Discussion on the mechanism of Guizhi Fuling Pills in the treatment of atherosclerosis based on network pharmacology and molecular docking technology / 国际中医中药杂志

Objective:To explore the active components, targets and mechanism of Guizhi Fuling Pills in the treatment of atherosclerosis (AS) based on network pharmacology and molecular docking technology.Methods:The active components and potential target information of Guizhi Fuling Pills in the treatment of AS was obtained using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), SwissTargetPrediction database and Genecards database. The target protein interaction network was constructed by using STRING database. The DAVID database was used to perform the Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment on potential targets. AutoDockVina and PyMOL software were used to verify the molecular docking of the main active components and key targets of Guizhi Fuling Pills.Results:A total of 74 active components, 239 potential targets and 4 710 AS-related disease targets were screened, and 182 intersection targets were obtained. A total of 484 biological process items, 132 molecular function items and 74 cellular component items were obtained by GO functional enrichment analysis, and 116 signal pathways were screened by KEGG enrichment analysis. The results of molecular docking suggested that the active components of Guizhi Fuling Pills have good binding activity to the key intersection targets.Conclusion:The active components of Guizhi Fuling Pills, such as sitosterol and paeoniflorin, mainly treat AS by regulating estrogen signal pathway and inflammatory signal pathway through TNF, VEGFA and other targets.

Exploring the mechanisms of Gui Zhi Fu Ling Wan on varicocele via network pharmacology and molecular docking.

Varicocele (VC) is a common urogenital disease that leads to a high risk of testicular pain or male infertility. The purpose of this research was to explore the molecular mechanism of the Gui Zhi Fu Ling Wan (GFW) in the treatment of VC. The main active ingredients and targets information of GFW were screened by Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and the targets related to VC were determined by GeneCards, Online Mendelian Inheritance in Man (OMIM), and Disease Gene Network (DisGeNET) databases. The intersection of active ingredient targets and disease targets was selected to construct a protein-protein interaction (PPI) network through the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. Based on the use of CytoNCA plug-in to find the main targets, a 'component-target-disease' network was constructed by Cytoscape 3.8.2. Metascape was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of drug and disease targets. Molecular docking was employed to investigate the binding interaction between the main active components and core targets. A total of 76 active components of GFW were screened out. The main targets of the active components on VC were tumour protein p53 (TP53), tumour necrosis factor (TNF), hypoxia inducible factor 1 subunit alpha (HIF1A), interleukin-6 (IL-6), caspase 3 (CASP3), catalase (CAT), prostaglandin-endoperoxide synthase 2 (PTGS2), vascular endothelial growth factor A (VEGFA). The PI3K-Akt signalling pathway, HIF-1 signalling pathway, and apoptosis signalling pathway were mainly involved in the regulation of VC. The results of molecular docking showed that the binding potential and activity of the main active components and the core targets of GFW were good. We found that GFW could alleviate apoptosis, participate in venous vessel morphogenesis, and reduce oxidative stress in the treatment of VC. This study can provide a reference for subsequent clinical and scientific research experiments, which can be used to design new drugs and develop new therapeutic instructions to treat VC.

Significant Tumor Reduction With Traditional Chinese Medicine in a Patient With Advanced Prostate Cancer: A Case Report.

Prostate cancer (PC) is the most common malignancy of the male genitourinary system. For patients with advanced progressive PC, the treatment strategies include second-line endocrine therapy, chemotherapy, and immunotherapy. Such therapeutic techniques are either too expensive or too toxic for some patients, and traditional Chinese medicine (TCM) has become an alternative for its low cost and low toxicity. The application of Shi-pi-san and Gui-zhi-Fu-ling-wan in PC has never been reported. We report their application on a 71-year-old male patient, who was diagnosed with PC and was undergoing endocrine therapy. He originally chose chemotherapy, and experienced acute renal failure, which required hemodialysis during hospitalization. He felt weak and opted for Chinese herbal medicine treatment. After treatment with Shi-pi-san and Gui-zhi-Fu-ling-wan, the patient's tumor and other symptoms were significantly reduced, and he reported feeling "refreshed." This case indicates that TCM treatment has unique advantages and is more tolerable than endocrine therapy and chemotherapy. Considering that the patient was undergoing hemodialysis treatment and using low-molecular-weight heparin (LMWH) to prevent blood coagulation while taking TCM, whether LMWH has a synergistic anticancer effect remains to be explored.

