Deciphering the potential mechanism of Siwu decoction for treating cancer-related anemia based on network pharmacology and molecular docking technology

Background:Siwu decoction(SWD)is a traditional Chinese herbal decoction commonly used for treating various symptoms of blood deficiency and blood stasis,including cancer-related anemia(CRA).However,due to its complex composition,the key active ingredients and underlying mechanisms of its therapeutic effects often remain unknown.This research aims to use network pharmacology and molecular docking technology to systematically elucidate the potential mechanisms underlying the efficacy of SWD in treating cancer-related anemia.Methods:The key constituents of SWD were procured from the TCMSP database.Leveraging the Swiss ADME and Swiss Target Prediction databases,potential targets were recognized.Disease-related targets were assembled via the GeneCards and DrugBank databases.Constructing the PPI network involved the utilization of the STRING database,followed by visualization through Cytoscape 3.9.1 software.Subsequently,GO and KEGG enrichment analysis was conducted utilizing the DAVID database,with visual analysis performed on the macrobiotic platform.For molecular docking,the Autodock software was employed,and the molecular docking outcomes were visualized using the PyMOL software.Results:In this investigation,a comprehensive revelation of 18 primary active compounds and 511 associated targets linked to CRA was accomplished.The outcomes of protein-protein interaction(PPI)analysis unequivocally identified AKT1,EGFR,SRC,VEGFA,HRAS,MAPK3,and STAT3 as pivotal proteins within the SWD’s framework for effective CRA intervention.Notably,signaling pathways such as the HIF-1,JAK-STAT,TNF-α,and PI3K-Akt pathways,intricately involved in hematopoietic stem cell proliferation,differentiation,and inflammatory response,emerged as closely intertwined with the therapeutic application of SWD for CRA treatment.The congruence between these potential targets and SWD’s primary therapeutic constituents for CRA treatment was substantiated by the outcomes of molecular docking analysis.Conclusion:This work provided a reference for further fundamental research by outlining the primary active ingredients and putative molecular mechanisms of SWD in the treatment of CRA.

Screening of active ingredients of Taohong Siwu Decoction on platelet membrane receptor

OBJECTIVE To screen the active ingredients preventing platelet aggregations from Taohong Siwu Decoction. METHODS Fresh blood from healthy adult volunteer was collected with vacuum tube for preparation of platelet suspension. Platelet suspension was incubated with Taohong Siwu Decoction for one hour at 37℃,then centrifuged. The precipitate was washed and desorbed with buffer solutions.The differences of chemical constituents between incubated and unincubated were identified with high performance liquid chromatography-diode array detector. RESULTS According to the chromatograph at 254 nm,at least three kinds of different components were detected in Taohong siwu decoction before and after incubated with platelet. CONCLUSION Platelet suspension can be used for screening active ingredients on platelet membrane receptor from the traditional Chinese medicine.

Effects of Taohong Siwu Decoction on coagulation function and PI3K/AKT/mTOR pathway after femoral artery anastomosis in rabbits

