ANTIFUNGAL EFFECT OF HYPTIS SUAVEOLENS OIL MICROEMULSION BASED CARBOXYMETHYL MUNGBEAN GEL FOR TOPICAL DELIVERY

Objective: Conventional topical antifungal formulations limit the effectiveness of antifungal therapy. The aim of this study was to formulate effective antifungal microemulsion of H. suaveolens oil based carboxymethyl mungbean (CMMS) gel.Methods: H. suaveolens oil was obtained by steam distillation. Standard of H. suaveolens oil was performed by gas chromatography mass spectrometry (GC/MS). A high-viscosity CMMS was prepared and its mucoadhesive property was determined using modified USP dissolution test apparatus. H. suaveolens oil microemulsion based CMMS gel as transdermal drug carrier was then developed. Finally, in vitro drug release study and antifungal activity were determined.Results: GC/MS analysis exhibited that b-Caryophyllene, Sabinene and Limonene are the major components of H. suaveolens oil. CMMS gel revealed good mucoadhesive potential which depended on pH of the medium. A higher retention time in pH 4.5 medium than pH 10 medium was observed. Clotrimazole-loaded H. suaveolens oil microemulsions based CMMS gel was successful prepared and in vitro sustained release of clotrimazole was determined. Clotrimazole-loaded H. suaveolens oil microemulsions based CMMS gel had potent antifungal activity against all studied dermatophytes and Candida albican with higher inhibition zone than H. suaveolens oil microemulsions based CMMS gel, H. suaveolens oil and commercial clotrimazole cream.Conclusion: H. suaveolens oil microemulsions based CMMS gel present promising as an effective alternative for topical delivery of antifungal agents.Â

PREPARATION, CHARACTERIZATION AND ANTIOXIDANT ACTIVITY OF XANTHONE-LOADED MAKING (HODGSONIA HETEROCLITA) MICROEMULSIONS

Objective: The aim of this study was to incorporate xanthone into Making (Hodgsonia heteroclita) microemulsions and to evaluate the antioxidant activity of the formulations.Methods: Making oil was obtained from the seed of Hodgsonia heteroclite by a screw press machine. The solubility of xanthone in various oils, surfactants, and co-surfactants was investigated. Stable Making microemulsion and microemulsion-based gel were simultaneously loaded with xanthone. Finally, an in vitro xanthone release study was carried out and antioxidant activity was determined.Results: The optimal formulations of the Making microemulsion consisted of Making oil, capryol 90, tween 80, propylene glycol, and water. The average droplet size of xanthone-loaded Making microemulsion was around 110–130 nm. It was found that the stability of the xanthone-loaded Making microemulsion-based gel was higher than the xanthone-loaded Making microemulsion. Besides, the release of xanthone from the Making microemulsion-based gel was lower than that of the Making microemulsion. Moreover, it was found that the antioxidant activity of both xanthone-loaded Making microemulsion (TEAC and EC values of 9.8 mmol/mg and 14.8 mmol/mg, respectively) and microemulsion-based gel (TEAC and EC values of 9.4 mmol/mg and 18.5 mmol/mg, respectively) remained high even after extended storage conditions.Conclusion: It was concluded that Making oil is an attractive material to deliver xanthone in pharmaceutical applications

Hydrolyzed Flavonoids from Cyrtosperma johnstonii with Superior Antioxidant, Antiproliferative, and Anti-Inflammatory Potential for Cancer Prevention

Cyrtosperma johnstonii is one of the most interesting traditional medicines for cancer treatment. This study aimed to compare and combine the biological activities related to cancer prevention of the flavonoid glycosides rutin (RT) and isorhamnetin-3-o-rutinoside (IRR) and their hydrolysis products quercetin (QT) and isorhamnetin (IR) from C.johnstonii extract. ABTS and MTT assays were used to determine antioxidant activity and cytotoxicity against various cancer cells, as well as normal cells. Anti-inflammatory activities were measured by ELISA. The results showed that the antioxidant activities of the compounds decreased in the order of QT > IR > RT > IRR, while most leukemia cell lines were sensitive to QT and IR with low toxicity towards PBMCs. The reduction of IL-6 and IL-10 secretion by QT and IR was higher than that induced by RT and IRR. The combination of hydrolysis products (QT and IR) possessed a strong synergism in antioxidant, antiproliferative and anti-inflammatory effects, whereas the combination of flavonoid glycosides and their hydrolysis products revealed antagonism. These results suggest that the potential of the combination of hydrolyzed flavonoids from C. johnstonii can be considered as natural compounds for the prevention of cancer

