Traditional Chinese Medicine for adjuvant treatment of breast cancer: Taohong Siwu Decoction

The high incidence of breast cancer is the greastest threat to women’ health all over the world. Among them, HER-2 positive breast cancer has the characteristics of high malignancy, easy recurrence and metastasis, and poor prognosis. Traditional Chinese medicine (TCM) has a rich theoretical basis and clinical application for breast cancer. TCM believes that blood stasis syndrome is one of the important pathogenesis of breast formation and development. Taohong Siwu Decoction (TSHWD) is based on the “First Prescription of Gynecology” Siwu Decoction. It is widely used in various blood stasis and blood deficiency syndromes, mainly in gynecological blood stasis. Clinical studies have found that THSWD can treat breast cancer by reducing blood vessel and lymphangiogenesis with auxiliary chemotherapy. In this study, we aim to explore the material basis and mechanism of THSWD in the treatment of HER-2 positive breast cancer through literature review and network pharmacology studies. Through a literature review of the traditional application, chemical composition of Chinese herbal medicine of THSWD, as well as its clinical reports and pharmacological research on breast cancer treatment. Meanwhile, we conducted “component-pathway-target” network through network pharmacology reveals the main material basis, possible targets and pathways of THSWD in inhibiting HER-2 positive breast cancer. Literature review and network pharmacology research results had predicted that, baicalein, kaempferol, caffeic acid, amygdalin, quercetin, ferulic acid, gallic acid, catalpol, hydroxysafflor yellow A, paeoniflorin in THSWD are the main effective chemical composition. THSWD regulates 386 protein targets and 166 pathways related to breast cancer. The molecular mechanism is mainly to improve the microenvironment of tumor cells, regulate the process of tumor cell EMT, and inhibit tumor cell proliferation and metastasis. This study revealed the mechanism of action of THSWD in the treatment of HER-2 positive breast cancer through literature review and network pharmacology studies, providing a scientific basis for clinical application.

Inhibition of JAK3/STAT3 Activation in Rats Uterine Leiomyoma by formula of Taohong Siwu Decoction: A Randomized Controlled Trial

Background: Traditional Chinese medicine (TCM) formula of Taohong Siwu decoction (THSW) is often used in traditional Chinese medicine for the treatment of uterine leiomyoma (UL). The effectiveness of THSW for the treatment of UL has been confirmed in previous studies. At present, there are few relevant mechanism studies. The purpose of this study is to explore the efficacy and mechanism of THSW in the treatment of uterine leiomyoma. Methods: A Sprague Dawley (SD) rat model of UL was established via estrogen and progesterone load combined with external stimulation for 5 weeks. We randomly assigned adult female non-pregnant rats into six groups: a control group, a UL model group, and a positive drug group, THSW(18g/ml) group, THSW(9g/ml) group, THSW(4.5g/ml) group. THSW group and positive drug group were treated with THSW medicinal solutions and gongliuxiao capsule medicinal solutions respectively after daily modeling for 3 weeks. Histological analyses, Polymerase Chain Reaction and western blotting were performed to evaluate the effect of THSW on UL and elucidate its mechanism of action. Results: The uterus morphology of the model group showed significantly more swelling than that of the control group, and pathological of changes of rats were obvious in the model group. Compared with model group, the pathological changes of UL were relieved in the THSW group. Our data showed that the treatment of rats with THSW significantly reduced the expression of cytotoxic T lymphocyte associated antign 4 (CTLA4) and indoleamine 2, 3-dioxygenase 1 (INDO). The phosphorylation of JAK3 and STAT3 which are the main signal transduction molecule of cytokines and growth factorswere were also inhibited. Conclusions: Our results suggest that THSW is effective in the prevention and treatment of UL in rats, and THSW may exert its functions by inhibiting the activation of Tumor-related signal transduction pathway (JAK3/STAT3), immune escape, proliferation of tumor cell and improving apoptosis.

Taohong Siwu Decoction Regulates Cell Necrosis and Neuroinflammation in the Rat Middle Cerebral Artery Occlusion Model

Cell necrosis and neuroinflammation play an important role in brain injury induced by ischemic stroke. Previous studies reported that Taohong Siwu decoction (THSWD)can reduce heart muscle cell necrosis and has anti-inflammatory properties. In this study, we investigated the effects of THSWD on cell necrosis and neuroinflammation in a rat model of middle cerebral artery occlusion (MCAO). Thirty-six male Sprague-Dawley (SD) rats were randomly divided into three groups with 12 rats in each group. They were the sham operation group, MCAO model group, and MCAO + THSWD group. We used ELISA to determine the levels of TNF-α, Mcp-1, and IL-1β inflammatory factors in rat serum, qRT‐PCR to detect the expression of TNF‐α, Mcp‐1 and IL‐1β mRNA in rat brain, and immunohistochemistry to detect the number of microglia and neutrophils in rat brain. qRT-PCR and Western blot were used to detect the mRNA and protein expression levels of IBA-1 and MPO inflammatory factors and the TNF-α/RIP1/RIP3/MLKL pathway in the rat brain and protein expression levels. Compared with the sham operation group, the expression of MCP-1, IL-1β, IBA-1, and MPO inflammatory factors and the TNF-α/RIP1/RIP3/MLKL pathway were significantly upregulated in the MCAO group. Compared with the MCAO group, the expressions of MCP-1, IL-1β, IBA-1, and MPO inflammatory factors and the TNF-α/RIP1/RIP3/MLKL pathway were significantly downregulated in the MCAO + THSWD group. THSWD can reduce the expression levels of MCP-1, IL-1β, IBA-1, and MPO inflammatory factors as well as the TNF-α/RIP1/RIP3/MLKL pathway. Meanwhile, it can reduce the necrosis and inflammation of brain cells after cerebral ischemia, so as to protect the brain tissue of rats.

