Effect of limonin and nomilin on HIV-1 replication on infected human mononuclear cells.
ABSTRACT In the last years several plant-derived natural compounds have been screened for their anti-HIV activity in order to find lead compounds with novel structures or mechanisms of action. Among these, several triterpenoids have been found to exhibit an antiretroviral activity with different mechanisms of action. In this study the effect of two limonoids, limonin and nomilin, on the growth of human immunodeficiency virus-1 (HIV-1) in culture of human peripheral blood mononuclear cells (PBMC) and on monocytes/macrophages (M/M) is described. Limonin and nomilin were found to inhibit the HIV-1 replication in all cellular systems used. A dose-dependent inhibition of viral replication was observed in PBMC isolated from healthy donors and infected with HIV-1 strain after incubation with limonin and nomilin (EC (50) values: 60.0 microM and 52.2 microM, respectively). The two terpenoids inhibited at all concentrations studied the production of HIV-p24 antigen even when the PBMC employed were chronically infected (EC (50) values of 61.0 microM for limonin and 76.2 microM for nomilin). Moreover, these compounds inhibited the HIV-1 replication even in infected M/M. In this cellular system the inhibitory effect was significant at the concentrations of 20 microM, 40 microM and 80 microM starting from day 14 and reached the maximum effect after 18 days of incubation. As regards the mechanism of action, limonin and nomilin inhibit in vitro HIV-1 protease activity. In general, the results obtained point out a similar anti-HIV activity of limonin and nomilin indicating that this activity is not drastically influenced by the structural difference between the two compounds.
Article: Limonin methoxylation influences the induction of glutathione S-transferase and quinone reductase.[show abstract] [hide abstract]
ABSTRACT: Previous studies have indicated the chemopreventive potential of citrus limonoids due to the induction of phase II detoxifying enzymes. In the present study, three citrus limonoids were purified and identified from sour orange seeds as limonin, limonin glucoside (LG), and deacetylnomilinic acid glucoside (DNAG). In addition, limonin was modified to defuran limonin and limonin 7-methoxime. The structures of these compounds were confirmed by NMR studies. These five compounds were used to investigate the influence of phase II enzymes in female A/J mice. Our results indicated the highest induction of glutathione S-transferase (GST) activity against 1-chloro-2,4-dinitrobenzene (CDNB) by DNAG (67%) in lung homogenates followed by limonin-7-methoxime (32%) in treated liver homogenates. Interestingly, limonin-7-methoxime showed the highest GST activity (270%) in liver against 4-nitroquinoline 1-oxide (4NQO), while the same compound in the stomach induced GST by 51% compared to the control. The DNAG treated group induced 55% in stomach homogenates. Another phase II enzyme, quinone reductase (QR), was significantly induced by limonin-7-methoxime by 65 and 32% in liver and lung homogenates, respectively. Defuran limonin induced QR in lung homogenates by 45%. Our results indicated that modification of limonin has differential induction of phase II enzymes. These findings are indicative of a possible mechanism for the prevention of cancer by aiding in the detoxification of xenobiotics.Journal of Agricultural and Food Chemistry 07/2009; 57(12):5279-86. · 2.82 Impact Factor
Article: Isolimonic acid interferes with Escherichia coli O157:H7 biofilm and TTSS in QseBC and QseA dependent fashion.[show abstract] [hide abstract]
ABSTRACT: BACKGROUND: E. coli O157:H7 (EHEC) is an important human pathogen. The antibiotic treatment of EHEC reportedly results in release of Shiga toxin and is therefore discouraged. Consequently, alternative preventive or therapeutic strategies for EHEC are required. The objective of the current study was to investigate the effect of citrus limonoids on cell-cell signaling, biofilm formation and type III secretion system in EHEC. RESULTS: Isolimonic acid and ichangin were the most potent inhibitors of EHEC biofilm (IC25=19.7 and 28.3 M, respectively) and adhesion to Caco-2 cells. The qPCR analysis revealed that isolimonic acid and ichangin repressed LEE encoded genes by 3 to 12 fold. In addition, flhDC was repressed by the two limonoids (3 to 7 fold). Further studies suggested that isolimonic acid interferes with AI-3/epinephrine activated cell-cell signaling pathway. Loss of biofilm inhibitory activity of isolimonic acid in qseBC mutant, which could be restored upon complementation, suggested a dependence on functional QseBC. Additionally, overexpression of qseBC in wild type EHEC abated the inhibitory effect of isolimonic acid. Furthermore, the isolimonic acid failed to differentially regulate ler in qseA mutant, while plasmid borne expression of qseA in qseA background restored the repressive effect of isolimonic acid. CONCLUSIONS: Altogether, results of study suggest that isolimonic acid and ichangin are potent inhibitors of EHEC biofilm and TTSS. Furthermore, isolimonic acid seems to interfere with AI-3/epinephrine pathway in QseBC and QseA dependent fashion.BMC Microbiology 11/2012; 12(1):261. · 3.04 Impact Factor
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ABSTRACT: Terpenoids, biosynthetically related ubiquitous compounds found in virtually all living organisms from marine invertebrates to blooming plants, are derived from the same precursor but their structures and biological and/or pharmacological activities are widely different. Our review concerns terpenoid compounds with antiviral activities, from the simplest sesquiterpenes to diterpenes and sesterterpenes. They include commercially produced therapeutics, compounds with documented antiviral effects and potential future medical use, as well as substances in different stages of clinical research and testing. All of them are based on natural compounds, with only partial man-made changes in the basic structure or mere substituent modifications.Anti-Infective Agents in Medicinal Chemistry (Formerly ?Current Medicinal Chemistry - Anti-Infective Agents) 06/2009; 8(3):169-192.