Panax notoginseng saponins inhibit areca nut extract-induced oral submucous fibrosis in vitro.
BACKGROUND
Oral submucous fibrosis (OSF) is a premalignant and fibrosing disease, which is closely associated with the habit of chewing areca nut. Panax notoginseng Buck F. H. Chen is an often used antifibrotic and antitumor agent. To treat areca nut-induced OSF, we have developed a chewable tablet, in which one of the major medicines is total Panax notoginseng saponins (PNS). In this study, we have investigated the antifibrotic effect and mechanism of PNS on areca nut-induced OSF in vitro.


METHODS
Through human procollagen gene promoter luciferase reporter plasmid, hydroxyproline assay, gelatin zymography, qRT-PCR, ELISA, and Western blot, the influences of PNS on areca nut extract (ANE)-induced cell growth, collagen accumulation, procollagen gene transcription, MMP-2/-9 activity, MMP-1/-13 and TIMP-1/-2 expression, cytokine secretion, and the activation of PI3K/AKT, ERK/JNK/p38 MAPK, and TGFβ/Smads pathways were detected.


RESULTS
Panax notoginseng saponins could inhibit the ANE-induced abnormal growth and collagen accumulation of oral mucosal fibroblasts in a concentration-dependent manner. PNS (25 μg/ml) could significantly inhibit the ANE-induced expression of Col1A1 and Col3A1, augment the ANE-induced decrease of MMP-2/-9 activity, inhibit the ANE-induced increase of TIMP-1/-2 expression, and decrease the ANE-induced transcription and release of CTGF, TGFβ1, IL-6, and TNFα. PNS (25 μg/ml) also significantly inhibited the ANE-induced activation of AKT and ERK/JNK/p38 MAPK pathways in oral mucosal fibroblasts and the ANE-induced activation of TGFβ/smad pathway in HaCaT cells.


CONCLUSIONS
Panax notoginseng saponins possess excellent anti-OSF activity, and its mechanism may be related to its ability to inhibit the ANE-induced activation of PI3K/AKT, ERK/JNK/p38 MAPK, and TGFβ/smad pathways.
Department of Microbiology and Immunology, Shantou University Medical College, Shantou, Guangdong, China.
Jian-Ping
JP
Dai
Xiao-Xuan
XX
Chen
Dan-Xia
DX
Zhu
Qian-Ying
QY
Wan
Cheng
C
Chen
Ge-Fei
GF
Wang
Wei-Zhong
WZ
Li
Kang-Sheng
KS
Li
D000818:Animals; D001114:Areca / Q000009:adverse effects*; D018929:Cell Culture Techniques; D002460:Cell Line; D024042:Collagen Type I / Q000187:drug effects; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III / Q000187:drug effects; D055513:Connective Tissue Growth Factor / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006909:Hydroxyproline / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009061:Mouth Mucosa / Q000166:cytology / Q000187:drug effects*; D009754:Nuts / Q000009:adverse effects*; D009914:Oral Submucous Fibrosis / Q000209:etiology / Q000473:pathology*; D053723:Panax notoginseng; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects; D010936:Plant Extracts / Q000009:adverse effects / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D012503:Saponins / Q000494:pharmacology*; D051785:Smad Proteins / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D055513:Connective Tissue Growth Factor; D006909:Hydroxyproline; D015850:Interleukin-6; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019869:Phosphatidylinositol 3-Kinases; D010936:Plant Extracts; D051057:Proto-Oncogene Proteins c-akt; D012503:Saponins; D051785:Smad Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha
Panax notoginseng saponins; areca nut; oral submucous fibrosis; signal pathway