Manassantin A

Korean Journal of Pharmacognosy, 2007, 38(2):176-180.

Hepatoprotective constituents of Saururus chinensis roots against tacrine-induced cytotoxicity in human liver-derived Hep G2 cells.[Reference: WebLink]

METHODS AND RESULTS:
Five lignans, sauchinone (1), di-O-methyltetrahydrofuriguaiacin B (2), Manassantin A (3), manassantin B (4) and saucerneol B (5), have been isolated from the MeOH extract of Saurunis chinensis roots. The evaluation for protective effect of compounds 1-5 against tacrine-induced cytotoxicity in human liver-derived Hep G2 cells was conducted.
CONCLUSIONS:
Compounds 1, 2, and 5 showed significant protective effects with the EC 50 values of 74.2±0.9, 111.3±0.8, 64.3±0.8 μM, respectively. Silybin, one of the well-known hepatoprotective agents, used as a positive control, and also showed protective effect with an EC 50 value of 86.2±0.5 μM.

Experimental dermatology, 2011, 20(9):761-763.

Manassantin A inhibits cAMP-induced melanin production by down-regulating the gene expressions of MITF and tyrosinase in melanocytes.[Reference: WebLink]

Microphthalmia-associated transcription factor (MITF) is inducible in response to cAMP through the cAMP-responsive element-binding protein (CREB) and plays a pivotal role in the melanocyte-specific expression of tyrosinase or tyrosinase-related proteins (TRPs) for melanin biosynthesis. Manassantin A from Saururus chinensis inhibits cAMP-induced melanin production in B16 melanoma cells.
METHODS AND RESULTS:
Here, we focused on molecular basis of the antimelanogenic activity. Manassantin A consistently inhibited the cAMP elevator 3-isobutyl-1-methylxanthine (IBMX)- or dibutyryl cAMP-induced melanin production in B16 cells or in melan-a melanocytes by down-regulating the expression of tyrosinase or TRP1 gene. Moreover, Manassantin A suppressed MITF induction through IBMX-activated CREB pathway, directly inhibiting the Ser-133 phosphorylation of CREB. However, Manassantin A did not affect IBMX-increased cAMP levels in these cells but also other cAMP-dependent melanogenic pathways through post-translational modifications of MITF.
CONCLUSIONS:
This putative molecular mechanism of Manassantin A in the inhibition of melanin production suggests its pharmacological potential in skin hyperpigmentation.

Biochemical Pharmacology, 2003, 66(10):1925-1933.

Suppression of RelA/p65 transactivation activity by a lignoid manassantin isolated from Saururus chinensis.[Reference: WebLink]

In our search for NF-κB inhibitors from natural resources, we have previously identified two structurally related dilignans, Manassantin A and manassantin B as specific inhibitors of NF-κB activation from Saururus chinensis. However, their molecular mechanism of action remains unclear.
METHODS AND RESULTS:
We here demonstrate that Manassantin A and manassantin B are potent inhibitors of NF-κB activation by the suppression of transciptional activity of RelA/p65 subunit of NF-κB. These compounds significantly inhibited the induced expression of NF-κB reporter gene by LPS or TNF-α in a dose-dependent manner. However, these compounds did not prevent the DNA-binding activity of NF-κB assessed by electrophoretic mobility shift assay as well as the induced-degradation of IκB-α protein by LPS or TNF-α. Further analysis revealed that Manassantin A and manassantin B dose-dependently suppressed not only the induced NF-κB activation by overexpression of RelA/p65, but also transactivation activity of RelA/p65. Furthermore, treatment of cells with these compounds prevented the TNF-α-induced expression of anti-apoptotic NF-κB target genes Bfl-1/A1, a prosurvival Bcl-2 homologue, and resulted in sensitizing HT-1080 cells to TNF-α-induced cell death. Similarly, these compounds also suppressed the LPS-induced inducible nitric oxide synthase expression and nitric oxide production.
CONCLUSIONS:
Taken together, Manassantin A and manassantin B could be valuable candidate for the intervention of NF-κB-dependent pathological condition such as inflammation and cancer.

Journal of Pharmacological Sciences, 2011, 115(1):84-88.

Manassantin A and B from Saururus chinensis inhibit interleukin-6-induced signal transducer and activator of transcription 3 activation in Hep3B cells.[Reference: WebLink]

Inhibition of interleukin-6 (IL-6) has been postulated to be an effective therapy in the pathogenesis of several inflammatory diseases. The current study was performed to examine potential effects of Manassantin A and manassantin B isolated from Saururus chinensis on the IL-6-induced response to human hepatoma cells.
METHODS AND RESULTS:
We found that Manassantin A and manassantin B inhibit signal transducer and activator of transcription 3 (Stat3) activity stimulated by IL-6. We also found that both compounds decreased IL-6-induced Stat3 phosphorylation and nuclear translocation. Both compounds blocked suppressor of cytokine signaling 3 (SOCS-3)-mRNA expression induced by IL-6. In addition, we found that Stat3 inhibitory effects of these compounds could be related to protein tyrosine phosphatase.
CONCLUSIONS:
These findings suggest that Manassantin A and manassantin B could be useful remedies for treatment of inflammatory diseases by inhibiting IL-6 action.