A Review on the Mechanism and Application of Keishibukuryogan.

The concept of "blood stasis" - called yu xie in Chinese, Oketsu in Japanese - is one of the unique pathophysiology of traditional medicine that originated in China and inherited in Korea and Japan. This concept is related to the multiple aspects of hemodynamic disorders brought on by quantitative and qualitative changes. It theorizes that the quantitative changes of "blood stasis" are related to peripheral circulatory insufficiency. When chronic qualitative changes of "blood stasis" produce stagnant blood that turns into a pathological product, it could cause inflammation and lead to organic changes. Trauma induced hematomas, that are considered to be a quantitative change of blood, are also a form of blood stasis. The basic medicine research on Keishibukuryogan (KBG)-a Japanese name in Traditional Japanese Medicine (Kampo) for one of the most common anti- "blood stasis" prescriptions, also known as gui-zhi-fu-ling-wan (GFW) in Chinese in Traditional Chinese Medicine (TCM)-indicated that the initiation of quantitative changes was closely related to loss of redox balances on endothelial function induced by oxidative stress. The following qualitative changes were related to coagulopathy, hyper viscosity; anti-platelet aggregation, lipid metabolism; a regulation of systemic leptin level and/or lipid metabolism, inflammatory factor; cyclooxygenase-1,2 (COX-1, 2), interleukin-6, 8 tumor necrosis factor-α, macrophage infiltration, hyperplasia, tissue fibrosis and sclerosis caused by transforming growth factor-ß1 and fibronectin, the dysfunction of regulated cell deaths, such as, apoptosis, autophagy, ferroptosis and ovarian hormone imbalance. Clinically, KBG was often used for diseases related to Obstetrics and Gynecology, Endocrine Metabolism, Rheumatology and Dermatology. In this review, we give an overview of the mechanism and its current clinical application of KBG through a summary of the basic and clinical research and discuss future perspective.

Effectiveness of Gyejibongnyeong-Hwan for shoulder pain: study protocol for a randomised, wait-list controlled pilot trial.

BACKGROUND: Shoulder pain is an uncomfortable feeling in the muscle around the shoulder. The cause of myalgia is the accumulation of lactic acid in muscles and impaired blood circulation, which is called blood stasis in traditional East Asian medicine. This study aimed to explore the therapeutic effect of Gyejibongnyeong-Hwan (GBH) for shoulder discomfort related to blood stasis before and after treatment. METHODS/DESIGN: This study will be a double-centre, randomised, wait-list controlled pilot trial. Participants with shoulder pain and with a visual analogue scale score of 4 or higher out of 10, blood stasis score of 9 or higher, and triglyceride level of ≥150 mg/dl or total cholesterol level of ≥200 mg/dl will be recruited from two university hospitals. A total of 40 participants will be assigned to the immediate and waiting treatment groups. The immediate treatment group will receive GBH for 8 weeks on enrolment while the waiting treatment group will receive GBH for 8-16 weeks after 8 weeks of controlled waiting. The primary outcome is shoulder pain, and the secondary outcomes are the blood stasis score, blood pressure, ankle-brachial pressure index, brachial-ankle pulse wave velocity, body mass index, waist circumference, indexes of oximetry, and levels of blood lipid, blood sugar, resistin, C-reactive protein, serum amyloid P, and D-dimer. DISCUSSION: The results of this pilot trial will be the bases for a full-scale clinical trial of GBH. TRIAL REGISTRATION: Clinical Research Information Service, KCT0003837. Registered on 23 April 2019. https://cris.nih.go.kr/cris/en/search/search_result_st01.jsp?seq=14258.

