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Sophora alopecuroides, a plant of the family Leguminosae, is one of the Daodi herbs in Ningxia. The active constituents of Sophora alopecuroides are abundant and complex, including alkaloids, flavonoids, volatile oils, steroids, polysaccharides, fatty acids and so on. In recent decades, a great number of domestic and overseas studies have been carried out on Sophora alopecuroides alkaloids, which have anti-hepatitis, anti-liver fibrosis, anti-cirrhosis, anti-liver failure and anti-liver cancer and other pharmacological effects. Clinically, Matrine-related drugs are used to treat hepatitis B virus infection and other diseases. This review aims to summarize the main active ingredients of Sophora alopecuroides, mainly focusing on the research progress in their treatment activities for liver diseases.
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Objective To find novel lead compounds as p53-MDM2 inhibitors by drug repurposing strategy. Methods The p53-MDM2 inhibitory activities of compounds were determined by FP and western blotting. MTT method was used to determine the in-vitro antitumor activities. The metabolites in human liver microsomes were tested. Results Bepridil showed excellent in-vitro anti-tumor activity and strong p53-MDM2 protein binding inhibitory activity, which can significantly reduce the expression of MDM2 protein in a dose-dependent manner. The metabolites in human liver microsomes are mainly benzene ring hydroxyl mono-oxidation metabolites. Conclusion Bepridil can be used as a lead compound for p53-MDM2 protein binding small molecule inhibitors for subsequent structural optimization design studies.
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Receptor-interacting protein (RIP) kinase 1 is involved in immune-mediated inflammatory diseases including ulcerative colitis (UC) by regulating necroptosis and inflammation. Our group previously identified TAK-632 (
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Objective To develop novel NAE inhibitors with non-nucleoside scaffold by a scaffold hopping strategy and study the in vitro antitumor activities. Methods Disulfonamideindazole 14 was synthesized through 23 steps with a good yield. Its chemical structure was confirmed by 1H NMR and MS. MTT method was used to determine the in vitro antitumor activities. Results Compound 14 exhibited moderate antitumor activities against various cancer cells and promoted significant UBC12 accumulation in a dose-dependent manner. Conclusion Compound 14 is a potent NAE inhibitor with remarkable apoptosis induction and cell cycle arrest in prostate cancer PANC-1 cells. Our work provides a valuable leading compound for the further design and development of NAE inhibitors.
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Natural product evodiamine and its derivatives represent a promising class of multi-target antitumor agents. However, the clinical development of these compounds has been hampered by a poor understanding of their antitumor mechanisms. To tackle this obstacle, herein, novel fluorescent probes were designed to elucidate the antitumor mode of action of 10-hydroxyevodiamine. This compound was proven to be distributed in the mitochondria and lysosomes and to act by autophagy and apoptosis mechanisms.
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OBJECTIVE:To study the diastolic effect and mechanism of Hui medicine Hexin oil solution on isolated thoracic aortic vascular rings of rats,and provide reference for its treatment for cardiovascular diseases. METHODS:Thoracic aortic vascu-lar rings of rats were taken and then soaked in Kelvin's nutrient solution(K-H). Using 1×10-6 mol/L norepinephrine(PE)or 60 mmol/L potassium chloride (KCl) for inducing the contraction of vascular rings,biological signal acquisition and analysis system was used to determine the diastolic effect and mechanism of Hexin oil solution with concentrations of 0.0204,0.0408,0.0612, 0.0816,0.1020 mg/mL on vascular rings,and diastolic rate was calculated. After culturing vascular rings by 0.1 mmol/L nitric ox-ide synthase inhibitor L-nitro-arginine methyl ester (L-NAME),cyclooxygenase inhibitor indomethacin (INDO),and potassium ion channel blocker glibenclamide(Gli)for 20 min,the diastolic effects of above-mentioned 5 mass concentrations of Hexin oil so-lution on the contraction of vascular rings pre-contracted by PE were determined,and diastolic rate was calculated. The test was based on K-H solution as blank control. RESULTS:Compared with blank control,Hexin oil solution with concentration of 0.0204-0.1020 mg/mL had obvious diastolic effect on the contraction of vascular rings induced by PE and KCl (P<0.05 or P<0.01), showing concentration-dependent relationship. INDO pre-treatment can relieve the diastolic effect of Hexin oil solution on vascular rings pre-contracted by PE;and compared with blank control group,the diastolic rate had no statistical significance (P>0.05). While the pre-treatment of Gli,L-NAME did not affect the diastolic effect of Hexin oil solution on vascular rings pre-contracted by PE;and compared with blank control group,diastolic rate was obviously increased(P<0.05 or P<0.01). CONCLUSIONS:Hex-in oil solution can concentration-dependently conduct the relaxation of thoracic aortic vascular rings pre-contracted by PE,KCl. The mechanism may be associated with activation of cyclooxygenase pathway.
