A plant sesquiterpene lactone and its derivative reduce cutaneous side effect of vemurafenib,a BRAF inhibitor drug to treat late stage melanoma

OBJECTIVE To investigate the pharmacological effect of a plant sesquiterpene lactone(designated D)and its semi-organically synthesized novel derivative(designated S)and the role of lipid mediators,viz.,oxylipins in attenuating vemurafenib-induced cutaneous side effects.METHODS A DMBA/TPAinduced skin carcinogenesis mouse model mimicking cutaneous side effect caused by vemurafenib was established to evaluate the efficacy of compound D and S in reversal of vemurafenib side effect.Comparative oxylipin metabolomics platform using UPLC-TQD mass spectrometry coupled with partial least squares-discriminant analysis(PLS-DA)analysis,cell-based assays,and immunochemistry analysis were performed to elucidate the mechanism insights of DET and S compounds and the role of specific oxylipins in skin cancer carcinogenesis.RESULTS Vemurafenib treatment expedited the skin papillomas formation in DMBA-TPA treated mouse from week 6 to week 3.Both D and S compounds could suppress the vemurafenib side effect and also decrease total papillomas numbers(55% to 72%)and average sizes(66% to 89%).Oxylipins metabolome analysis shows that specific arachidonic acid metabolites may play a role in vemurafenib-induced squamous cell carcinoma or keratoacanthomas formation in mouse skin that can be deregulated by D or S compound treatment.Notably,S compound can inhibit vemurafenib-induced paradoxical activation of MAP kinases in mouse skin or in NRAS mutant melanoma cells.CONCLUSION Our results indicate that plant sesquiterpene lactone D and its novel analog can reduce cutaneous side effect of vemurafenib through novel modes of action by inhibiting paradoxical activation of MAP kinases and de-regulating pro-inflammation mediators COX-2 and specific ecosanoid-type of oxylipins.This study may suggest a novel adjuvant therapy approach in treatment of BRAFV600 Emutant melanoma.

Antioxidant Capacity and Phenolic Content of Some Nepalese Medicinal Plants

Antioxidant capacities and phenolic contents of medicinal plants namely Usnea longifolia, Cetraria nepalensis, Parmelia minarum, Everniastrum nepalense, Rhododendron anthopogon and Fritillaria delavayi were analyzed via Folin-Ciocaltau assay, Ferric reducing activity power assay and 2,2-Diphenyl-1-picrylhydrazyl assay. All the tested plants depicted the antioxidant activity with variation in extent of activity among the plants. The FRAP (F-value: 387.4), DPPH (F-value: 89.684) and TPC (F-value: 559.163) values between the extracts showed the highly significant differences (P < 0.01). This study indicated the strong antioxidant potential of R. anthopogon among the plants tested.

Evaluation of the Insecticidal Activity of the Aerial Part of Pseudocytisus integrifofius （Salisb） Rehder on Grain Borer, Rhyzopertha dominica Fab, （Bostrychidae） and Wheat Weevil, Sitophilus granarius Linn, （Curculionidae）

This study aims to evaluate the potentialities of Pseudocytisus integrifolius （Salisb） Rehder （Brassicaceae） as a botanical insecticide for the protection of stored wheat against two pests of stored grain. The essential oil of Pseudoeytisus integrifolius was tested at different doses on adults of Rhyzopertha dominica Fab. （Bostrychidae） and Sitophilus granarius Linn. （Curculionidae）, at a temperature of 28 ~C and a relative humidity of 75%. This oil has insecticidal activity and gives, for the studied adults, a very significant reduction. The essential oil extracted from Pseudocytisus integrifolius is toxic on Rhyzopertha dominica with LDs0 = 2.61 ~tL/30g grain and LDs0 = 3.99 ~L/30g grain for Sitophilus granarius, the chemical composition analysis shows the richness of the essential oil compounds known for their insecticidal properties as dimethyl disulfide （DMDS） and dimethyl trisulfide explains the results.