Objective:To observe the effect of Taohong Siyu Decoction on the coagulation function and the signaling pathway of PI3K(phosphatidylinositol 3-kinase)/AKT(protein kinase B)/mTOR(mammalian target of rapamycin)after femoral artery anastomosis in rabbits.Methods:30 New Zealand white rabbits were divided into blank control group,model control group,papavine hydrochloride injection group and low,medium and high dose groups of Taohong Siwu decoction by random number table method,with 5 rabbits in each group.The rabbits in the model control group,papavine hydrochloride injection group and low,medium and high dose groups of Taohong Siwu decoction were treated with the femoral artery simple intermittent end-to-end suture model.After the successful modeling,the low,medium and high dose groups of Taohong Siwu decoction were given the Taohong Siwu decoction,while the model control group,the blank control group and papavine hydrochloride injection group were given the same amount of normal saline.APTT(activated partial thromboplastin time),FIB(fibrinogen)and PI3K/AKT/mTOR concentrations were measured in aural venous blood samples from six groups of rabbits 30min before operation and 1d,2D,3D and 7d after operation,respectively.Statistical analysis was conducted on the data of the six groups.Results:Compared with blank control group,APTT of model control group was significantly shortened 1d to 7d after operation(P<0.05),FIB values were significantly increased from 1d to 7d after operation(P<0.05);Compared with model control group,APTT in Taohong Siwu decoction low-dose,medium-dose and high-dose groups were significantly prolonged 1d to 7d after operation(P<0.05),FIB value of Taohong Siwu decoction medium and high dose groups decreased significantly from 1d to 7d after operation(P<0.05),the FIB value of Taohong Siwu decoction low-dose group was significantly decreased from 2d to 7d after surgery(P<0.05);Compared with papaverine hydrochloride injection group,APTT in Taohong Siwu decoction medium dose group was significantly prolonged 2d to 7d after surgery(P<0.05),APTT of Taohong Siwu decoction high-dose group was significantly prolonged on 1d to 7d after operation(P<0.05).FIB in Taohong Siwu decoction medium and high dose groups decreased significantly 1d to 7d after operation(P<0.05);Compared with the blank control group,the expression concentrations of PI3K,Akt and mTOR in serum of the model control group were significantly increased from 1d to 7d after surgery(P<0.05);Compared with the model control group,the expression levels of PI3K,Akt and mTOR in serum were significantly increased in the low dose group of Taohong Siwu decoction and Papaverine Hydrochloride Injection group on postoperative 7 days(P<0.05),Taohong Siwu decoction high-dose group was significantly increased from 1d to 7d after surgery(P<0.05),the expression concentrations of PI3K and Akt in Taohong Siwu decoction medium dose group were significantly increased from 2d to 7d after operation(P<0.05),mTOR expression levels were significantly increased from 3d to 7d after operation(P<0.05);Compared with papaverine hydrochloride injection group,the expression concentrations of PI3K,Akt and mTOR in serum of Taohong Siwu decoction medium dose group were significantly increased from 3d to 7d after operation(P<0.05),the expression concentrations of PI3K and mTOR in Taohong Siwu decoction high-dose group were significantly increased from 1d to 7d after operation(P<0.05),and the expression concentration of Akt increased significantly from 3d to 7d after operation(P<0.05).Conclusion:The Taohong Siwu decoction can improve the coagulation function of rabbit femoral artery anastomosis,prevent thrombosis,activate PI3K/Akt/mTOR signaling pathway,promote angiogenesis,and improve tissue ischemia after artery anastomosis.

Meta-analysis of efficacy of Taohong Siwu Decoction in the treatment of diabetic peripheral neuropathy

Objective:To evaluate the clinical efficacy of combined/single use of Taohong Siwu decoction in the treatment for diabetic peripheral neuropathy(DPN)by meta-analysis.Methods:Database were searched electronically from the time databases established to November 2020 to collect randomized controlled trials of Taohong Siwu decoction combined with non-specific therapy for DPN in Chinese or English.The trial was assessed by 2 researchers independently,RevMan 5.3 software was used for meta-analysis.Results:A total of 13 studies included 970 patients.Meta-analysis showed that the combined/single use of Taohong Siwu decoction can further improve median sensory nerve velocity〔MD=4.86,95%CI(2.70,7.03),P<0.00001〕,and the curative effect〔OR=4.35,95%CI(3.1,6.06),P<0.00001〕,increase the velocity of the motor nerve〔MD=6.84,95%CI(6.14,7.55),P<0.00001〕,and the velocity of the sensory nerve〔MD=7.46,95%CI(5.84,9.08),P<0.00001〕,decrease TCM syndrome score〔MD=-5.61,95%CI(-6.63,-4.60),P<0.00001〕,and fasting blood-glucose〔MD=-0.24,95%CI(-0.37,-0.11),P<0.00001〕.The GRADE showed B level of evidence.Conclusion:Combined/single use of Taohong Siwu decoction in the treatment for DPN is effective.The safety is not clear,and more high-quality clinical studies are expected to be included to provide evidence support.

