Efficacy and potential mechanism of atherosclerosis prevention by the active components of leech based on network pharmacology combined with animal experiments.

Introduction: Leeches are flesh-eating and bloodsucking parasitic worms. They are being used as a traditional Chinese medicine for centuries in activating blood and dissolving statis, dreging the meridims and tick. Hirudin, an active peptide product present in leech, has blood anticoagulant property and can assist in the treatment of thrombosis and diseases related to blood circulation. The efficacy and potential mechanism of action of leeches in such diseases should be further explored. Materials and methods: First, network pharmacology was used to screen the predicted potential targets of the active constituents of leech and AS. The common targets of the active constituents of leech and AS were obtained using Venn diagram. Further, the drug-active-constituent-target network diagram, protein-protein interaction, and GO and KEGG pathway enrichment analyses were used to construct the active-constituent-AS target-pathway network diagram. Subsequently, the protein-drug molecule docking model was drawn. Finally, the results of network pharmacology were validated using a mouse model of AS. Results: In total, 34 active constituents of leech and 1172 AS-related gene targets were selected, took the drug action targets and potential disease targets to get the common targets, and took the top 10 of degree value as the main active constituents for the treatment of atherosclerosis. There were 89 common targets and 12 core targets. The main targets included MAPK, EGFR, PIK3CB, etc. Potential regulatory pathways included cancer pathways, EGFR tyrosine kinase inhibitor resistance, Rap1 signaling pathway, PPAR signaling pathway, PI3K-Akt signaling pathway, C-type lectin receptor signaling pathway, and AGE-RAGE signaling pathway in diabetic complications. Animal experiments using mouse model of AS confirmed that AS plaques were smaller after treatment with leeches. SRC level was measured using western blotting. Expression of SRC in myocardial tissue was remarkably lower in the mice treated with leech than in the mice from model group fed on high-fat chow. Conclusions: To the best of our knowledge, this is the first study to explore the mechanism of action of the active components of leech in AS prevention. The active components of leeches play a coordinated role in preventing AS through multicomponent, multitarget, and multichannel mechanism of action related to inflammatory response, oxidative stress, and lipid metabolism. This study provided a reference for subsequent cellular and animal experiments.

[Research progress in prevention and treatment of radiation-induced intestinal injury by traditional Chinese medicine active components].

Radiation-induced intestinal injury(RIII), a common complication of radiotherapy for pelvic malignancies, affects the quality of life and the radiotherapy efficacy for cancer. Currently, the main clinical approaches for the prevention and treatment of RIII include drug therapy, hyperbaric oxygen therapy, and surgical treatment. Among these methods, drug therapy is cost-effective. Traditional Chinese medicine(TCM) containing a variety of active components demonstrates mild side effects and good efficacy in preventing and treating RIII. Studies have proven that TCM active components, such as flavonoids, terpenoids, phenylpropanoids, and alkaloids, can protect the intestine against RIII by inhibiting oxidative stress, regulating the expression of inflammatory cytokines, modulating the mitochondrial apoptosis pathway, adjusting intestinal flora, and suppressing cell apoptosis. These mechanisms can help alleviate the symptoms of RIII. The paper aims to provide a theoretical reference for the discovery of new drugs for the prevention and treatment of RIII by reviewing the literature on TCM active components in the last 10 years.

Potential Protective Mechanisms of S-equol, a Metabolite of Soy Isoflavone by the Gut Microbiome, on Cognitive Decline and Dementia.

S-equol, a metabolite of soy isoflavone daidzein transformed by the gut microbiome, is the most biologically potent among all soy isoflavones and their metabolites. Soy isoflavones are phytoestrogens and exert their actions through estrogen receptor-ß. Epidemiological studies in East Asia, where soy isoflavones are regularly consumed, show that dietary isoflavone intake is inversely associated with cognitive decline and dementia; however, randomized controlled trials of soy isoflavones in Western countries did not generally show their cognitive benefit. The discrepant results may be attributed to S-equol production capability; after consuming soy isoflavones, 40-70% of East Asians produce S-equol, whereas 20-30% of Westerners do. Recent observational and clinical studies in Japan show that S-equol but not soy isoflavones is inversely associated with multiple vascular pathologies, contributing to cognitive impairment and dementia, including arterial stiffness and white matter lesion volume. S-equol has better permeability to the blood-brain barrier than soy isoflavones, although their affinity to estrogen receptor-ß is similar. S-equol is also the most potent antioxidant among all known soy isoflavones. Although S-equol is available as a dietary supplement, no long-term trials in humans have examined the effect of S-equol supplementation on arterial stiffness, cerebrovascular disease, cognitive decline, or dementia.

