Mechanistic aspects of antifibrotic effects of honokiol in Con A-induced liver fibrosis in rats: Emphasis on TGF-β/SMAD/MAPK signaling pathways

Elfeky, Maha G.; Mantawy, Eman M.; Gad, Amany M.; Fawzy, Hala M.; El‐Demerdash, Ebtehal

doi:10.1016/j.lfs.2019.117096

Cited by 31 publications

(24 citation statements)

References 52 publications

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“…As shown in in the present study, TGF-β1 also activated the MAPK signalling pathway. Of note, honokiol preconditioning significantly reduced the TGF-β1-induced phosphorylation of p38 and JNK, but not p-ERK, which is consistent with the findings of previous studies ( 32 , 66 ). Taken together, it was surmised that the anti-EF effects of honokiol may be associated with the inhibition of CTGF via the Smad2/3 and MAPK (p38 and JNK) pathways.…”

Section: Discussionsupporting

confidence: 92%

“…Similarly, honokiol has been reported to ameliorate fibrosis by inhibiting the expression of pro-fibrotic factors and ECM proteins in a rat model of renal fibrosis ( 31 ). Additional findings provide evidence that the promising anti-fibrotic effects of honokiol in rats with liver fibrosis are related to the suppression of the TGF-β/Smad and MAPK signalling path-ways ( 32 ). Based on these findings, it was hypothesized that honokiol may attenuate the development of EF.…”

Section: Introductionmentioning

confidence: 98%

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Honokiol protects against epidural fibrosis by inhibiting fibroblast proliferation and extracellular matrix overproduction in rats post‑laminectomy

Zeng

Han

et al. 2020

Int J Mol Med

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Epidural fibrosis (EF)-induced failed back surgery syndrome (FBSS) in patients post-laminectomy remains a medical challenge. Although the scarring mechanisms remain unclear, the majority of aetiological studies have reported fibroblast dysfunction. Honokiol, the major bioactive constituent of the magnolia tree, exerts a variety of pharmacological effects, including anti-proliferative and anti-fibrotic effects, on various cell types. The present study investigated whether honokiol attenuates EF progression. In vitro , it was found that honokiol inhibited excessive fibroblast proliferation induced by transforming growth factor-β1 (TGF-β1) and the synthesis of extracellular matrix (ECM) components, including fibro-nectin and type I collagen, in a dose-dependent manner. These effects were attributed to the ability of honokiol to suppress the activity of connective tissue growth factor (CTGF), which is indispensable for the progression of fibrosis. Mechanistically, honokiol attenuated the TGF-β1-induced activation of the Smad2/3 and mitogen-activated protein kinase (MAPK) signalling pathways in fibroblasts. In vivo , honokiol reduced the proliferation of fibroblasts and the synthesis of ECM components, thus ameliorating EF in a rat model post-laminectomy. Taken together, these preclinical findings suggest that honokiol deserves further consideration as a candidate therapeutic agent for EF.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 98%

Honokiol protects against epidural fibrosis by inhibiting fibroblast proliferation and extracellular matrix overproduction in rats post‑laminectomy

Zeng

Han

et al. 2020

Int J Mol Med

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“…In recent years, a number of studies have focused extensive attention on the hepatoprotective effect of honokiol and magnolol. Treatment with honokiol at 10 mg/kg alleviated ConA-induced liver fibrosis by downregulating hydroxyproline, α -SMA, and collagen fiber deposition, which was associated with restoring antioxidant defense, regulating inflammatory cascades, and inhibiting the TGF- β /Smad/MAPK signaling pathway [ 139 ]. In vitro research showed that 12.5–50 μ mol/L honokiol induced apoptotic death in activated rat HSCs through the release of mitochondrial cytochrome C [ 140 ].…”

Section: Lignansmentioning

confidence: 99%

A Comprehensive Review of Natural Products against Liver Fibrosis: Flavonoids, Quinones, Lignans, Phenols, and Acids

Pan

Jiang

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Liver fibrosis resulting from continuous long-term hepatic damage represents a heavy burden worldwide. Liver fibrosis is recognized as a complicated pathogenic mechanism with extracellular matrix (ECM) accumulation and hepatic stellate cell (HSC) activation. A series of drugs demonstrate significant antifibrotic activity in vitro and in vivo. No specific agents with ideally clinical efficacy for liver fibrosis treatment have been developed. In this review, we summarized the antifibrotic effects and molecular mechanisms of 29 kinds of common natural products. The mechanism of these compounds is correlated with anti-inflammatory, antiapoptotic, and antifibrotic activities. Moreover, parenchymal hepatic cell survival, HSC deactivation, and ECM degradation by interfering with multiple targets and signaling pathways are also involved in the antifibrotic effects of these compounds. However, there remain two bottlenecks for clinical breakthroughs. The low bioavailability of natural products should be improved, and the combined application of two or more compounds should be investigated for more prominent pharmacological effects. In summary, exploration on natural products against liver fibrosis is becoming increasingly extensive. Therefore, natural products are potential resources for the development of agents to treat liver fibrosis.