Research progress of Taohong Siwu Decoction and its modified prescription in the treatment of diabetic peripheral neuropathy

Western medicine mainly focuses on the conventional basic treatment of Diabetic peripheral neuropathy(DPN),such as blood glucose control,anti-oxidative stress,and nerve nutrition,but the efficacy and safety of the drugs cannot be guaranteed.As an important prescription for promoting blood circulation,removing blood stasis and nourishing blood,Taohong Siwu Decoction can not only promote cell proliferation and repair,reduce inflammatory factors in the blood,reduce the whole blood viscosity and plasma viscosity,and has a good anticoagulation effect.Moreover,Taohong Siwu Decoction and its added or subtracted prescription,foot bath and combined acupuncture have the effect of regulating blood sugar,improving nerve conduction velocity and relieving clinical symptoms,without obvious adverse reactions.This article reviews Taohong Siwu Decoction and its addition and subtraction in the treatment of diabetic peripheral neuropathy.

The famous Chinese medicine doctor Xue Jing-Dong Taohong Siwu Decoction cured 1 case of primary liver cancer stage Ⅲa

Primary liver cancer is the most common malignant tumor of the liver.Surgery,intervention,radiotherapy,and chemotherapy are the main treatment methods in the early stage,and the basic principles of post-treatment are palliative treatment and symptomatic treatment.Xue Jing-Dong,a famous Chinese doctor,started from the etiology and pathogenesis of liver cancer,used the methods of promoting blood circulation to remove blood stasis,nourishing blood and replenishing liver,and applied Taohong Siwu Decoction based on long-term clinical experience to cure 1 case of primary liver cancer stage Ⅲa in two years.The patient’s survival period can be prolonged and the quality of life can be improved.The author begins with the diagnosis of stage Ⅲa liver cancer,western medicine treatment methods,and previous treatment experience of traditional Chinese medicine,and briefly describes the diagnosis and treatment of this patient.

Taohong Siwu Decoction:a classical Chinese prescription for treatment of orthopedic diseases

The pathogenesis of orthopedic diseases is intimately linked to blood stasis,frequently arising from damage to primary and secondary blood channels.This disruption can lead to“blood leaving the meridians”or Qi stagnation,resulting in blood stasis syndrome.Taohong Siwu Decoction(THSWD)is a renowned classical Chinese medicinal formula extensively used to promote blood circulation and mitigate blood stasis.Clinical studies have demonstrated its significant therapeutic effects on various orthopedic conditions,particularly its anti-inflammatory and analgesic properties,as well as its efficacy in preventing deep vein thrombosis post-surgery.Despite these findings,research on THSWD remains fragmented,and its interdisciplinary impact is limited.This review aims to provide a comprehensive evaluation of the efficacy and pharmacological mechanisms of THSWD in treating common orthopedic diseases.Additionally,we employ bibliometric analysis to explore research trends and hotspots related to THSWD.We hope this review will enhance the recognition and application of THSWD in orthopedic treatments and guide future research into its pharmacological mechanisms.

Taohong Siwu decoction(桃红四物汤)ameliorates atherosclerosis in rats possibly through toll-like receptor 4/myeloid differentiation primary response protein 88/nuclear factor-κB signal pathway