Biological & Pharmaceutical Bulletin, 2011, 34(11):1769-1772.

Manassantin A isolated from Saururus chinensis inhibits 5-lipoxygenase-dependent leukotriene C4 generation by blocking mitogen-activated protein kinase activation in mast cells.[Reference: WebLink]

In this study, Manassantin A (Man A), an herbal medicine isolated from Saururus chinensis (S. chinensis), markedly inhibited 5-lipoxygenase (5-LO)-dependent leukotriene C(4) (LTC(4)) generation in bone marrow-derived mast cells (BMMCs) in a concentration-dependent manner.
METHODS AND RESULTS:
To investigate the molecular mechanisms underlying the inhibition of LTC(4) generation by Man A, we assessed the effects of Man A on phosphorylation of cytosolic phospholipase A(2) (cPLA(2)) and mitogen-activated protein kinases (MAPKs). Inhibition of LTC(4) generation by Man A was accompanied by a decrease in cPLA(2) phosphorylation, which occurred via the MAPKs including extracellular signal-regulated protein kinase-1/2 (ERK1/2) as well as p38 and c-Jun N-terminal kinase (JNK) pathways.
CONCLUSIONS:
Taken together, the present study suggests the Man A represents a potential therapeutic approach for the treatment of airway allergic-inflammatory diseases.

Acta Pharmaceutica Sinica, 2014, 49(5):622-626.

A novel HIF-1 inhibitor--manassantin A derivative LXY6099 inhibits tumor growth.[Reference: WebLink]

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor on hypoxia responses in mammalian tissues. HIF-1 plays as a positive factor in solid tumor and leads to hypoxia-driven responses that enhance its downstream gene expression for tumor growth and survival. LXY6099 was obtained by the structural modification and optimization of Manassantin A (MA) as a high potent HIF-1 inhibitor.
METHODS AND RESULTS:
Antitumor activity of LXY6099 was observed in this study. LXY6099 with an IC50 value of 2.46 x 10(-10) mol x L(-1) showed more sensitive inhibition activity to HIF-1 than that of MA detected by reporter gene assay (> 100 folds). It showed strong inhibition on the growth of human solid tumor cell lines. Furthermore, LXY6099 exhibited significant antitumor activity against established human tumor xenografts in nu/nu mice with treatment of MX-1 breast cancer.
CONCLUSIONS:
Thus, LXY6099 as a novel HIF-1 inhibitor could be further developed into anti-cancer agents.

Biological & Pharmaceutical Bulletin, 2016, 39(2):221-229.

Protective Effects of Manassantin A against Ethanol-Induced Gastric Injury in Rats.[Reference: WebLink]

Manassantin A, a neolignan isolated from Saururus chinensis, is a major phytochemical compound that has various biological activities, including anti-inflammatory, neuroleptic, and human acyl-CoA : cholesterol acyltransferase (ACAT) inhibitory activities.
METHODS AND RESULTS:
In this study, we investigated the protective effects of Manassantin A against ethanol-induced acute gastric injury in rats. Gastric injury was induced by intragastric administration of 5 mL/kg body weight of absolute ethanol to each rat. The positive control group and the Manassantin A group were given oral doses of omeprazole (20 mg/kg) or Manassantin A (15 mg/kg), respectively, 1 h prior to the administration of absolute ethanol. Our examinations revealed that Manassantin A pretreatment reduced ethanol-induced hemorrhage, hyperemia, and epithelial cell loss in the gastric mucosa. Manassantin A pretreatment also attenuated the increased lipid peroxidation associated with ethanol-induced acute gastric lesions, increased the mucosal glutathione (GSH) content, and enhanced the activities of antioxidant enzymes. The levels of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were clearly decreased in the Manassantin A-pretreated group. In addition, Manassantin A pretreatment enhanced the levels of cyclooxygenase (COX)-1, COX-2, and prostaglandin E2 (PGE2) and reduced the inducible nitric oxide synthase (iNOS) overproduction and nuclear factor kappa B (NF-κB) phosphorylation.
CONCLUSIONS:
Collectively, these results indicate that Manassantin A protects the gastric mucosa from ethanol-induced acute gastric injury, and suggest that these protective effects might be associated with COX/PGE2 stimulation, inhibition of iNOS production and NF-κB activation, and improvements in the antioxidant and anti-inflammatory status.