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OBJECTIVE:To study the diastolic effect and mechanism of Hui medicine Hexin oil solution on isolated thoracic aortic vascular rings of rats,and provide reference for its treatment for cardiovascular diseases. METHODS:Thoracic aortic vascu-lar rings of rats were taken and then soaked in Kelvin's nutrient solution(K-H). Using 1×10-6 mol/L norepinephrine(PE)or 60 mmol/L potassium chloride (KCl) for inducing the contraction of vascular rings,biological signal acquisition and analysis system was used to determine the diastolic effect and mechanism of Hexin oil solution with concentrations of 0.0204,0.0408,0.0612, 0.0816,0.1020 mg/mL on vascular rings,and diastolic rate was calculated. After culturing vascular rings by 0.1 mmol/L nitric ox-ide synthase inhibitor L-nitro-arginine methyl ester (L-NAME),cyclooxygenase inhibitor indomethacin (INDO),and potassium ion channel blocker glibenclamide(Gli)for 20 min,the diastolic effects of above-mentioned 5 mass concentrations of Hexin oil so-lution on the contraction of vascular rings pre-contracted by PE were determined,and diastolic rate was calculated. The test was based on K-H solution as blank control. RESULTS:Compared with blank control,Hexin oil solution with concentration of 0.0204-0.1020 mg/mL had obvious diastolic effect on the contraction of vascular rings induced by PE and KCl (P<0.05 or P<0.01), showing concentration-dependent relationship. INDO pre-treatment can relieve the diastolic effect of Hexin oil solution on vascular rings pre-contracted by PE;and compared with blank control group,the diastolic rate had no statistical significance (P>0.05). While the pre-treatment of Gli,L-NAME did not affect the diastolic effect of Hexin oil solution on vascular rings pre-contracted by PE;and compared with blank control group,diastolic rate was obviously increased(P<0.05 or P<0.01). CONCLUSIONS:Hex-in oil solution can concentration-dependently conduct the relaxation of thoracic aortic vascular rings pre-contracted by PE,KCl. The mechanism may be associated with activation of cyclooxygenase pathway.
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OBJECTIVE:To optimize supercritical CO2 fluid extraction (SFE-CO2) technology of volatile oil from Hui medi-cine Huihui Naogengtong for stroke,and to analyze and identify its component. METHODS:With yield of volatile oil and the con-tent of cinnamaldehydeas indexes,and extraction pressure,temperature and time as factors,single factor test and orthogonal test were designed to optimize SFE-CO2 technology;optimized technology was also validated. Physical and chemical indexes of volatile oil were determined,and the constituents of volatile oil were analyzed by GC-MS and retention index. Relative percentage contents of each component were calculated by area normalization method. RESULTS:Optimal technology was as follows as extraction pres-sure 30 MPa,extraction temperature 50 ℃ and extraction time 100 min. In verification test,the yield of volatile oil was 4.8%(RSD=0.02%,n=3),and the content of cinnamylaldehyde was 2.0 mg/g (RSD=1.8%,n=3). Physicochemical properties of volatile oil were as follows as relative density 1.05,refractive index 1.52,acid value 28.128 mg(KOH)/g,iodine value 74.47 g(I)/100 g,saponification value 54.2 mg(KOH)/g,peroxide 19.42 meq/kg. GC-MS analysis showed the similarity with retention index in literatures of 31 compounds were more than 80%,21 of them were identified and accounted for 44% of total volatile oil, among which E-cinnamaldehyde (9.14%),β-caryophyllene (3.21%),α-bisabolol (3.11%) and β-bisabolene (2.56%) had high relative percentage content. CONCLUSIONS:Optimal extraction technology is stable and feasible. The results of extraction technol-ogy and component analysis can provide important trail base and reference data for the exploration and utilization of Huihui Nao-gengtong.
