BACKGROUNDThe incidence of halitosis has a prevalence of 22-50% throughout the world and is generally caused by anaerobic oral microorganisms, such as Fusobacterium nucleatum, Clostridium perfringens, and Porphyromonas gingivalis. Previous investigations on the structure-activity relationships of ginsenosides have led to contrasting results. Particularly, the antibacterial activity of less polar ginsenosides against halitosis-related bacteria has not been reported.METHODSCrude saponins extracted from the Panax quinquefolius leaf-stem (AGS) were treated at 130°C for 3 h to obtain heat-transformed saponins (HTS). Five ginsenoside-enriched fractions (HTS-1, HTS-2, HTS-3, HTS-4, and HTS-5) and less polar ginsenosides were separated by HP-20 resin absorption and HPLC, and the antimicrobial activity and mechanism were investigated.RESULTSHPLC with diode-array detection analysis revealed that heat treatment induced an extensive conversion of polar ginsenosides (-Rg1/Re, -Rc, -Rb2, and -Rd) to less polar compounds (-Rg2, -Rg3, -Rg6, -F4, -Rg5, and -Rk1). The antimicrobial assays showed that HTS, HTS-3, and HTS-4 were effective at inhibiting the growth of F. nucleatum, C. perfringens, and P. gingivalis. Ginsenosides-Rg5 showed the best antimicrobial activity against the three bacteria, with the lowest values of minimum inhibitory concentration and minimum bactericidal concentration. One major reason for this result is that less polar ginsenosides can more easily damage membrane integrity.CONCLUSIONThe results indicated that the less polar ginsenoside-enriched fraction from heat transformation can be used as an antibacterial agent to control halitosis.

01 Apr 2016·Nucleic Acid TherapeuticsQ3 · MEDICINE

Development of a Method for Profiling Protein Interactions with LNA-Modified Antisense Oligonucleotides Using Protein Microarrays

Q3 · MEDICINE

Article

Author: Mathialagan, Nagappan ; Whiteley, Lawrence O. ; Kakiuchi-Kiyota, Satoko ; Ryan, Anne M.

Development of locked nucleic acid (LNA) gapmers, antisense oligonucleotides used for efficient inhibition of target RNA expression, is limited by nontarget-mediated hepatotoxicity. Increased binding of hepatocellular proteins to toxic LNA gapmers may be one of the mechanisms contributing to LNA gapmer-induced hepatotoxicity in vivo. In the present study, we investigated the protein binding propensity of nontoxic sequence-1 (NTS-1), toxic sequence-2 (TS-2), and severely highly toxic sequence-3 (HTS-3) LNA gapmers using human protein microarrays. We previously demonstrated by the transcription profiling analysis of liver RNA isolated from mice that TS-2 and HTS-3 gapmers modulate different transcriptional pathways in mice leading to hepatotoxicity. Our protein array profiling demonstrated that a greater number of proteins, including ones associated with hepatotoxicity, hepatic system disorder, and cell functions, were bound by TS-2 and HTS-3 compared with NTS-1. However, the profiles of proteins bound by TS-2 and HTS-3 were similar and did not distinguish proteins contributing to severe in vivo toxicity. These results, together with the previous transcription profiling analysis, indicate that the combination of sequence-dependent transcription modulation and increased protein binding of toxic LNA gapmers contributes to hepatotoxicity.

01 Mar 2014·Toxicological SciencesQ2 · MEDICINE

Comparison of Hepatic Transcription Profiles of Locked Ribonucleic Acid Antisense Oligonucleotides: Evidence of Distinct Pathways Contributing to Non-target Mediated Toxicity in Mice

Q2 · MEDICINE

Article

Author: Lori A. Reed ; Lawrence O. Whiteley ; Satoko Kakiuchi-Kiyota ; Ahmed E. Enayetallah ; James A. Warneke ; Srinivasa R. Mantena ; Andrew D. Burdick ; Anne M. Ryan ; Linda F. Nelms ; Nagappan Mathialagan ; Petra H. Koza-Taylor ; Brett D. Hollingshead

Development of LNA gapmers, antisense oligonucleotides used for efficient inhibition of target RNA expression, is limited by non-target mediated hepatotoxicity issues. In the present study, we investigated hepatic transcription profiles of mice administered non-toxic and toxic LNA gapmers. After repeated administration, a toxic LNA gapmer (TS-2), but not a non-toxic LNA gapmer (NTS-1), caused hepatocyte necrosis and increased serum alanine aminotransferase levels. Microarray data revealed that, in addition to gene expression patterns consistent with hepatotoxicity, 17 genes in the clathrin-mediated endocytosis (CME) pathway were altered in the TS-2 group. TS-2 significantly down-regulated myosin 1E (Myo1E), which is involved in release of clathrin-coated pits from plasma membranes. To map the earliest transcription changes associated with LNA gapmer-induced hepatotoxicity, a second microarray analysis was performed using NTS-1, TS-2, and a severely toxic LNA gapmer (HTS-3) at 8, 16, and 72 h following a single administration in mice. The only histopathological change observed was minor hepatic hypertrophy in all LNA groups across time points. NTS-1, but not 2 toxic LNA gapmers, increased immune response genes at 8 and 16 h but not at 72 h. TS-2 significantly perturbed the CME pathway only at 72 h, while Myo1E levels were decreased at all time points. In contrast, HTS-3 modulated DNA damage pathway genes at 8 and 16 h and also modulated the CME pathway genes (but not Myo1E) at 16 h. Our results may suggest that different LNAs modulate distinct transcriptional genes and pathways contributing to non-target mediated hepatotoxicity in mice.

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