PMID- 25389767
OWN - NLM
STAT- MEDLINE
DCOM- 20160429
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 11
DP  - 2014
TI  - Preventive effect of Daiokanzoto (TJ-84) on 5-fluorouracil-induced human gingival 
      cell death through the inhibition of reactive oxygen species production.
PG  - e112689
LID - 10.1371/journal.pone.0112689 [doi]
LID - e112689
AB  - Daiokanzoto (TJ-84) is a traditional Japanese herbal medicine (Kampo 
      formulation). While many Kampo formulations have been reported to regulate 
      inflammation and immune responses in oral mucosa, there is no evidence to show 
      that TJ-84 has beneficial effects on oral mucositis, a disease resulting from 
      increased cell death induced by chemotherapeutic agents such as 5-fluorouracil 
      (5-FU). In order to develop effective new therapeutic strategies for treating 
      oral mucositis, we investigated (i) the mechanisms by which 5-FU induces the 
      death of human gingival cells and (ii) the effects of TJ-84 on biological events 
      induced by 5-FU. 5-FU-induced lactate dehydrogenase (LDH) release and pore 
      formation in gingival cells (Sa3 cell line) resulted in cell death. Incubating 
      the cells with 5-FU increased the expression of nucleotide-binding domain and 
      leucine-rich repeat containing PYD-3 (NLRP3) and caspase-1. The cleavage of 
      caspase-1 was observed in 5-FU-treated cells, which was followed by an increased 
      secretion of interleukin (IL)-1beta. The inhibition of the NLRP3 pathway slightly 
      decreased the effects of 5-FU on cell viability and LDH release, suggesting that 
      NLRP3 may be in part involved in 5-FU-induced cell death. TJ-84 decreased 
      5-FU-induced LDH release and cell death and also significantly inhibited the 
      depolarization of mitochondria and the up-regulation of 5-FU-induced reactive 
      oxygen species (ROS) and nitric oxide (NO) production. The transcriptional 
      factor, nuclear factor-kappaB (NF-kappaB) was not involved in the 5-FU-induced cell death 
      in Sa3 cells. In conclusion, we provide evidence suggesting that the increase of 
      ROS production in mitochondria, rather than NLRP3 activation, was considered to 
      be associated with the cell death induced by 5-FU. The results also suggested 
      that TJ-84 may attenuate 5-FU-induced cell death through the inhibition of 
      mitochondrial ROS production.
FAU - Yoshida, Kaya
AU  - Yoshida K
AD  - Department of Oral Healthcare Education, Institute of Health Biosciences, 
      University of Tokushima Graduate School, Tokushima, Japan.
FAU - Yoshioka, Masami
AU  - Yoshioka M
AD  - Department of Oral Health Science and Social Welfare, Institute of Health 
      Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
FAU - Okamura, Hirohiko
AU  - Okamura H
AD  - Department of Histology and Oral Histology, Institute of Health Biosciences, 
      University of Tokushima Graduate School, Tokushima, Japan.
FAU - Moriyama, Satomi
AU  - Moriyama S
AD  - Department of Hygiene and Oral Health Science, Institute of Health Biosciences, 
      University of Tokushima Graduate School, Tokushima, Japan.
FAU - Kawazoe, Kazuyoshi
AU  - Kawazoe K
AD  - Department of Clinical Pharmacy, Institute of Health Biosciences, University of 
      Tokushima Graduate School, Tokushima, Japan.
FAU - Grenier, Daniel
AU  - Grenier D
AD  - Oral Ecology Research Group, Faculty of Dentistry, Laval University, Quebec City, 
      QC, Canada.
FAU - Hinode, Daisuke
AU  - Hinode D
AD  - Department of Hygiene and Oral Health Science, Institute of Health Biosciences, 
      University of Tokushima Graduate School, Tokushima, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141112
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Drugs, Chinese Herbal)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 3.4.22.36 (Caspase 1)
RN  - U3P01618RT (Fluorouracil)
SB  - IM
MH  - Caspase 1/metabolism
MH  - Cell Death/*drug effects/physiology
MH  - Drugs, Chinese Herbal/*pharmacology
MH  - Fluorouracil/*pharmacology
MH  - Gingiva/*drug effects/metabolism/pathology
MH  - Humans
MH  - Medicine, Kampo
MH  - Reactive Oxygen Species/*metabolism
MH  - Stomatitis/chemically induced/drug therapy/metabolism/pathology
PMC - PMC4229234
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/11/13 06:00
MHDA- 2016/04/30 06:00
PMCR- 2014/11/12
CRDT- 2014/11/13 06:00
PHST- 2014/08/11 00:00 [received]
PHST- 2014/10/09 00:00 [accepted]
PHST- 2014/11/13 06:00 [entrez]
PHST- 2014/11/13 06:00 [pubmed]
PHST- 2016/04/30 06:00 [medline]
PHST- 2014/11/12 00:00 [pmc-release]
AID - PONE-D-14-36000 [pii]
AID - 10.1371/journal.pone.0112689 [doi]
PST - epublish
SO  - PLoS One. 2014 Nov 12;9(11):e112689. doi: 10.1371/journal.pone.0112689. 
      eCollection 2014.