A clinical study of Guizhi-Fuling pill combined with conventional therapy for the patients with oviduct obstructive infertility / 国际中医中药杂志

Objective In order to evaluate the clinical curative effect of Guizhi-Fuling pill combined with conventional therapy for the patients with oviduct obstructive infertility.Methods In this study,102 patients with oviduct obstructive infertility (OO1) that accorded with the inclusion criteria were randomly divided into two groups according to the order of treatment.During the study,a total of 5 patients were lost in the two groups,and so 49 in the treatment group and 48 in the control group completed the protocol.The control group was given fallopian tube recanalization under the hysteroscopy,and the treatment group was given oral Guizhi-Fuling pill at day 2 after surgery on the basis of the control group treatment.Both groups were observed for 6 months.Before and after treatment,TCM symptom score was conducted,and IL-6 level was determined by radioimmunoassay;the uterine fallopian tube was examined after the 6th month of treatment,and pregnancy rate was observed and recorded.Results After treatment,abdominal pain degree (0.6 ± 0.1 vs.1.3 ± 0.1,t=3.612),the low back pain (0.9 ± 0.2 vs.1.6 ± 0.2,t=2.553),abdominal distension (0.5 ± 0.0 vs.1.0 ± 0.8,t=2.364),menstrual blood clots (0.5 ± 0.1 vs.1.0 ± 0.1,t=2.331) in the treatment group were significantly lower than those in the control group (Ps＜0.05).After treatment,the rate of oviduct patency was 75.5％ (37/49) in thetreatment group,50.0％ (24/48) in the control group,and the comparison difference between the two groups was statistically significant (x2=8.075,P=0.044).After 6 months of treatment,the pregnancy rate of the treatment group was 63.3％ (31/49),and that of the control group was 37.5％ (18/48),the difference of pregnancy rate between the two groups was statistically significant (x2=6.724,P=0.035).After treatment,serum IL-6 (31.04 ± 2.47 ng/ml vs.42.71 ± 2.52 ng/ml,t=7.593) in the treatment group was signicantly lower than the control group (P＜0.05).Conelusions Guizhi-Fuling pill combined with conventional therapy can reduce IL-6 level,promote fallopian tube recanalization,improve the intrauterine pregnancy rate,and improve the clinical symptoms of OOI patients.

Effect on Guizhi-Fuling decoction and Danggui-Shaoyao decoction combined with metformin for follicle numbers and ovarian volume of fueling the polycystic ovarian syndrome / 国际中医中药杂志

Objective To evaluate the efficacy of Guizhi-Fuling decoction and Danggui-Shaoyao decoction combined with metformin in patients with polycystic ovarian syndrome. Methods A total of 120 patients with fueling the polycystic ovarian syndrome were enrolled and divided into two group by random number table method, the treatment group (60 patients) and the control group (60 patients). Patients in the control group were treated with metformin, and those in the treatment group with Guizhi-Fuling decoction and Danggui-Shaoyao decoction plus metformin for 6 menstrual cycle. The vagina or rectum two-dimensional ultrasound was detected by follicle numbers (FN) and ovarian volume (OV). The height, weight, BMI calculation were recorded and evaluated before and after treatment. Results After treatment and follow-up, the OV (2.4 ± 1.5 cm3 vs. 4.7 ± 2.6 cm3, t=5.935; 1.6 ± 0.8 cm3 vs. 2.9 ± 1.3 cm3, t=-6.597), FN (8 ± 2 vs. 10 ± 2, t=-5.477; 6 ± 1 vs. 8 ± 2, t=-6.928) and BMI (20.5 ± 2.6 kg/m2 vs. 23.8 ± 2.7 kg/m2, t=-6.866; 20.1 ± 1.3 kg/m2 vs. 22.6 ± 1.7 kg/m2, t=-9.074) of the treatment group were significantly lower than those of the control group(P<0.01). Conclusions The Guizhi-Fuling decoction and Danggui-Shaoyao decoction combined with metformin can reduce the weight, ovarian volume, follicle numbers of PCOS patients.