Sesquiterpene Lactone Deoxyelephantopin Isolated from Elephantopus scaber and Its Derivative DETD-35 Suppress BRAFV600E Mutant Melanoma Lung Metastasis in Mice.

Melanoma is a highly metastatic disease with an increasing rate of incidence worldwide. It is treatment refractory and has poor clinical prognosis; therefore, the development of new therapeutic agents for metastatic melanoma are urgently required. In this study, we created a lung-seeking A375LM5IF4g/Luc BRAFV600E mutant melanoma cell clone and investigated the bioefficacy of a plant sesquiterpene lactone deoxyelephantopin (DET) and its novel semi-synthetic derivative, DETD-35, in suppressing metastatic A375LM5IF4g/Luc melanoma growth in vitro and in a xenograft mouse model. DET and DETD-35 treatment inhibited A375LM5IF4g/Luc cell proliferation, and induced G2/M cell-cycle arrest and apoptosis. Furthermore, A375LM5IF4g/Luc exhibited clonogenic, metastatic and invasive abilities, and several A375LM5IF4g/Luc metastasis markers, N-cadherin, MMP2, vimentin and integrin α4 were significantly suppressed by treatment with either compound. Interestingly, DET- and DETD-35-induced Reactive Oxygen Species (ROS) generation and glutathione (GSH) depletion were found to be upstream events important for the in vitro activities, because exogenous GSH supplementation blunted DET and DETD-35 effects on A375LM5IF4g/Luc cells. DET and DETD-35 also induced mitochondrial DNA mutation, superoxide production, mitochondrial bioenergetics dysfunction, and mitochondrial protein deregulation. Most importantly, DET and DETD-35 inhibited lung metastasis of A375LM5IF4g/Luc in NOD/SCID mice through inhibiting pulmonary vascular permeability and melanoma cell (Mel-A+) proliferation, angiogenesis (VEGF+, CD31+) and EMT (N-cadherin) in the tumor microenvironment in the lungs. These findings indicate that DET and DETD-35 may be useful in the intervention of lung metastatic BRAFV600E mutant melanoma.

Authentication of Processed Epimedii folium by EA-IRMS.

Processing of crude drug is a key character of traditional Chinese medicine (TCM), which could enhance the efficacy and/or reduce the toxicity of crude drugs to fulfill different requirements of TCM clinical practice. Epimedii folium (EF) is a widely used TCM. As a traditional method of TCM, EF is processed with refined mutton fat before being used in clinical practice. It has been reported that processing EF with mutton fat could improve the bioavailability and intestinal absorption of epimedium flavonoids and thus enhances the pharmacological effects. For economic benefits, it is possible to adulterate processed EF with unprocessed drug or process EF with cheaper plant oils. In the present study, 17 batches of crude and processed EF samples were collected from the Chinese market and 10 batches of replica processed drugs were prepared with different edible plant oils and animal fats in our laboratory. Elemental analyzer coupled with isotopic ratio mass spectrometry (EA-IRMS) was applied to determine the δ 13C values of the cyclohexane extracts of those samples. Significant differences could be observed in the results. EA-IRMS could be used to discriminate raw EF, processed EF, and EF processed with C3 plant oils.

Effect of compatible herbs on the pharmacokinetics of effective components of Panax notoginseng in Fufang Xueshuantong Capsule.

