DL0410,a candidate for anti-Alzheimer disease with multiple targets in multiple pathways

OBJECTIVE To find a promising candidate for anti-Alzheimer disease(AD)with multiple targets in multiple pathways.METHODS A series of classifiers were constructed for predicting the active compounds against 51 key targets toward Alzheimer disease(AD)using the multitargetquantitative structure-activity relationships(mt-QSAR)method.While drug screening assays were established to evaluate the predicted active molecules.In addition,various cellular models and animal models related with AD were set up to further study the effects of the active compounds.RESULTS A system for the discovery of Multitarget-Directed Ligands against AD was set up and applied,the predicted active compounds were validated by the drug screening assays,and several active compounds with multiple targets were discovered.Among them,DL0410 exerted high activity on H3R,α7n ACh R,ACh E and ERα,also displayed the most significant effect in improving the ability of memory and learning in several AD animal models.The study on its action mechanisms showed that it′s effect may partially through increasing neurotransmitter,inhibiting oxidative emergency,inhibiting the expression of APP,and promoting long-term potentiation.Besides,DL0410 is of more safety than the first-line clinical medicines.CONCLUSION DL0410 is a promising candidate for further development for AD treatment.

Frankincense myrrh attenuates hepatocellular carcinoma by regulating tumor blood vessel development through multiple epidermal growth factor receptor-mediated signaling pathways

BACKGROUND In traditional Chinese medicine(TCM),frankincense and myrrh are the main components of the antitumor drug Xihuang Pill.These compounds show anticancer activity in other biological systems.However,whether frankincense and/or myrrh can inhibit the occurrence of hepatocellular carcinoma(HCC)is unknown,and the potential molecular mechanism(s)has not yet been determined.AIM To predict and determine latent anti-HCC therapeutic targets and molecular mechanisms of frankincense and myrrh in vivo.METHODS In the present study,which was based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(http://tcmspw.com/tcmsp.php),Universal Protein database(http://www.uniprot.org),GeneCards:The Human Gene Database(http://www.genecards.org/)and Comparative Toxicogenomics Database(http://www.ctdbase.org/),the efficacy of and mechanism by which frankincense and myrrh act as anti-HCC compounds were predicted.The core prediction targets were screened by molecular docking.In vivo,SMMC-7721 human liver cancer cells were transplanted as xenografts into nude mice to establish a subcutaneous tumor model,and two doses of frankincense plus myrrh or one dose of an EGFR inhibitor was administered to these mice continuously for 14 d.The tumors were collected and evaluated:the tumor volume and growth rate were gauged to evaluate tumor growth;hematoxylineosin staining was performed to estimate histopathological changes;immunofluorescence(IF)was performed to detect the expression of CD31,α-SMA and collagen IV;transmission electron microscopy(TEM)was conducted to observe the morphological structure of vascular cells;enzyme-linked immunosorbent assay(ELISA)was performed to measure the levels of secreted HIF-1αand TNF-α;reverse transcription-polymerase chain reaction(RT-qPCR)was performed to measure the mRNA expression of HIF-1α,TNF-α,VEGF and MMP-9;and Western blot(WB)was performed to determine the levels of proteins expressed in the EGFR-mediated PI3K/Akt and MAPK signaling pathways.RESULTS The results of the network pharmacology analysis showed that there were 35 active components in the frankincense and myrrh extracts targeting 151 key targets.The molecular docking analysis showed that both boswellic acid and stigmasterol showed strong affinity for the targets,with the greatest affinity for EGFR.Frankincense and myrrh treatment may play a role in the treatment of HCC by regulating hypoxia responses and vascular system-related pathological processes,such as cytokine-receptor binding,and pathways,such as those involving serine/threonine protein kinase complexes and MAPK,HIF-1 and ErbB signaling cascades.The animal experiment results were verified.First,we found that,through frankincense and/or myrrh treatment,the volume of subcutaneously transplanted HCC tumors was significantly reduced,and the pathological morphology was attenuated.Then,IF and TEM showed that frankincense and/or myrrh treatment reduced CD31 and collagen IV expression,increased the coverage of perivascular cells,tightened the connection between cells,and improved the shape of blood vessels.In addition,ELISA,RT-qPCR and WB analyses showed that frankincense and/or myrrh treatment inhibited the levels of hypoxia-inducible factors,inflammatory factors and angiogenesis-related factors,namely,HIF-1α,TNF-α,VEGF and MMP-9.Furthermore,mechanistic experiments illustrated that the effect of frankincense plus myrrh treatment was similar to that of an EGFR inhibitor with regard to controlling EGFR activation,thereby inhibiting the phosphorylation activity of its downstream targets:the PI3K/Akt and MAPK(ERK,p38 and JNK)pathways.CONCLUSION In summary,frankincense and myrrh treatment targets tumor blood vessels to exert anti-HCC effects via EGFR-activated PI3K/Akt and MAPK signaling pathways,highlighting the potential of this dual TCM compound as an anti-HCC candidate.