Chemical Composition,Antioxidant and Antimicrobial Activity of the Oil and Plant Extract Myrocarpus frondosus Allemao

The objective of this study was to evaluate the chemical profile of extracts (aqueous and ethanol) and the essential oil of Myrocarpus frondosus Allem?o, the sensitivity of strains of Escherichia coli, Staphylococcus aureus, Salmonella typhimurium and Listéria monocytogenes, front the extracts and essential oil, by means of the microdilution method in broth, the antioxidant activity by the ABTS method, and the content of phenolic compounds present in the extracts and oil. For the preparation of extracts from plant leaves used with ethanol and water, then separated, the chemical identification of compounds was performed by high-performance liquid chromatography (CLAE-DAD) and gas chromatography coupled to mass spectrum (CG/MS). With the chemical analysis of the extracts obtained the presence of the major compound rutin, and oil major compound was found germacrene B. In the microdilution method in broth, oil and extracts showed inhibition against all the bacteria tested in the concentrations 1 mg/ml to 0.25 mg/ml, except for Staphylococcus aureus at a concentration of 0.25 mg/ml of the essential oil and trans-caryophyllene. The results of Minimum Bactericidal Concentration showed that the essential oil had bactericidal activity at a concentration of 1mg/ml for all bacteria tested and trans-caryophyllene at the same concentration only for Listeria monocytogenes. In relation to the essential oil, antioxidant activity showed higher radical reduction capacity of 40.92% and the content of phenolic compounds ethanol extract showed more 12.72%. The in vitro results support the conclusion that the essential oil is very promising both in antimicrobial action as antioxidant activity and the leaf extracts on antioxidant activity.

单叶细辛中一个新的马兜铃酸类化合物

为了研究单叶细辛(Asarum himalaicum)的化学成分,利用溶剂提取、硅胶柱色谱、凝胶(SephadexLH-20)柱色谱和半制备型高效液相色谱(semi-preparative high performance liquid chromatography,HPLC)等手段进行分离、纯化,从单叶细辛全草中共分离鉴定了15个化合物。其结构经1H NMR、13C NMR、HR-ESI-MS等谱学方法分别鉴定为4-去甲氧基马兜铃酸BII(4-demethoxyaristolochic acid BII,1)、马兜铃酸I(aristolochicacid I,2)、马兜铃酸Ia(aristolochic acid Ia,3)、7-羟基马兜铃酸I(7-hydroxyaristolochic acid I,4)、马兜铃酸IV(aristolochic acid IV,5)、马兜铃次酸II(aristolic acid II,6)、青木香酸(debilic acid,7)、马兜铃内酰胺I(aristololactam I,8)、9-羟基马兜铃内酰胺I(9-hydroxyaristololactam I,9)、7-甲氧基马兜铃内酰胺IV(7-methoxyaristololactam IV,10)、(2S)-柚皮素-5,7-二-O-β-D-吡喃葡萄糖苷((2S)-naringenin 5,7-di-O-β-D-pyranosylglucoside,11)、4-羟基苯甲酸(4-hydroxybenzoic acid,12)、3,4-二羟基苯甲酸(3,4-dihydroxybenzoic acid,13)、4-羟基肉桂酸(4-hydroxycinnamic acid,14)和β-谷甾醇(β-sitosterol,15)。其中,化合物1为新化合物,化合物3～6、9、12～14为首次从细辛属植物中分离得到,所有化合物均为首次从单叶细辛中分离得到。据文献报道,马兜铃酸和马兜铃内酰胺类成分具肾毒性,本研究提示单叶细辛药用的安全问题值得关注。

Applications of Pueraria lobata in treating diabetics and reducing alcohol drinking

Pueraria lobata is one of the most important medicinal herbs used traditionally in China. According to Shanghan Lun(Treatise on Exogenous Febrile Disease), it has been used traditionally to relieve body heat,eye soring, dry mouth, headache associated with high blood pressure, and stiff neck problems. Modern studies in the 1970 s revealed that isoflavonoids extracted from P. lobata were the bioactive components of an herbal remedy namely Yufeng Ningxin Tablets for the treatment of patients after stroke. This article reviews recent application of P. lobota in the treatment of diabetics and in reducing alcohol drinking. In view of its low toxicity profile, P. lobota stands an excellent chance to be developed as a phytomedicine for treating human diseases.