OBJECTIVE:To investigate the effect of Taohong Siwu decoction(桃红四物汤,TSD)on atherosclerosis in rats as well as investigate the underlying mechanism based on molecular docking.METHODS:Sixty healthy male Sprague-Dawley rats were randomly divided into 6 groups with 10 rats in each group:control group,model group,atorvastatin group(AT,2.0 mg/kg),and TSD groups(20,10,5 g/kg)after 7 d of acclimation.The model of atherosclerosis was successfully established except the control group by high fat diet(HFD)and vitamin D2.Biochemical analyzers were used to detect the levels of triglyceride(TG),total cholestero(TC),low density lipoprotein-cholesterol(LDLC)and high density lipid-cholesterol(HDL-C)in blood lipid.The levels of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and interleukin-1β(IL-1β)were determined by enzyme-linked immunosorbent assay.Sudan IV staining and Hematoxylin and eosin staining(HE staining)were performed to observe the pathological changes in aortic tissue.Molecular docking technology was used to predict the best matching between the main components of TSD and the target proteins.The expression of target proteins was further detected by quantitative real time polymerase chain reaction(q RTPCR)and Western blot analysis.RESULTS:The results showed that TSD restricted atherosclerosis development and decreased the inflammatory cytokines in plasma.Molecular docking results predicted that the main components of TSD showed a strong binding ability with toll-like receptor(TLR4),myeloid differentiation primary response protein 88(My D88),and nuclear factor kappa-B(NF-κB).The results of q RT-PCR and Western blot analysis showed that the m RNA and protein expressions of TLR4,My D88 and NF-κB p65 in the aorta were reduced in atorvastatin group and TSD group.CONCLUSIONS:TSD can ameliorate atherosclerosis in rats,and the underlying mechanism is supposed be related to the suppression of inflammatory response by regulating TLR4/My D88/NF-κB signal pathway.

Effects and mechanisms of Bazhen decoction,Siwu decoction,and Sijunzi decoction on 5-fluorouracil-induced anemia in mice

OBJECTIVE:To investigate the effects of Bazhen decoction(BZD),Siwu decoction(SWD) and Sijunzi decoction(SJZD) in mice with anemia induced by5-fluorouracil(5-FU) and discussed the possible pharmacological hematopoietic mechanism to provide experimental evidence for the clinical use of the three classical prescriptions in the treatment of anemia.METHODS:Anemia was induced by intravenous injection of 5-FU and 80 female Kunming mice were randomly,assigned to oral administration of SWD,SJZD,or BZD daily for 10 days.Peripheral blood cells count and bone marrow cell cycle were monitored to evaluate anti-anemia effects.Serum cytokines,interferon-γ(IFN-γ),interleukin-3(IL-3),erythropoietin(EPO),granulocyte-macrophage colonystimulating factor(GM-CSF),and tumor necrosis factor-α(TNF-α) were assayed.EPO m RNA expression was assayed in kidney and liver tissue homogenates.RESULTS:BZD and SWD significantly increased the number of red blood cells,hemoglobin concentration,and hematocrit,promoted bone marrow cells to enter the cell cycle,proliferate and differentiate,significantly increased IL-3 secretion,and significantly inhibited IFN-γ secretion.BZD stimulated transcription of EPO m RNA in the kidney and liver and enhanced serum EPO expression.A therapeutic effect of SJZD was not observed.CONCLUSION:BZD and SWD treatment specifically enhanced hematopoietic function and mediated myelopoiesis by altering serum cytokines levels and accelerating entry of bone marrow cells into the cell cycle.Better curative effects were achieved via nourishing both Qi and blood(BZD) than by enriching the blood(SWD) or invigorating Qi(SWZD)alone.

Regulative effect of Taohong Siwu decoction(桃红四物汤) on extracellular matrix of endometrium in drug-induced abortion

OBJECTIVE: To explore the effects of Taohong Siwu decoction(桃红四物汤, THSWD) on the extracellular matrix of endometrium in rats following drug-induced abortion.METHODS: Thirty-six pregnant female rats were administered mifepristone and misoprostol to induce abortion, and amounts of uterine bleeding were recorded. Pathological damage and collagen accumulation were detected by hematoxylin-eosin staining and Masson’s trichrome staining in uterus, respectively. Myeloperoxidase was evaluated by immunohistochemistry.The expression levels of fibronectin, laminin, matrix metalloproteinase 9(MMP-9), and tissue inhibitor of metalloproteinase 1(TIMP-1) were quantified using western blotting.RESULTS: THSWD could promote endometrial protection in rats following drug-induced abortion.The contents of cellulose and myeloperoxidase were significantly decreased in uterine tissue of THSWD-treated groups. Moreover, THSWD significantly decreased the expression levels of fibronectin, laminin, and TIMP-1. THSWD also significantly increased MMP-9 expression and the MMP-9/TIMP-1 ratio.CONCLUSION: THSWD plays a critical role in endometrial protection by reducing extracellular matrix deposition and uterine fibrosis. These effects may have been achieved by increasing MMP-9, reducing TIMP-1, and/or altering the ratio of MMP-9/TIMP-1.

