Gomisin A

Int J Mol Med. 2013 Apr;31(4):888-98.

Protective effects of gomisin A isolated from Schisandra chinensis against CCl(4)-induced hepatic and renal injury.[Pubmed: 23381504]

The aim of the present study was to investigate the protective effects of Gomisin A, a lignan compound isolated from Schisandra chinensis, against liver and kidney damage induced by CCl(4) exposure.
METHODS AND RESULTS:
We assessed alterations in organ weights, levels of serum biochemical indicators, and activation of the caspase-3 and MAPK signaling pathways and carried out histological analysis of liver and kidney tissue in rats pretreated with Gomisin A for four days. In the Gomisin A/CCl(4)-treated group, only the liver experienced a significant increase in weight, whereas the other organs did not undergo any changes. Five biochemical indicators in serum indicated that liver and kidney toxicity dramatically decreased upon Gomisin A pretreatment, although the decrease in ratios varied. Upon histological analysis, the Gomisin A/CCl(4)-treated group showed less hepatocellular necrosis, a poorly dilated central vein in the liver section, decreased diameter of the glomerulus, a lower number of capillaries, and a convoluted tubule in the kidney section. Furthermore, the formation of active caspase-3 was inhibited by Gomisin A pretreatment in the Gomisin A/CCl(4)-treated group, whereas the expression level of Bax protein was slightly increased. Western blot analysis revealed that there were differences between the liver and kidney in terms of activation of the MAPK signaling pathway. In the liver, Gomisin A pretreatment increased phosphorylation of three members of the MAPK pathway when compared to that in the vehicle pretreatment group. However, in the kidney, only the phosphorylation level of p38 was elevated upon Gomisin A pretreatment, whereas levels of the other two members were decreased.
CONCLUSIONS:
These results suggest that Gomisin A induces marked protective effects against hepatic and renal injury induced by CCl(4) exposure through differential regulation of the MAPK signal transduction pathway.

Biol Pharm Bull. 2012;35(11):1997-2003.

Gomisin A enhances tumor necrosis factor-α-induced G1 cell cycle arrest via signal transducer and activator of transcription 1-mediated phosphorylation of retinoblastoma protein.[Pubmed: 23123471]

Gomisin A, a dibenzocyclooctadiene lignan isolated from the fruit of Schisandra chinensis, has been reported as an anti-cancer substance. In this study, we investigated the effects of Gomisin A on cancer cell proliferation and cell cycle arrest in HeLa cells.
METHODS AND RESULTS:
Gomisin A significantly inhibited cell proliferation in a dose-dependent manner after 72 h treatment, especially in the presence of tumor necrosis factor-α (TNF-α), due to cell cycle arrest in the G1 phase with the downregulation of cyclin D1 expression and Retinoblastoma (RB) phosphorylation. In addition, Gomisin A in combination with TNF-α strongly suppressed the expression of signal transducer and activator of transcription 1 (STAT1).
CONCLUSIONS:
Inhibition of STAT1 pathways by a small-interfering RNA against STAT1 and AG490 Janus kinase (JAK) kinase inhibitor AG490 reduced the cyclin D1 expression and RB phosphorylation, indicating that JAK-mediated STAT1 activation is involved in Gomisin A-induced G1 cell cycle arrest.

2018 Jun;45(6):547-555.

Gomisin A modulates aging progress via mitochondrial biogenesis in human diploid fibroblast cells[Pubmed: 29319901]

Gomisin A from the fruit of Schisandra chinensis has many pharmacological properties, including hepato-protective, anti-diabetic, and anti-oxidative stress. However, the potential benefit of Gomisin A is still not well understood, especially in aging progression. Therefore, the aim of this study was to clarify whether the promotion of mitochondrial biogenesis and autophagy of Gomisin A affects anti-aging progression, and its mechanism. Intermediate (PD32) human diploid fibroblast (HDF) cells were brought to stress-induced premature senescence (SIPS) using hydrogen peroxide. Gomisin A inhibited reactive oxygen species production even in the SIPS-HDF cells. Gomisin A was also able to attenuate the activity of senescence-associated β-galactosidase and the production of pro-inflammatory molecules in the SIPS as well as aged HDF cells. The antioxidant activity of Gomisin A was determined by recovering the Cu/Zn, Mn-SOD, and HO-1 expression in the SIPS-HDF cells. In mechanistic aspect, Gomisin A inhibited the mitogen-activated protein kinase pathway and the translocation of nuclear factor kappa B to the nucleus. In addition, Gomisin A promoted the autophagy and mitochondrial biogenesis factors through the translocation of nuclear factor erythroid 2-related factor-2, and inhibited aging progression in the SIPS-HDF cells. In summary, the enhanced properties of mitochondrial biogenesis and autophagy of Gomisin A has a benefit to control age-related molecules against SIPS-induced chronic oxidative stress, and Gomisin A may be a potential therapeutic compound for the enhancement of intracellular homeostasis to aging progression.