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With the development of science and the progress of age,medicinal chemistry is not only limited to the lead discovery and the structure-activity relationship studies,but also finding the target of bioactive small molecule drugs has be-come a tough issue to be solved.The identification and validation of bioactive small molecule targets has become the most criti-cal and difficult task,which plays a decisive role in academic and pharmaceutical research.Herein we summarize the current methods for target identification of small molecules,and mainly discuss about the target identification method by the chemical probes.Recent cases of successful application were also introduced to demonstrate the strategy of probe synthesis and design.
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Tyrosyl-DNA phosphodiesterase Ⅰ (TdpⅠ ) is a recently discovered proteinthat catalyzes the hydrolysis of 3′-phosphotyrosyl bonds .Such linkages form in vivo during the interaction of DNA and topoisomerase Ⅰ (TopⅠ) .TdpⅠ has been regarded as a potential therapeutic co-target of TopⅠ because it has the functions of repairing Top Ⅰ compound and coun-teracting the effects of Top Ⅰ inhibitors .TdpⅠ inhibitors can not only synergizing with Top Ⅰ-targeting drugs (camptoth-ecins) ,but also strength the function of bleomycin ,topoisomerase Ⅱ (TopⅡ ) inhibitors (etoposide ,doxorubicin) and DNA alkylating agents .We summarized the researching advance of TdpⅠ inhibitors and focused on the introduction of the mecha-nism ,bioactivity and structure-activity relationship .
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Objective To study the hemostasis activity of iodine complex with carboxymethyl chitosan .Methods The polymers were prepared with azodiisobutyronitrile as the initiating agent and sodium acrylate ,N‐vinylpyrrolidone ,carboxym‐ethyl chitosan and N ,N′‐methylene diacrylamide as the raw materials .It was then complexed with iodine to generate iodine complex with carboxymethyl chitosan ,and the hemostasis activity was tested at the same time .Results The polymers could absorb water with the value of 103g/g and showed potent hemostasis activity for auricular veins and femoral veins .Conclusion The results showed that hemostatic effect of polymers was better than that of hemostatic sponge and Quikclot .
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Cancer is a serious threat to human life and health .Therefore, there is an emergent need to develop novel anti-cancer agents with new structural type , new mechanism of action and higher efficacy .Natural products had played a key role in the dis-covery of anticancer agents .The anti-cancer activity , mechanism of action , structure and activity relationship of several lead-com-pounds which were derived from natural products were summarized in this review .
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In recent years, the incidence and mortality rate of invasive fungal infection have increased dramatically, and it is of great significance to develop novel antifungal agents with new chemical structure and new mode of action. In this review, novel antifungal lead compounds reported from 2007 to 2009 are reviewed. Moreover, their chemical structures, antifungal activities and structure-activity relationships have been summarized, which can provide useful information for future study of antifungal agents.
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The Y118A、Y118F、Y118T、S378A、S378T、H310A、H310R mutants of Candida albicans sterol 14?-demethylase (CACYP51) were constructed and heterologously expressed in D12667, the reconstructed strain with the deletion of CYP51 gene of the Y12667. With the strains obtained and microsome enzymes separated, the western blot and the ultraviolet absorption spectrophotometry were used to qualitative and quantitative detect the expressed protein, the GC-MS was used to detect the metabolism activity of the protein. The results showed that, the target protein expressed successfully in the reconstructed strains, with the expression level up to 25% of the total microsome proteins. The results also showed that, the wild type protein had the catalytic activity to its nature substrate. While after alteration the wild gene with Y118A、Y118F、Y118T、S378A、S378T、H310A、H310R by a single base substitution, the catalytic activity of protein markedly decreased respectively. So the wild type and mutation CYP51 were expressed successfully in Saccharomyces cerevisiae and the expression products preserved the activity to metabolism their nature substrate.