Guizhi-Fuling Pill combined with conventional western medicine therapy for diabetic peripheral neuropathy / 国际中医中药杂志

Objective To evaluate the therapeutic effect ofGuizhi-Fuling Pill combined with conventional western medicine therapy for diabetic peripheral neuropathy (DPN).Methods A total of 78 patients with DNP were randomly divided into treatment group (40 patients) and control group (38 patients).The patients in the control group were administrated with mecobalamin on the basis of conventional treatment. In addition to the therapy of control group,patients in treatment group were givenGuizhi-Fuling Pill. The patients in both groups were treated for 2 weeks.The level of homocysteine (Hcy) and sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) in both groups were measured. Toronto clinical scoring system (TCSS) was used to evaluate the curative effect.Results The total effect rate in the treatment group was significantly higher than that in the control group (95.0%vs. 76.3%;χ2=5.616,P=0.018). After treatment, the MNCV of common peroneal nerve (46.1 ± 6.3 m/svs.42.5 ± 5.5 m/s;t=2.734,P<0.01 ), MNCV of median nerve (49.8 ± 5.2 m/svs.46.3 ± 5.9 m/s;t=2.607,P<0.05 ), SNCV of common peroneal nerve (38.5 ± 4.6 m/s vs. 35.4 ± 4.3 m/s;t=3.105,P<0.05 ), SNCV of median nerve (45.3 ± 5.2 m/svs. 42.3 ± 4.8 m/s;t=2.627, P<0.05 ) in the treatment group were significantly increased than those in the control group. The integral of TCSS (5.3 ± 3.1vs. 7.2 ± 2.9;t=2.823,P<0.01) and the level of Hcy (13.3 ± 3.2 μmol/Lvs. 17.1 ± 3.4 μmol/L;t=5.178, P<0.05) were significantly lower in treatment group than those in control group (P<0.05).Conclusions The Guizhi-Fuling Pill combined with conventional western medicine therapy could improve MNCV and SNCV and reduce the level of Hcy and improve the clinical effect.

Clinical study of Guizhi-Fuling pill combined with danazol in the treatment of ;endometriosis / 国际中医中药杂志

Objective To investigate the therapeutic effect of Guizhi-Fuling pill combined with danazol for endometriosis and its possible therapeutic mechanisms. Methods A total of 316 patients with endometriosis were recruited and randomly divided into a routine treatment group and a combined treatment group, 158 in each group. The conventional treatment group were treated by oral danazol tablets, and the combined treatment group by oral danazol and Guizhi-Fuling pill for 28 days. The serum levels of vascular endothelial growth factor (VEGF), VEGF receptor Flk-1, estrogen receptorα(ERα), 17β-estradiol (E2), IL-2, IL-6 and IL-8 were detected by the enzyme-linked immunosorbent assay. The expressions of VEGF and Flk-1 mRNAs in the ectopic endometriotic stromal cells were determined with the reverse transcriptase-polymerase chain reaction. Results The total effective rate in the combined treatment group was significantly higher than that in the routine treatment group (93.7% vs. 78.5%; χ2=13.968, P<0.01), and the recurrence rate was significantly lower (5.4%vs. 13.7%;χ2=19.984, P<0.01). After the treatment, the serum levels of VEGF (2.93 ± 0.07 pg/ml vs. 6.85 ± 0.12 pg/ml;t=354.679, P<0.01), Flk-1 (2.97 ± 0.12 pg/ml vs. 5.87 ± 0.17 pg/ml;t=175.179, P<0.01), ERα(4.93 ± 0.29 pg/ml vs. 6.85 ± 0.37 pg/ml;t=51.337, P<0.01), E2 (11.69±1.09 pg/ml vs. 14.10 ± 0.78 pg/ml;t=22.601, P<0.01), IL-2 (2.27 ± 0.12 pg/ml vs. 2.31 ± 0.16 pg/ml;t=2.514, P<0.05), IL-6 (0.39 ± 0.03 pg/ml vs. 0.59 ± 0.06 pg/ml;t=37.476, P<0.01) and IL-8 (0.47 ± 0.04 pg/ml vs. 0.81 ± 0.09 pg/ml;t=43.393, P<0.01) in the combined treatment group were significantly lower than those in the routine treatment group;the expressions of VEGF (0.69 ± 0.08 vs. 2.11 ± 0.09; t=148.229, P<0.01) and Flk-1 (4.67 ± 0.14 vs. 5.61 ± 0.22;t=45.311, P<0.01) mRNAs in the ectopic endometriotic stromal cells in the combined treatment group were significantly lower than those in the routine treatment group. Conclusions Guizhi-Fuling pill combined with danazol can downregulate the expressions of VEGF and Flk-1 in the ectopic endometriotic stromal cells, reduce the serum levels of VEGF, Flk-1, ERαand E2, alleviate inflammation, and improve symptoms.