Biol Pharm Bull. 2012;35(2):171-7.

The molecular mechanisms of the hepatoprotective effect of gomisin A against oxidative stress and inflammatory response in rats with carbon tetrachloride-induced acute liver injury.[Pubmed: 22293346]

Oxidative damage and inflammation are implicated in the pathogenesis of liver injury and fibrosis. In the present study, we investigated the molecular mechanism by which Gomisin A conferred a hepatoprotective effect, focusing on its antioxidant and anti-inflammatory effects using rats with carbon tetrachloride (CCl(4))-induced acute liver injury.
METHODS AND RESULTS:
Pretreatment with Gomisin A prior to the administration of CCl(4) markedly prevented an increase in alanine aminotransferase, aspartate aminotransferase, and histological hepatic lesions. Gomisin A was also associated with a decrease in hepatic lipid peroxidation, and increased superoxide dismutase activity, suggesting that Gomisin A has an antioxidant effect. In addition Gomisin A treatment ameliorated mRNA levels of CCl(4)-induced inflammatory mediators, including tumor necrosis factor-α, interleukin-1β and inducible nitric oxide (NO) synthase, and the protein levels of transcriptional upregulator nuclear factor kappa B (NF-κB) and phospho-inhibitor of NF-κB (IκB). Furthermore, α-smooth muscle actin (α-SMA), a myofibroblast marker, was also inhibited by Gomisin A treatment.
CONCLUSIONS:
These results suggest that Gomisin A inhibits the oxidative stress and activation of NF-κB, leading to down-regulation of pro-inflammatory mediators and amelioration of fibrogenesis.

Food Chem Toxicol. 2014 Jan;63:119-27.

Gomisin A inhibits lipopolysaccharide-induced inflammatory responses in N9 microglia via blocking the NF-κB/MAPKs pathway.[Pubmed: 24211520]

Gomisin A, one of the major dibenzocyclooctadiene lignans isolated from Schisandra chinensis Baill., has proved to possess a variety of pharmacological effects. The aim of the present study was to investigate the anti-inflammatory and neuroprotective effects of Gomisin A as well as its potential molecular mechanisms.
METHODS AND RESULTS:
It was found that Gomisin A not only inhibited the production of NO and PGE2 in a concentration-dependent manner but also suppressed the expressions of iNOS and COX-2 in LPS-stimulated N9 microglia without observable cytotoxicity. Gomisin A was also able to attenuate the mRNA expression and the production of pro-inflammatory factors TNF-α, IL-1β and IL-6. Moreover, LPS induced reactive oxygen species (ROS) production, NADPH oxidase activation, and gp91phox expression, which were markedly inhibited by Gomisin A in microglia. Furthermore, the data showed that Gomisin A significantly down-regulated the TLR4 protein expression, and inhibited nuclear transcription factor (NF)-κB and mitogen-activated protein kinases (MAPKs) signaling pathways. Additionally, Gomisin A alleviated the cell death of SH-SY5Y neuroblastoma, rat primary cortical and hippocampal neurons induced by the conditioned-media from activated microglia.
CONCLUSIONS:
In summary, Gomisin A may exert neuroprotective effects by attenuating the microglia-mediated neuroinflammatory response via inhibiting the TLR4-mediated NF-κB and MAPKs signaling pathways.

Biochem Pharmacol. 2006 Sep 28;72(7):824-37.