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AIM To study the synthesis of zinc chlorin e4 (1), its experimental antigastrelcosis activity as well as the protection against acute liver injuries. METHODS Chlorin e6 (3) was prepared through acidic and alkaline oxidative degradation using silkworm excrement crude chlorophyll extracts as starting material. Compound 1 was synthesized via Zn(OAc)2 complex action with Chlorin e4 (2) which was prepared by refluxing 3 in pyridine. Gastric ulcers were induced by abdominal injection of 0.2% indomethacin at 20 mg.kg-1 in rats. The ulcer indexes and ulcer numbers in gastric mucosa were determined. Acute liver injuries were induced by abdominal injection of 0.3% thioacetamide (TAA) or 0.3% CCl4 at 20 mg.kg-1 in mice, and activities of SGPT in mice were determined. RESULTS Compound 1 is previously unknown. Compared with control group, abdominal administration of 1 at 100 mg.kg-1 reduced significantly the gastric ulcer index (P<0.001) and the number of ulcer (P<0.001) induced by indomethacin in rats. Abdominal administration of 1 at 100 mg.kg-1×3 exhibited marked inhibitory effects on elevated activities of SGPT induced by TAA (P<0.02) or CCl4 (P<0.01) in mice. CONCLUSION These results show that 1 has significant protective effect against indomethacin-induced gastric lesion in rats and TAA or CCl4 induced acute liver injuries in mice. It is suggested that 1 may be a promising new drug candidate for antigastrelcosis and liver injury protection.
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The effect of hyperestrogenemia induced by intramuscular injectied estradiol (E_2) on myocardial contractility and relaxation was observed in female rats with myocardial infarction (MI). The results showed that: (1) In MI group, the plasma estradiol level increased slyghtly and then droped, while the level of estradiol increased markedly in rats treated by E_2 in MI (MIE_2) group. (2) Diameter of myofibril in MIE_2 grows more than that of control sham operation(CS) and MI (10.65?0.59 VS 7.65?0.40 and 10.15?0.54?m, P
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To determine the effects of testosterone (T) on hypertrophy and cardiac function of rats with myocardial infarction (MI), the rats were divided into 3 groups: ie, the sham-operated group (S group), the coronary artery ligating groups with or without the injection of T (MIT and MI group). T level of plasma was tested on all rats, by RIA on1/4, 1, 3, 9, 20 day after operation; then the nuclear profiles per unit area of myocardium N_((n)A) the average nuclear length D_((n)) and the volume fraction of number of myoeytes in the myoeardium V_((m)v) were measured under microscope; The number of myocyte nuclei per unit ovolume of myocardium N_((n)v) and average myocyte cell volume per nucleus V_((m)n) were calculated. The results were as follows: (1) Comparing with S group N_((n)A), N_((n)v) and V_((m)n) in MI had marked changes (P0.05). Of all the mentioned changes were more marked in MIT group than that in MI group. (2) The total plasma concentration of T was correlated with V_((m)n) (r=0.60, P0.05) were not found in MIT rats. These results indicated that T may improve myocardial hypertrophy and promote the recovery of eardial function of MI.
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The immune-gold-silver stain and image analysis methods were used to check up estrodial receptor (ER) in rat heart at myocardial infarction (MI) conditions.Animals were divided randomly into four groups: one serves as normal control, another as sham-operation, the third was treated as myocardial infarction and the last one estrogen (E_2) was injected after MI. The results showed that all the parts of the heart have ER,but the distributions are not equal in atrium and ventricle, the former is less than that of the latter (0.1687?0.005, 0.2072?0.006, P
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The relationship between the sex hormone in plasma and left ventricular performance was studied with myocardial infarction(MI) in rats. It was found that in orchidectomized rats testosterone(T) in plasma decreased significantly (P
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The correlation of premature stimulation and local ventricular contraction state was studied by ultrasonic dimension gauge in the conscious dogs. When the anterior wall of LV was stimulated, the total percent thickening (TPT) the anterior wall reduced from the control value 19.6?3.2% to 6.7?6.6% (P