Efficacy and Safety Evaluation of Taohong Siwu Decoction(桃红四物汤)for Patients with Angina Pectoris:A Meta-Analysis of Randomized Controlled Trials

Objective To assess the efficacy and safety of Taohong Siwu Decoction(桃红四物汤,TSD),a Chinese herbal compound prescription,in patients with angina pectoris(AP).Methods Randomized clinical trials(RCTs)comparing TSD plus conventional treatment(CT)with CT plus placebo or CT only in the patients with AP were searched in PubMed,Cochrane Library,Excerpta Medica Database,Chinese National Knowledge Infrastructure,Chinese Biomedical Literature Database,Wanfang Database,Chinese Scientific Journal Database,Chinese Clinical Trial Registry and International Clinical Trial Registry from their inception to March 2017.The primary outcomes include a composite event of death,acute myocardial infarction(AMI),and target vessel revascularization.The secondary outcomes include angina symptom,electrocardiogram(ECG)improvement and serum high-sensitivity C-reactive protein(hs-CRP),endothelin-1(ET-1),triglycerides(TG),total cholesterol(TC)and low-density lipoprotein cholesterol(LDL-C)levels.The methodological quality of included studies and extracted available data were assessed.RevMan 5.3 software was used to conduct statistical analysis.The relative risk(RR)and standardized mean difference(SMD)with 95%confidence interval(CI)was calculated.A funnel plot was used to evaluate the publication bias.Results Among 204 studies identified in the literature search,12 trials including 959 patients with AP met the inclusion criteria.No studies reported the primary outcome including death,AMI and target vessel revascularization.TSD combined with CT showed significant improvement in relieving angina symptom[RR=3.70,95%CI(2.42,5.67)]and ECG[RR=3.20,95%CI(2.20,4.65)]compared with CT alone.TSD combined with CT reduced the serum hs-CRP,TG,TC and LDL-C levels compared with CT alone.No serious adverse events were reported in TSD combined with CT.Conclusions TSD combined with CT has a potential benefit on relieving AP without significant adverse events.However,the efficacy on the cardiovascular events needs to be assessed by more rigorously-designed,largescale,and multi-center RCTs in future.

Clinical Observation on Treatment of Pediatric Intractable Nephropathy with Modified Taohong Siwu Decoction(桃红四物汤)

Objective: To observe the clinical effect of Modified Taohong Siwu Decoction (MTSD) in treating pediatric intractable nephropathy (PIN). Methods: Ninety-five patients with PIN were divided into 2 groups at random. The 60 patients in the treated group were treated with MTSD and the 35 patients in the control group were treated with heparin. The clinical therapeutic effect and levels of thromboxane B2 (TXB2) and 6-keto-prostacyclin F1α (6-keto-PGF1α) before and after treatment were observed. Results: The total effective rate in the treated group was 81.7%, which was similar to that in the control group (80.0%, P>0.05). The levels of TXB2 and TXB2/6-keto-PGF1α ratio were higher in both groups of the patients as compared with those of the healthy control (P<0.01). After treatment, the two criteria were significantly improved in the two treated groups, as compared with those before treatment, the difference was significant (P<0.01), while in comparison between the MTSD treated group and the control group, no significant difference was found (P>0.05). Conclusion: MTSD has good effect in treating PIN, it could improve the metabolic unbalance of thromboxane and prostacyclin.

