherapy in patients with NMIBC， reduce urethral and intestinal discomfort reactions， improve immune function and enhance quality of life for patients.
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Objective:To investigate the targets and possible mechanism of Didangtang in the treatment of bladder cancer. Method:Based on multiple traditional Chinese medicine and disease databases, the network pharmacology was used to screen potential targets, analyze the biological functions of potential targets, and construct a network of "Chinese medicine-target-path-disease". Bioinformatics analysis was applied in population and gene databases, in order to explore the differential expressions of core targets in tissues, distribution in the population and the correlation with prognosis. The in vitro experiment was used to verify the biological function of Didangtang. The underlying mechanism of Didangtang on the candidate target was detected. Result:A total of 21 core target genes and 16 highly enriched pathways were screened out. A functional network of Didangtang was constructed systematically. At the same time, six targets, namely cadherin 1 (CDH1), CAMP responsive element binding protein 1 (CREB1), colony stimulating factor 2 (CSF2), AP-1 transcription factor (JUN), matrix metalloproteinase 2 (MMP2), and prostaglandin-endoperoxide synthase (PTGS2), were differentially expressed in bladder cancer tissues (P<0.05). Furthermore, JUN and MMP2 were also differentially distributed in population (P<0.05). At the same time, the expression level of JUN was correlated with the prognosis of patients with bladder cancer (P<0.05). The in vitro experiment revealed that Didangtang inhibited the proliferation of bladder cancer cells and decreased the expression of candidate target JUN (P<0.01). Conclusion:Didangtang has the characteristics of multiple targets and multiple pathways in treatment of bladder cancer. It is initially confirmed that Didangtang can affect the expression of target JUN and inhibit the proliferation of bladder cancer, which lays a good foundation for further studies on mechanism.
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Objective To approach the effects of decoction changed from Didangtang and Xiaoxianxiongtang Modified Formula on mucoprotein in stratum medium and the III-type collagen level of serum in experimental rats with fibrosis disease in lung interstitial tissue. Methods 40 male Wistar rats were randomly divided into 4 groups, that is pseudo-operation group, model control group, traditional Chinese drug group (TCD) and western medicine group (WM). Every group has 10 rats. Acid hydroc bleocin was dripped disposably into trachea of every group rats except pseudo-operation group, and Sodium Chloride with same volume as Acid hydroc bleocin was dripped disposably into trachea of pseudo-operation group. 24 hours after operation, the rats of TCD was lavaged with Decoction changed from Didangtang and Xiaoxianxiongtang Modified Formula, and the rats of WM was lavaged with Prednisone physiological saline solution. The rats of pseudo-operation group and model control group was lavaged with Sodium Chloride of same volume as TCD and WM. 28 days after operation, the rats was executed. And contents of mucoprotein in stratum medium of and the III-type collagen serum was detected. Results Didangtang and Xiaoxianxiongtang Modified Formula could decrease contents of mucoprotein in stratum medium of and the III-type collagen in serum of experimental rats, and extenuate fibro-accrementition in lung interstitial tissue. Conclusion Didangtang and Xiaoxianxiongtang Modified Formula has the function of treating fibrosis disease in lung interstitial tissue probably by decreasing contents of extracellular matrix in experimental rats with fibrosis disease in lung interstitial tissue.
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Objective To investigate the expression of neuron nitric oxide synthase (nNOS) mRNA of brain tissue at early stage of intracerebral hemorrhage (ICH) in rats and the intervention effect of Didangtang.Methods 72 male Sprague-Dawley rats were randomly divided into four groups: intracerebral hemorrhage group, Didangtang treatment group, NOS inhibition group and normal saline group. Quantitate fresh autologous blood was infused into right caudate nucleus of rat sterotaxically to build up experimental ICH model and normal saline was instead in control group. The neurological function deficit scores were observed by Bederson method (3 grades) at 6 h, 24 h and 72 h after operation. At the same time points, the rats were sacrificed and the brain tissues were taken out for the measurement of nNOS mRNA by technique of hybridization in situ.Results Neurological function deficit scores of the rats were significantly improved both in intracerebral hemorrhage group and Didangtang treatment group at 72 h after operation(all P