Taohong Siwu Decoction Ameliorates Ischemic Stroke Injury Via Suppressing Pyroptosis

Objective: Taohong Siwu decoction (THSWD) is one of the classic prescriptions for promoting blood circulation and removing blood stasis, and it has a good therapeutic effect on ischemic stroke. We sought to explore the therapeutic effects of THSWD on pyroptosis in rats with middle cerebral artery occlusion-reperfusion (MCAO/R).Methods: MCAO/R model of rats were established by suture-occluded method. MCAO/R rats were randomly divided into five groups, which were model group, nimodipine group, THSWD high, medium and low dose group (18, 9, and 4.5 g/kg, respectively), rats of sham group without thread embolus. All rats were treated by intragastric administration for 7 days. We detected the level of inflammatory factors. NLRP3 and Caspase-1 were detected by immunofluorescence. Western blot was used to detect NLRP3, Caspase-1, ASC, and GSDMD in penumbra. Also, the expression of TXNIP, HMGB1, toll-like receptors (TLR4), NF-κB, and MAPK were detected.Results: THSWD treatment improved the behavioral function and brain pathological damage. These results showed that the levels of TNF-α, TGF-β, IL-2, IL-6, IL-1β, and IL-18 were significantly reduced in THSWD treatment groups. THSWD could significantly decrease the expression levels of NLRP3, Caspase-1, Caspase-1 p10, ASC, TXNIP, GSDMD, HMGB1, TLR4/NFκB, p38 MAPK, and JNK in penumbra.Conclusion: Our results showed that THSWD could reduce the activation level of NLRP3 inflammatory corpuscle, down-regulate GSDMD, and inhibit pyroptosis in MCAO/R rats. These may be affected by inhibiting HMGB1/TLR4/NFκB, MAPK signaling pathways.

Modified Taohong Siwu Decoction Improved Heart Function After Myocardial Infarction by Inhibiting Inflammatory Factor and Promoting Chemotactic and Pro-Angiogenic Factors

BackgroundTraditional Chinese medicine has been applied to prevent and treat myocardial infarction (MI) in the clinic for a long history. We recently found that Taohong Siwu decoction (THSWD) exerted a beneficial effect on heart function after MI through improving the local hostile microenvironment. However, the improvement of cardiac function after THSWD administration was moderate. In this study, four Chinese medicine herbs, which have the properties of warming Yang or removing phlegm, were added into THSWD to constitute a new and multifunctional Chinese herbal compound, named modified THSWD (MTHSWD). MethodsA rat model of MI was established by the ligation of left anterior descending coronary artery and MTHSWD was intragastrically administered for 2 weeks. The heart function was examined by echocardiography, cell apoptosis was detected by TUNEL staining and the infarct size was determined by Masson's trichrome staining. The expressions of cytokines, including chemotactic and inflammatory factors, were examined by ELISA in the infarcted myocardium and serum. The level of p-Akt and VEGF in the damaged myocardial tissues was further detected by Western blot. ResultsMTHSWD improved heart function and decreased infarct size and collagen deposition in the infarcted area. In addition, MTHSWD increased the expression of cTnT and Cx43, reduced cell apoptosis in the infarcted area by activating Akt signal and promoted angiogenesis by increasing the expression of VEGF. Interestingly, MTHSWD significantly increased the level of IGF-1, SDF-1 and TNF-α, and significantly reduced the expression of IL-1β in the infarcted myocardium. MTHSWD could also significantly increase the expression of IGF-1, SDF-1 and SCF in the serum. ConclusionsMTHSWD reduced cell apoptosis, promoted angiogenesis and improved heart function after MI probably through the downregulation of inflammatory factor IL-1β, upregulation of chemotactic factors SDF-1 and SCF as well as pro-angiogenic factor VEGF, and activation of Akt signaling pathway.

Uncovering the protective mechanism of Taohong Siwu decoction against diabetic retinopathy via HIF-1 signaling pathway based on network analysis and experimental validation

Background Diabetic retinopathy (DR) is a common and serious microvascular complication of diabetes. Taohong Siwu decoction (THSWD), a famous traditional Chinese medicine (TCM) prescription, has been proved to have a good clinical effect on DR, whereas its molecular mechanism remains unclear. Our study aimed to uncover the core targets and signaling pathways of THSWD against DR. Methods First, the active ingredients of THSWD were searched from Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database. Second, the targets of active ingredients were identified from ChemMapper and PharmMapper databases. Third, DR associated targets were searched from DisGeNET, DrugBank and Therapeutic Target Database (TTD). Subsequently, the common targets of active ingredients and DR were found and analyzed in STRING database. DAVID database and ClueGo plug-in software were used to carry out the gene ontology (GO) and KEGG enrichment analysis. The core signaling pathway network of “herb-ingredient-target” was constructed by the Cytoscape software. Finally, the key genes of THSWD against DR were validated by quantitative real-time PCR (qRT-PCR). Results A total of 2340 targets of 61 active ingredients in THSWD were obtained. Simultaneously, a total of 263 DR-associated targets were also obtained. Then, 67 common targets were found by overlapping them, and 23 core targets were identified from protein-protein interaction (PPI) network. Response to hypoxia was found as the top GO term of biological process, and HIF-1 signaling pathway was found as the top KEGG pathway. Among the key genes in HIF-1 pathway, the mRNA expression levels of VEGFA, SERPINE1 and NOS2 were significantly down-regulated by THSWD (P < 0.05), and NOS3 and HMOX1 were significantly up-regulated (P < 0.05). Conclusion THSWD had a protective effect on DR via regulating HIF-1 signaling pathway and other important pathways. This study might provide a theoretical basis for the application of THSWD and the development of new drugs for the treatment of DR.