Effects of Traditional Herbal Formulae on Human CYP450 Isozymes

Objective：To assess the effects of traditional herbal formulae Sijunzi Decoction（四君子汤,Sagunja-tang,SJZD）,Siwu Decoction（四物汤,Samul-tang,SWD）,Bawu Decoction（八物汤,Palmul-tang,BWD）and Shiquan Dabu Decoction（十全大补汤,Sipjeondaebo-tang,SDD）on the activities of human cytochrome P450（CYP450）,a drug-metabolizing enzyme.Methods：Herbal formula water extracts were filtered and lyophilized after the powder extracts were dissolved in distilled water.The activities of major human CYP450isozymes（CYP3A4,CYP2C19,CYP2D6 and CYP2E1）were measured using in vitro fluorescence-based enzyme assays.The inhibitory effects of the herbal formulas on the activities of CYP450 were characterized as half maximal inhibition concentration（IC50）values.Results：All the tested herbal formulae inhibited CYP2C19activity（IC50：SJZD,83.28μg/m L;SWD,235.54μg/m L;BWD,166.82μg/m L;SDD,178.19μg/m L）;SJZD（IC50=196.46μg/m L）,SWD（IC50=333.42μg/m L）and SDD（IC50=163.42μg/m L）inhibited CYP2E1-mediated metabolism;whereas BWD exhibited comparatively weak inhibition of CYP2E1（IC50=501.78μg/m L）.None of the four herbal formulas significantly affected CYP3A4 or CYP2D6.Conclusions：These results suggest that SJZD,SWD,BWD and SDD could potentially inhibit the metabolism of co-administered synthetic drugs whose primary route of elimination is via CYP2C19.In addition,clinically relevant pharmacokinetic interactions could occur when SJZD,SWD or SDD is co-administered with drugs metabolized by CYP2E1.Our findings provide information for the safety and effective clinical use of these four classic herbal formulas.

Chinese Medicines and Bioactive Compounds for the Treatment of Stroke

Stroke is an important cause of mortality and morbidity worldwide but effective therapeutic strategy for the prevention of brain injury in patients with cerebral ischemia is lacking. Although tissue plasminogen activator has been used to treat stroke patients, this therapeutic strategy is confronted with ill side effects and is limited to patients within 3 h of a stroke. Due to the complexity of the events and the disappointing results from single agent trials, the combination of thrombolytic therapy and effective neural protection therapy may be an alternative strategy for patients with cerebral ischemia. Chinese medicine （CM） is the most widely practiced form of herbalism worldwide, as it is a sophisticated system of medical theory and practice that is specifically different from Western medicine. Most traditional therapeutic formulations consist of a combination of several drugs. The combination of multiple drugs is thought to maximize therapeutic efficacy by facilitating synergistic actionsand preventing possible adverse effects while at the same time marking at multiple targets. CM has been labeled in ancient medicine systems as a treatment for various diseases associated with stroke. This review summarizes various CMs, bioactive compounds and their effects on cerebral ischemia.

Clinical Observation on Treatment of Acute Retrobulbar Optic Neuritis with Integrated Traditional Chinese and western medicine

Objective: To evaluate the clinical effect of integrated Chinese and Western medicine in treating acute retrobulbar optic neuritis. Methods: Combined Therapy of modified prescription of Danzhi Xiaoyao San and Taohong Siwu Decoction and Mailuoning was applied to 12 patients (13 diseased eyes) and changes of such criteria as visual acuity, optic fundus, visual field, fundus fluorescein angiogram, pattern visual evoked potential and contrast sensitivity were observed. Results: 5 eyes (38. 46 % ) were cured, 5 (38. 46% ) markedly effective, 2 (15. 38% ) effective and 1 ineffective, the total effective rate being 92. 31 %. After treatment, visual acuity of 10 eyes was elevated to over 1. 0, and the other criteria were also improved in various degrees. Conclusion: The program of integrated therapy was effective in treating acute retrobulbar optic neuritis.

Coronary Heart Disease Complicating With Impaired Glucose Tolerance and Constipation:A Case Report Cured by Integrated Chinese-Western Medicine

Complications are more frequent in elderly patients with coronary heart disease （CHD）, such as impaired glucose tolerance and constipations. It is always difficult to cure these complications in clinical practice. In this case we had successfully cured an eighty-three years old man with CHD complicating impaired glucose tolerance and constipation by integrated Chinese-Western medicine.