Prescription patterns of Chinese herbal products for patients with uterine fibroid in Taiwan: A nationwide population-based study.

ETHNOPHARMACOLOGICAL RELEVANCE: Uterine fibroid (myoma) is one of the most common diseases in women. Although there are several studies on the efficacy of Chinese herbs, there is a lack of large-scale survey on the use of traditional Chinese medicine (TCM) for the treatment of uterine fibroid. This study aimed to investigate the utilization of Chinese herbal products for patients with uterine fibroid, prescribed by licensed TCM doctors in Taiwan. MATERIALS AND METHODS: A random sample comprised of one million individuals with newly diagnosed uterine fibroid between 2002 and 2010 from the Taiwanese National Health Insurance Research Database was analyzed. Demographic characteristics, TCM usage, the frequency as well as average daily dose of Chinese herbal formulas and the single herbs prescribed for patients with uterine fibroid, were analyzed. RESULTS: Overall, 35,786 newly diagnosed subjects with uterine fibroid were included. Majority of these patients (87.1%; n=31,161) had visited TCM clinics. Among them, 61.8% of their visits used Chinese herbal remedies. Patients less than 45 years of age tended to use TCM more frequently than elder patients. Gui-Zhi-Fu-Ling-Wan (Cinnamon Twig and Poria Pill) was the most frequently prescribed Chinese herbal formula, while San-Leng (Rhizoma Sparganii) was the most commonly prescribed single herb. CONCLUSIONS: Our study identified the characteristics and prescription patterns of TCM for patients with uterine fibroid in Taiwan. Further basic mechanistic studies and clinical trials are needed to confirm the therapeutic effects and mechanisms.

Effect of Gui-Zhi Fu-Ling Wan on HIF-1α and VEGF in Patients with Endometriosis / 世界科学技术-中医药现代化

This study was aimed to explore effect of Gui-Zhi Fu-Ling W an (GZFLW) on HIF-1α and vascular en-dothelial growth factor (VEGF) in patients with endometriosis. A total of 68 endometriosis patients in the First Peo-ple's Hospital of Xining from June 2011 to June 2013 were included. All patients received treatment of GZFLW, once a day. After one-month treatment, the treatment efficacy was analyzed. The endometrial tissues (both ectopic endometrium and eutopic endometrium) were obtained before and after treatment. The protein levels of HIF-1α and VEGF as well as the relationship of HIF-1α and VEGF were analyzed by SP immunohistochemistry. The results showed that the total treatment efficacy was 86.76%. Compared with pretreatment, the posttreatment protein levels of HIF-1α and VEGF were significantly reduced (P< 0.05). The decreasing of VEGF protein level and HIF-1α expres-sion level were positively correlated (P< 0.05). It was concluded that GZFLW had better efficacy in the treatment of endometriosis. One of the reasons may be the downregulation of protein levels of HIF-1α and VEGF in endometriosis tissues.