Monoterpene indole alkaloid azine derivatives as MDR reversal agents

International audienceAiming at generating a library of bioactive indole alkaloid derivatives as multidrug resistance (MDR) reversers, two epimeric indole alkaloids (1 and 2) were submitted to chemical transformations, giving rise to twenty-four derivatives (5-28), bearing new aromatic or aliphatic azine moieties. The structure of the compounds was established by 1D and 2D NMR (COSY, HMBC, HMQC and NOESY) experiments. Two different strategies were employed for assessing their anti-MDR potential, namely through the evaluation of their activity as inhibitors of typical MDR ABC transporters overexpressed by cell transfection, such as ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP), or by evaluating their ability as collateral sensitivity (CS) agents in cells overexpressing MRP1. A considerable MDR reversing activity was observed for compounds bearing the aromatic azine moiety. The strongest and most selective P-gp inhibition was found for the epimeric azines 5 and 6, bearing a para-methylbenzylidene moiety. Instead, compounds 17 and 18 that possess a di-substituted benzylidene portion with methoxy and hydroxyl groups, selectively inhibited MRP1 drug-efflux. None of these compounds inhibited BCRP. Compounds 5, 6 and 18 were further investigated in drug combination experiments, which corroborated their anti-MDR potential. Moreover, it was observed that compound 12, with an aromatic azine moiety, and compounds 23-26, sharing a new aliphatic substituent, displayed a CS activity, selectively killing MRP1-overexpress-ing cells. Among these last compounds, it could be established that addition of 19, 23 and 25 to MRP1-overexpressing cells led to glutathione depletion triggering cell death through apoptosis

Optimizing the flavanone core toward new selective nitrogen-containing modulators of ABC transporters

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5-Oxo-hexahydroquinoline derivatives as modulators of P-gp, MRP1 and BCRP transporters to overcome multidrug resistance in cancer cells

Multidrug resistance (MDR) in cancer cells is often associated with overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2). Modulators of these transporters might be helpful in overcoming MDR. Moreover, exploiting collateral sensitivity (CS) could be another approach for efficient treatment of cancer. Twelve novel 5-oxo-hexahydroquinoline derivatives bearing different aromatic substitutions at C4, while having 2-pyridyl alkyl carboxylate substituents at the C3 were synthesized and evaluated for MDR reversal activity by flow cytometric determination of rhodamine 123, calcein and mitoxantrone accumulations in P-gp, MRP1 and BCRP-overexpressing cell lines, respectively. Furthermore, to confirm the P-gp inhibitory activity, the effect of compounds on the reduction of doxorubicin's IC50 of drug-resistant human uterine sarcoma cell line, MES-SA/DX5, was evaluated. Compounds D6, D5 and D3 (bearing 3-chlorophenyl, 2,3-dichlorophenyl and 4-chlorophenyl substituents at C4 position of 5-oxo-hexahydroquinoline core) were the most potent P-gp, MRP1 and BCRP inhibitors, respectively, causing significant MDR reversal at concentrations of 1–10 μM. Additionally, D4 (containing 3-flourophenyl) was the most effective MRP1-dependent CS inducing agent. Overall, chlorine containing compounds D6, C4 and D3 were capable of significant inhibition of all 3 important efflux pumps in cancer cells. Moreover, D6 also induced CS triggered by reducing glutathione efflux. In conclusion, some of the 5-oxo-hexahydroquinoline derivatives are effective efflux pump inhibitors capable of simultaneously blocking 3 important ABC transporters involved in MDR, and represent promising agents to overcome MDR in cancer cells. © 2018 Elsevier Inc

Molecular analysis of the massive GSH transport mechanism mediated by the human Multidrug Resistant Protein 1/ABCC1

International audienceThe transporter Multidrug Resistance Protein 1 (MRP1, ABCC1) is implicated in multidrug resistant (MDR) phenotype of cancer cells. Glutathione (GSH) plays a key role in MRP1 transport activities. In addition, a ligand-stimulated GSH transport which triggers the death of cells overexpressing MRP1, by collateral sensitivity (CS), has been described. This CS could be a way to overcome the poor prognosis for patients suffering from a chemoresistant cancer. The molecular mechanism of such massive GSH transport and its connection to the other transport activities of MRP1 are unknown. In this context, we generated MRP1/MRP2 chimeras covering different regions, MRP2 being a close homolog that does not trigger CS. The one encompassing helices 16 and 17 led to the loss of CS and MDR phenotype without altering basal GSH transport. Within this region, the sole restoration of the original G1228 (D1236 in MRP2) close to the extracellular loop between the two helices fully rescued the CS (massive GSH efflux and cell death) but not the MDR phenotype. The flexibility of that loop and the binding of a CS agent like verapamil could favor a particular conformation for the massive transport of GSH, not related to other transport activities of MRP1