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“…Here, honokiol repressed the expression of Wnt3 a and β‐catenin and induced the phosphorylation of GSK3β in LX‐2 cells. Similarly, honokiol was reported to block cancer progression via suppression of Wnt/β‐catenin signalling (Elfeky et al, 2020; Yao et al, 2013). Conversely, GSK3β inhibitor SP600125 blocked the apoptotic and antihepatofibrotic ability of honokiol to repress Pro‐PARP, α‐SMA and β‐catenin in LX‐2 cells, demonstrating that apoptotic and antihepatofibrotic effects of honokiol are mediated by inhibition of Wnt3 and β‐catenin and phosphorylation of GSK3β in LX‐2 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Honokiol, a lignan biphenol isolated from the Magnolia tree (Fang et al, 2015), was reported to have antiinflammatory (X. D. Wang, Wang, & Gao, 2015), antioxidant(Zhao & Liu, 2011), anticancer (Hahm, Singh, & Singh, 2016; Singh & Katiyar, 2013; Yao et al, 2013), antithrombotic (Hu, Zhang, Wang, & Chen, 2005), antiviral (Fang et al, 2015), antimetabolite (Dong et al, 2014), neurotrophic (Praveen Kumar et al, 2012) and antifibrotic effects in kidney(Chiang et al, 2011) and lung (Pulivendala, Bale, & Godugu, 2020). In addition, though honokiol‐induced apoptosis in rat hepatic stellate cells (Park, Zhao, Kim, Lee, & Sohn, 2005), showed hepatoprotective effect against carbon tetrachloride stimulated liver injury (Cao, Vo, & King, 2005) and inhibited liver fibrosis by Con A in rats via TGF‐β/SMAD/MAPK signalling (Elfeky, Mantawy, Gad, Fawzy, & El‐Demerdash, 2020), the underlying inhibitory mechanism of honokiol on liver fibrosis in HSCs is not fully understood so far. Hence, in the present study, inhibitory mechanism of honokiol on liver fibrosis was elucidated mainly in hepatic stellate cells (HSCs) in association with apoptosis and Wnt3a/β‐catenin signalling pathway.…”

Section: Introductionmentioning

confidence: 99%

Apoptotic and antihepatofibrotic effect of honokiol via activation of GSK3β and suppression of Wnt/β‐catenin pathway in hepatic stellate cells

Lee

et al. 2020

Phytotherapy Research

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Though honokiol, derived from the Magnolia tree, was known to suppress renal fibrosis, pulmonary fibrosis, non‐alcoholic steatoheptitis, inflammation and cancers, the underlying antifibrotic mechanisms of honokiol are not fully understood in hepatic stellate cells until now. Thus, in the present study, inhibitory mechanism of honokiol on liver fibrosis was elucidated mainly in hepatic stellate cells (HSCs) by 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay, cell cycle analysis and western‐blotting. Honokiol exerted cytotoxicity in LX‐2, HSC‐T6 and Hep‐G2 cells. Honokiol increased sub G1 population and activated caspase 3 and cleaved poly (ADP‐ribose) polymerase (PARP) in HSCs. Moreover, honokiol attenuated the expression of alpha smooth muscle actin (α‐SMA), transforming growth factor beta 1 (TGF‐β1), phospho‐Smad3, phospho‐AKT, cyclin D1, c‐Myc, Wnt3a, β‐catenin, and activated phosphorylation of glycogen synthase kinase 3 beta (GSK3β) in HSCs. Conversely, GSK3β inhibitor SB216763 reversed the effect of honokiol on PARP, α‐SMA, phospho‐GSK3β, β‐catenin and sub G1 population in LX‐2 cells. Overall, honokiol exerts apoptotic and antifibrotic effects via activation of GSK3β and inhibition of Wnt3a/β‐catenin signalling pathway.

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Mechanistic aspects of antifibrotic effects of honokiol in Con A-induced liver fibrosis in rats: Emphasis on TGF-β/SMAD/MAPK signaling pathways

Cited by 31 publications

References 52 publications

Honokiol protects against epidural fibrosis by inhibiting fibroblast proliferation and extracellular matrix overproduction in rats post‑laminectomy

Honokiol protects against epidural fibrosis by inhibiting fibroblast proliferation and extracellular matrix overproduction in rats post‑laminectomy

A Comprehensive Review of Natural Products against Liver Fibrosis: Flavonoids, Quinones, Lignans, Phenols, and Acids

Apoptotic and antihepatofibrotic effect of honokiol via activation of GSK3β and suppression of Wnt/β‐catenin pathway in hepatic stellate cells

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