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Background: The increasing incidence of multidrug-resistant tuberculosis (MDR-TB) infections has created a need for new effective drugs that also target extensively drug-resistant tuberculosis (XDR-TB) and/or augment the activities of existing drugs against tuberculosis.Aim: This study searched natural products for a new lead compound that targets MDR/XDR-TB.Methods: An active compound was purified from the roots of Cynanchum atratum Bunge (Asclepiadaceae) after screening 1640 plant extracts, and its inhibitory effects against MDR/XDR strains and synergistic effects with existing anti-TB drugs were assessed using the resazurin, MGIT, and checkboard assays.Results: (-)-Deoxypergularinine, purified from the roots of C. atratum, inhibited not only M. tuberculosis but also MDR/XDR strains. The minimum inhibitory concentrations (MICs) of (-)-deoxypergularinine for H37Ra, H37Rv, MDR, and XDR strains were all about 12.5 µg/ml. Moreover, combinations of (-)-deoxypergularinine with the first-line standard drugs rifampicin or isoniazid afforded six- and eight-fold reductions in drug MIC values, respectively, against strain H37Ra.Conclusions: (-)-Deoxypergularinine exerts anti-tubercular activities not only against normal tuberculosis strains but also MDR/XDR strains, and synergic effects with rifampicin and isoniazid for the H37Ra strain. The alkaloid may be valuable for targeting M/XDR M. tuberculosis. [ABSTRACT FROM AUTHOR]

Objective In order to protect against Mycobacterium tuberculosis (MTB) infection, novel drugs and new targets should be screened from the vast source of plants. We investigated the potentiality of the herbal plant of Artemisia capillaris extract (AC) against Mycobacterium tuberculosis. Design In this study, we isolated ursolic acid and hydroquinone by bio-activity guided fractionation from the methanol extracts of AC, and tested the inhibitory effects against several strains of MTB. Anti-mycobacterial evaluation of these compounds was carried out using the MGIT™ 960 and resazurin assay. Mycobacterial morphological changes due to the treatment of these compounds were further evaluated by Transmission electron microscopy (TEM). Results Ursolic acid (UA) and hydroquinone (HQ) inhibited the growth of both susceptible and resistant strains of M. tuberculosis. The MIC (minimum inhibitory concentration) values of both UA and HQ were 12.5 μg/ml against the susceptible strains of M. tuberculosis. Also both UA and HQ showed 12.5–25 μg/ml of MIC values against MDR/XDR MTB strains. However, against clinical strains of MTB, UA was found sensitive against those strains that are sensitive against both INH and RFP but resistant against those strains that are resistant to INH. On the other hand HQ was sensitive against all clinical strains. TEM image-analysis of the strain H37Ra after treatment with UA revealed cell wall lysis, whereas HQ-treated cells showed deformed cytoplasmic morphology. Conclusion All these results indicate that AC extracts containing UA and HQ possess promising chemotherapeutic potency against MTB for future use. [ABSTRACT FROM AUTHOR]

Abstract: The flowers of Inula britannica L. var. chinensis (Rupr.) Reg. (Compositae) are used in traditional medicine to treat asthma, chronic bronchitis, and acute pleurisy in China and Korea. However, the pharmacological actions of Inula britannica L. var. chinensis on endothelial cells and inflammatory monocytes are not clear. In this study, we investigated whether bigelovin, a sesquiterpene lactone isolated from the flowers of Inula britannica L. var. chinensis, inhibits monocyte adhesion and adhesion molecule expression in brain endothelial cells. We measured tumor necrosis factor-α (TNF-α)-enhanced Raw264.7 monocyte binding to brain endothelial cells and the levels of cell adhesion molecules, including vascular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and endothelial-selectin (E-selectin) on the surface of brain endothelial cells. Bigelovin significantly inhibited these in a dose-dependent manner without affecting cell viability. Furthermore, bigelovin suppressed the nuclear factor kappaB (NF-κB) promoter-driven luciferase activity, NF-κB activation, and degradation of NF-κB inhibitor protein alpha (IκBα). These results indicate that bigelovin inhibits inflammatory monocyte adhesion to endothelial cells and the expression of VCAM-1, ICAM-1, and E-selectin by blocking IκBα degradation and NF-κB activation. [Copyright &y& Elsevier]

Abstract: Tilianin has been shown to down-regulate TNF-α induced expression of vascular cell adhesion molecules in endothelial cells. In this study, we examined the anti-atherogenic effects and molecular mechanism of tilianin in vitro and in vivo. Male low-density lipoprotein receptor null mice (Ldlr−/−) fed a high cholesterol diet showed significant increases in the size of atherosclerotic lesions, as well as increased plasma levels of total cholesterol, triglycerides, and the pro-inflammatory cytokines TNF-α and IL-1β, when compared with Ldlr−/− mice fed a normal diet. Mice fed the high cholesterol diet supplemented with tilianin showed significantly reduced lesion sizes and reductions in cytokine levels, without significant changes in serum cholesterol levels. Primary cultured peritoneal macrophages from Ldlr−/− mice showed increased level of TNF-α andIL-1β mRNA in response to treatment with lipopolysaccharide; these increases were inhibited by co-treatment with tilianin. Moreover, tilianin inhibited NF-κB activation, as determined by electrophoretic mobility shift and NF-κB promoter assays. Upstream of NF-κB activation, tilianin inhibited IκB kinase activation and the subsequent phosphorylation and degradation of IκBα protein. These results suggest that tilianin ameliorates atherosclerosis by inhibiting the production of the NF-κB-dependent pro-inflammatory cytokines, TNF-α and IL-1β, via the inhibition of IκB kinase activity. [Copyright &y& Elsevier]

Due to the emergence of multidrug-resistant and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis , new antituberculosis drugs are urgently required to improve the efficacy of current tuberculosis (TB) treatment. To achieve this goal, ca. 1000 chemical compounds were screened for potential antimycobacterial activity, among which methyl 5-(2-diethylaminoethoxy)-7,12-dioxo-7,12 dihydrodinaphtho[1,2- b ;2′,3′- d ]furan-6-carboxylate (DNF-3) showed strong activity against all of the tested drug-susceptible and -resistant M. tuberculosis strains, with 50% minimum inhibitory concentrations (MIC 50 values) of 0.02–0.39 µg/mL both in culture broth and within murine RAW 264.7 macrophage cells. When DNF-3 was used in combination with rifampicin or streptomycin, it exhibited direct synergy against XDR-TB and an additive effect against M. tuberculosis H37Rv. DNF-3 displayed a long post-antibiotic effect (PAE) that was comparable with rifampicin but was superior to isoniazid, streptomycin and ethambutol. Importantly, DNF-3 showed no cytotoxicity to any cell line tested, with a selectivity index (SI) of >32. DNF-3 was also active against 27 nontuberculous mycobacteria (NTM) strains, Staphylococcus spp. and Streptococcus spp. Taken together, these results indicate that DNF-3 is a promising new candidate drug for treating TB. Further studies are warranted to establish the in vivo effect and therapeutic potential of DNF-3. [ABSTRACT FROM AUTHOR]