The Experience of Radiofrequency Ablation for Treatment of Multiple Accessory Pathways

Objective To analyse retrospectively the experience of radiofrequency ablation for successful treatment of multiple accessory pathways (APS). Methods 150 patients with supraventricu-lar tachycardia related to APS have undergone radiofrequency ablation since 1994; the data was analysed. Results 8 patients with multiple APS were cured, 4 patients could be diagnosed to have multiple APS during electrophysiologic study (EPS) before ablation, and in the remaining 4 patients the multiple APS could only be diagnosed after successful ablation of one AP. Conclusion right - sided multiple APS are sometimes very difficult to treat by ablation, because there are no standard reference electrograms for bracketing the earliest site. Mapping area should be broader rather than limited by preestablished idea.

Babao Dan Inhibits Gastric Cancer Progression in vivo Through Multiple Signaling Pathways

Objective:The aim of this study was to explore the effects of Babao dan(BBD),a traditional Chinese medicine,on gastric cancer(GC)progression in vivo.Materials and Methods:A subcutaneous xenograft mouse model of GC was established using MGC80-3 cells.The terminal deoxynucleotidyl transferase-mediated dUTP:2'-deoxyuridine 5'-triphosphate-biotin nick-end labeling method was adopted to detect cell apoptosis in vivo.The expression levels of proteins associated with proliferation,apoptosis,and angiogenesis were measured by immunohistochemical staining or western blotting(WB).The activation and protein levels of p-c-Jun N-terminal kinase(JNK),p-p38,p-extracellular-regulated kinase 1/2,p-nuclear factor-κB(NF-κB),and p-STAT3 were examined by Bio-plex and WB.Results:BBD significantly inhibited tumor growth in GC mouse models with no adverse effect on body weight or organ function.It was also found that BBD significantly suppressed the proliferation of GC tumor cells,induced the apoptosis of tumor cells,and inhibited angiogenesis through inactivating with mitogen-activated protein kinase,NF-κB,and STAT3 pathways.Conclusions:BBD exerts suppressive effects on GC tumor growth by regulating multiple pathways in vivo,which may provide a novel treatment option for GC therapy.

Stability Studies of Lysine Acetylsalicylate(Aspirin Derivative):Mechanisms of Hydrolysis

To control the stability of the lysine acetylsalicylate compound (LAS) in aqueous solution, some studies of the hydronium ion-catalyzed, hydroxide ion-catalyzed, and spontaneous reactions of this active ingredient in water solutions have been carried out. The pH-rate profile (log kobs = f(pH)), shows that the hydrolysis reaction of the LAS, is conducted by a catalysis acid-base mechanism, with multiple reaction pathways. The rate constants, kH, kOH and k0 to the reaction pathways catalyzed by H3O+, HO– ions and to the spontaneous reaction, for the hydrolysis reaction of the reagent LAS, were determined. The results show that the studied compound LAS is unstable in basic medium and the hydrolysis reaction catalyzed by HO– ions is predominant.For a known acidity (pH ≈ 10), studies conducted for different temperatures of the medium, clearly indicate, that the experimental rate constant kobs,depends on the temperature according to the Arrhenius equation. The activation parameters: activation energy (Ea), enthalpy (ΔH≠) and entropy (ΔS≠), for the transition state were determined, The very negative value obtained for the activation parameter ΔS*, first indicates that in the transition state there is gain in order, then this late state, resembles the products and that probably for the mechanism of the LAS hydrolysis reaction catalyzed by HO– ions, the rate-determining step is a bimolecular reaction. Finally from all these results, the mechanism for the reaction pathway catalyzed by HO– ions has been elucidated.

Disinfection byproducts in indoor swimming pool water: Detection and human lifetime health risk assessment

Quantification of regulated and emerging disinfection byproducts (DBPs) in swimming pool water,as well as the assessment of their lifetime health risk are limited in China.In this study,the occurrence of regulated DBPs (e.g.,trihalomethanes,haloacetic acids) and emerging DBPs (e.g.,haloacetonitriles,haloacetaldehydes) in indoor swimming pool water and the corresponding source water at a city in Eastern China were determined.The concentrations of DBPs in swimming pool water were 1-2 orders of magnitude higher than that in source water.Lifetime cancer and non-cancer risks of DBPs stemming from swimming pool water were also estimated.Inhalation and dermal exposure were the most significant exposure routes related to swimming pool DBP cancer and non-cancer risks.For the first time,buccal and aural exposure were considered,and were proven to be important routes of DBP exposure (accounting for 17.9%-38.9%of total risk).The cancer risks of DBPs for all swimmers were higher than 10^(-6)of lifetime exposure risk recommended by United States Environmental Protection Agency,and the competitive adult swimmers experienced the highest cancer risk (7.82×10^(-5)).These findings provide important information and perspectives for future efforts to lower the health risks associated with exposure to DBPs in swimming pool water.