Petiveria alliacea Suppresses Airway Inflammation and Allergen-Specific Th2 Responses in Ovalbumin-Sensitized Murine Model of Asthma

Objective： To examine the effect of metanol extract of Petiveria alliacea （PM） on airway inflammation in a murine model of chronic asthma. Methods： Two-month-old male BALB/c mice （n=6-8/group） were sensitized on days 0 and 14 by intraperitoneal injection of 20μg ovalbumin （OVA）. On day 25, the mice received an airway challenge with OVA （3%, w/v, in phosphate buffered saline）. PM was administered orally by oral gavage to mice at doses of 100, 200 and 400 mg/kg body weight once daily from days 18 to 23. Control mice were orally administered phosphate buffered saline （PBS） to induce a model of asthma. At the end of the test, respiratory reactivity was assayed, the total cell number, interleukin-4 （IL-4）, IL-5, IL-13, tumor necrosis factor-alpha （TNF-α） and reactive oxygen species （ROS） in the bronchoalveolar lavage fluid （BALF） were determined and the levels of serum IgE, intercellular cell adhesion molecule 1 （ICAM-1） and eotoxin were measured. In addition, lung tissue was used to qualify the IL-4, IL-5, IL-13, TNF-α and transforming growth factor beta 1 （TGF-β1）. Histologic examination was performed to observe inflammatory cellular infiltration. Results： The administration of PM in comparison with the OVA-only treated group significantly attenuated the infiltration of eosinophUs and other inflammatory cells （P〈0.01）. Airway resistance （RI） in the OVA-only induced group was significantly higher than that of the PBS control group （P〈0.01） when methacholine was added. TNF-α, IgE, TGF-β1 and cytokine levels IL-4, IL-5, IL-β in the BALF decreased compared to control mice （P〈0.01 or P〈0.05）. PM treatment also inhibited the production of chemokines, eotaxin and ICAM-1 in BALF （P〈0.01）, which improved lung function. Histopathological examination revealed that the sensitized treated PM groups had significant lower in inflammatory scores similar to dexamethasone treatments and the untreated group. Conclusion： Administration of PM could inhibit airway inflammation, regulate cytokines, chemokines and enhance pulmonary conditions in allergic murine model of asthma.

Prodrug design,synthesis and pharmacokinetic evaluation of(3'R,4'R)-3-hydroxymethyl-4-methyl-3',4'-di-O-(S)-camphanoyl-(t)-cis-khellactone

3-Hydroxymethyl-4-methyl-DCK(3,HMDCK)was discovered previously as a potent HIV non-nucleoside reverse transcriptase inhibitor(NNRTIs)(EC_(50):0.004 μM,TI:6225)with a novel mechanism of action.It exerts anti-HIV activity by inhibiting the production of HIV-1 double-stranded viral DNA from a single-stranded DNA intermediate,rather than blocking the generation of single-stranded DNA from a RNA template,which is the mechanism of action of current HIV-1 RT inhibitors.However,the insufficient metabolic stability of 3 limits its further clinical development.In the current study,a series of ester prodrugs of 3 was designed and synthesized to explore the new drug candidates as NNRTIs.The L-alanine ester prodrug 10 exhibited desirable pharmacokinetic properties in vitro and in vivo and showed improved oral bioavailability of 26%in rat,and would be a potential clinical candidate as a new anti-AIDS drug.