Gomisin A alters substrate interaction and reverses P-glycoprotein-mediated multidrug resistance in HepG2-DR cells.[Pubmed: 16889754 ]

Through an extensive herbal drug screening program, we found that Gomisin A, a dibenzocyclooctadiene compound isolated from Schisandra chinensis, reversed multidrug resistance (MDR) in Pgp-overexpressing HepG2-DR cells.
METHODS AND RESULTS:
Gomisin A was relatively non-toxic but without altering Pgp expression, it restored the cytotoxic actions of anticancer drugs such as vinblastine and doxorubicin that are Pgp substrates but may act by different mechanisms. Several lines of evidence suggest that Gomisin A alters Pgp-substrate interaction but itself is neither a Pgp substrate nor competitive inhibitor. (1) First unlike Pgp substrates Gomisin A inhibited the basal Pgp-associated ATPase (Pgp-ATPase) activity. (2) The cytotoxicity of Gomisin A was not affected by Pgp competitive inhibitors such as verapamil. (3) Gomisin A acted as an uncompetitive inhibitor for Pgp-ATPase activity stimulated by the transport substrates verapamil and progesterone. (4) On the inhibition of rhodamine-123 efflux the effects of Gomisin A and the competitive inhibitor verapamil were additive, so were the effects of Gomisin A and the ATPase inhibitor vanadate. (5) Binding of transport substrates with Pgp would result in a Pgp conformational change favoring UIC-2 antibody reactivity but Gomisin A impeded UIC-2 binding. (6) Photocrosslinking of Pgp with its transport substrate [125I]iodoarylazidoprazosin was inhibited by Gomisin A in a concentration-dependent manner.
CONCLUSIONS:
Taken together our results suggest that Gomisin A may bind to Pgp simultaneously with substrates and alters Pgp-substrate interaction.

Immunopharmacol Immunotoxicol. 2014 Jun;36(3):195-201.

Gomisin A decreases the LPS-induced expression of iNOS and COX-2 and activation of RIP2/NF-κB in mouse peritoneal macrophages.[Pubmed: 24749675]

Gomisin A (GA), a lignan component contained in the fruit of Schisandra chinensis Baillon, improves hepatic cell degeneration, vasodilatory activity and insulin sensitivity. These effects also impact the immune system, including various inflammatory mediators and cytokines. In this study, the anti-inflammatory effect of GA on lipopolysaccharide-stimulated mouse peritoneal macrophages was studied.
METHODS AND RESULTS:
Pretreatment with GA attenuated the expression of receptor-interacting protein 2 (RIP2) and IκB kinase-β (IKK-β) as well as IKK-β phosphorylation. The activation of nuclear factor-kappa B (NF-κB) in the nucleus, the phosphorylation of IκBα and degradation of IκBα in the cytosol were suppressed by GA. GA decreased the production and mRNA expression of the inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6. In addition, expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and production of nitric oxide were decreased by pretreatment with GA. In conclusion, these results show that the anti-inflammatory properties of GA potentially result from the inhibition of COX-2, iNOS, IL-6, TNF-α and NO through the down-regulation of RIP2 and NF-κB activation.
CONCLUSIONS:
These results impact the development of potential health products for preventing and treating inflammatory diseases.

Hypertens Res. 2012 Sep;35(9):928-34.

Antihypertensive effect of gomisin A from Schisandra chinensis on angiotensin II-induced hypertension via preservation of nitric oxide bioavailability.[Pubmed: 22534517 ]

Gomisin A (GA) is a small molecular weight lignan present in Schisandra chinensis, and has been demonstrated to have vasodilatory activity. In the present study, we investigated the effect of GA on blood pressure (BP) in angiotensin II (Ang II)-induced hypertensive mice.
METHODS AND RESULTS:
C57/BL6 mice infused subcutaneously with Ang II (1 and 2 μg kg⁻1 per min for 2 weeks) showed an increase in BP with a decrease in nitric oxide (NO) metabolites in plasma, and a negative correlation between these two parameters was demonstrated. In the thoracic aorta from Ang II-induced hypertensive mice, a decrease in vascular NO that was accompanied by a diminution of phosphorylated endothelial nitric oxide synthase (eNOS), as well as by increased reactive oxygen species (ROS) production, was demonstrated. These alterations in BP, eNOS phosphorylation and ROS production in the vasculature of Ang II-treated mice were markedly and dose-dependently reversed by simultaneous administration of GA (2 and 10 μg kg⁻1 per min). In addition, Ang II-induced ROS production in cultured vascular cells such as endothelial cells and vascular smooth muscle cells was markedly attenuated by GA.
CONCLUSIONS:
These results suggested that GA attenuated the increase in BP via preservation of vascular NO bioavailability not only by inhibiting ROS production but also by preventing the impairment of eNOS function in the vasculature of Ang II-induced hypertensive mice.