Fufang Xueshuantong (FXT) is a well-known Chinese herbal formula which has been used to treat cardiovascular and ophthalmic diseases, especially diabetic retinopathy. Panax notoginseng (Burkill) F.H. Chen (PN) is the main herb of FXT, whose major bioactive constituents are ginsenosides. However, the scientific basis of the compatibility of FXT is still ambiguous. The present study investigated the scientific basis of the compatibility of FXT by comparing the pharmacokinetics of marker compounds after oral administrations of PN and FXT. A high performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) method was developed for simultaneous detection of notoginsenoside R1 (NR1), ginsenoside Rg1 (GRg1), and ginsenoside Rb1 (GRb1) in rat plasma. The pharmacokinetic studies of FXT and PN were performed using the established method with the pharmacokinetic parameters being determined by non-compartmental analysis. The results showed that the pharmacokinetic parameters (maximum concentration, area under the curve (AUC0-t), clearance, and mean residence time) of NR1, GRg1, and GRb1 were significantly different after oral administration of FXT (P<0.05) compared with PN. The AUC0-t values of GRg1 and GRb1 were 1.7- and 3.4-fold greater, respectively, in FXT than in PN. The compatible herbs of FXT could prolong the retention time and increase the systemic exposure of NR1, GRg1, and GRb1 compared with PN in vivo, providing some scientific basis for the compatibility and clinical use of FXT.

Randomized, Double-Blinded, Double-Dummy, Active-Controlled, and Multiple-Dose Clinical Study Comparing the Efficacy and Safety of Mulberry Twig (Ramulus Mori, Sangzhi) Alkaloid Tablet and Acarbose in Individuals with Type 2 Diabetes Mellitus.

Aims. To evaluate the efficacy and safety of mulberry twig alkaloid (SZ-A) tablet compared with acarbose in patients with type 2 diabetes. Methods. This clinical trial enrolled 38 patients who were randomized into two groups (SZ-A: 23; acarbose: 15) and were treated for 24 weeks. Patients and clinical trial staffs were masked to treatment assignment throughout the study. The primary outcome measures were glycated hemoglobin (HbA1c) and 1-hour and 2-hour postprandial and fasting plasma glucose levels from baseline to the end of treatment. Analysis included all patients who completed this study. Results. By the end of this study, HbA1c level in SZ-A group was decreased from baseline significantly (P < 0.001). No significant difference was found when compared with acarbose group (P = 0.652). Similarly, 1-hour and 2-hour postprandial plasma glucose levels in SZ-A group were decreased from baseline statistically (P < 0.05), without any significant differences compared with acarbose group (P = 0.748 and 0.558, resp.). The fasting plasma glucose levels were not significantly changed in both groups. One of 23 patients in SZ-A group (4.76%) and 5 of 15 patients in acarbose group (33.33%) suffered from gastrointestinal adverse events. Conclusions. Compared with acarbose, SZ-A tablet was effective and safe in glycemic control in patients with type 2 diabetes.

Redox poly(ethylene glycol)-b-poly(L-lactide) micelles containing diselenide bonds for effective drug delivery.

Bioreducible polymers have appeared as the ideal drug carriers for tumor therapy due to their properties of high stability in extracellular circulation and rapid drug release in intracellular reducing environment. Recently, the diselenide bond has emerged as a new reduction-sensitive linkage. In this work, the amphiphilic poly(ethylene glycol)-b-poly(L-lactide) containing diselenide bond has been synthesized and used to load anti-tumor drug, docetaxel (DTX), to form the redox micelles. It was found that the redox micelles showed a rapid response to glutataione (GSH), which resulted in a fast release of DTX in the presence of GSH. In contrast, <40 % of DTX was released from the micelles within 72 h under the normal condition (absence of GSH). The DTX-loaded redox micelles showed the significant inhibition effect to MCF-7 cells, and the cytotoxicity was dependent on the intracellular GSH concentrations. Moreover, considering the potentially clinical applications of the micelles through intravenous injection, the blood compatibility was also studied by the hemolysis analysis, activated partial thromboplastin time, prothrombin time and thromboelastography assays. These results confirmed that the redox micelles showed good blood safety, suggesting a potential application in tumor therapy.