Schisandra sphenanthera Extract Facilitates Liver Regeneration after Partial Hepatectomy in Mice

Li, Xi; Fan, Xiaomei; Li, Dongshun; Zeng, Xuezhen; Zeng, Hang; Wang, Yongtao; Zhou, Yawen; Chen, Yixin; Huang, Min; Bi, Huichang

doi:10.1124/dmd.115.068288

Cited by 22 publications

(8 citation statements)

References 35 publications

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“…Based on our findings, we identified a working hypothesis to provide substrate for future investigations to define potential new therapies (FIGURE 8). Recently, cirrhotic patients and the coinciding muscle wasting have been well documented [64–66]. Here we reveal that livers in patients with ESLD also produce abundant Gdf8.…”

Section: Discussionsupporting

confidence: 57%

GDF8 Contributes to the Adverse Effects of Liver Injury on Skeletal Muscle Homeostasis and Regeneration

Wang

et al. 2021

Preprint

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Background: An emerging clinical phenomenon in patients with end stage liver disease is progressive skeletal muscle atrophy. This loss in lean mass predicts poor survival outcomes for liver disease patients and highlights an underappreciated crosstalk between injured liver and muscle that lacks defined mediators. The purpose of our study was to identify potential liver-muscle mediator(s) in pre-clinical in vivo models of liver injury which may contribute to the muscle loss observed in liver disease. Methods: Utilizing a mouse model of carbon tetrachloride CCl4-induced liver injury in the presence or absence of cardiotoxin-induced muscle injury, we evaluated whether neutralizing Activin type IIB receptor (ActRIIB) ligands, or specifically growth differentiation factor 8 (Gdf8), could preserve or reverse muscle atrophy associated with liver disease. Results: We found that hepatic injury via CCl4 or bile duct ligation (BDL) similarly caused significant muscle atrophy along with decreased gene expression in key myogenesis markers. This adverse effect of injured liver on muscle were completely prevented and reversed by the intervention of Activin type IIB receptor (ActRIIB)-Fc fusion protein, which neutralizes the ActRIIB ligands, including Activins and growth differentiation factor 8 (Gdf8 or myostatin). The results indicate that ActRIIB ligands promoted muscle atrophy which was manifested in response to hepatic injury/disease and conferred the negative communication of injured liver with muscle. Indeed, direct injection of exogenous Gdf8 protein into muscle along with acute focal muscle injury recapitulated similar dysregulated muscle regeneration as observed with liver injury. Furthermore, we found that hepatocytes produced Gdf8 in response to liver injury in rodents and in patients with end stage liver disease. A neutralizing antibody to Gdf8 attenuated muscle atrophy and unexpectedly ameliorated liver fibrosis in both CCl4 and BDL models. Following this observation, we demonstrated the ability of Gdf8 to induce fibrogenesis in stellate cells, potentially identifying a novel hepatic role for this protein. Moreover, hepatic Gdf8 promoted muscle wasting in response to liver damage and hindered skeletal muscle regeneration. Conclusion: Our findings identified Gdf8 as a novel hepatomyokine contributing to injured liver-muscle negative crosstalk and liver injury progression. Moreover, we demonstrated a promising therapeutic strategy for muscle atrophy accompanying liver diseases.

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Section: Discussionsupporting

confidence: 57%

GDF8 Contributes to the Adverse Effects of Liver Injury on Skeletal Muscle Homeostasis and Regeneration

Wang

et al. 2021

Preprint

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“…For the WZ-treated mice, the tablet was crushed to a powder, dissolved in 0.5% [w/v] sodium carboxymethyl cellulose (CMC-Na), and administered by gavage at single dose of 700 mg/kg, the control group were administered with CMC-Na. The dosage of WZ used in the current study was based on the dose used in clinical practice and calculated with correction for body surface difference between humans and mice, as described previously [7,9]. Mice were sacrificed for serum or urine sample collection at 2 or 24 h after dosing.…”

Section: Drug Administration and Biological Samples Preparationmentioning

confidence: 99%

“…In clinical practice, WZ is a prescribed drug in China used to protect liver function in patients with chronic hepatitis or liver dysfunction. Furthermore, our previous studies reveal that WZ and its active lignans significantly protect against liver injury including acetaminophen‐induced liver injury , partial hepatectomy and lithocholic acid‐induced cholestasis .…”

Section: Introductionmentioning

confidence: 95%

Metabolic mapping of Schisandra sphenanthera extract and its active lignans using a metabolomic approach based on ultra high performance liquid chromatography with high‐resolution mass spectrometry

Zhang

Jiang

et al. 2016

J of Separation Science

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Schisandra sphenanthera, the dried ripe fruit of Schisandra sphenanthera Rehd. et Wils, is widely used as a restorative, tonic and nutrition in many countries. Wuzhi tablet, an ethanol extract preparation of Schisandra sphenanthera, is a well-known herbal medicine widely used in China. Our previous studies show that Wuzhi tablet and its active lignans significantly protect liver injury. However, its metabolic profile remains unknown in vivo and in vitro. In this study, ultra high performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry based metabolomics was employed to decipher the metabolic map of Wuzhi tablet and its active lignans. Serum (2 h) and urine (24 h) samples after a 700 mg/kg single oral dose of Wuzhi tablet, and mice liver microsome samples after incubation with its active lignans were collected and analyzed. The data were further analyzed using metabolomics and metabolite identification software. In total, 33 metabolites in vivo and 34 metabolites in vitro were identified, and six among them were new metabolites. The major metabolic reactions encompassed demethylation, hydroxylation, dehydrogenation, and epoxidation. Taken together, in vitro and in vivo studies revealed the metabolic profile of Wuzhi tablet and its active lignans and demethylation and hydroxylation were their major metabolic pathways.

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“…Also, an active component of WZ, schisandrol B, could protect against acetaminophen-induced hepatotoxicity by inhibiting CYP-mediated APAP bioactivation and regulation of p53, p21, CCND1, PCNA and BCL-2 to promote liver regeneration 26 . In addition, WZ could also facilitate liver regeneration after partial hepatectomy in mice 27 . However, the protective effect of WZ against ethanol-induced liver injury and the involvement of NRF2-ARE signaling pathway are incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Schisandra sphenanthera extract (Wuzhi Tablet) protects against chronic-binge and acute alcohol-induced liver injury by regulating the NRF2-ARE pathway in mice

Zeng

et al. 2017

Acta Pharmaceutica Sinica B

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Alcohol abuse leads to alcoholic liver disease and no effective therapy is currently available. Wuzhi Tablet (WZ), a preparation of extract from Schisandra sphenanthera that is a traditional hepato-protective herb, exerted a significant protective effect against acetaminophen-induced liver injury in our recent studies, but whether WZ can alleviate alcohol-induced toxicity remains unclear. This study aimed to investigate the contribution of WZ to alcohol-induced liver injury by using chronic-binge and acute models of alcohol feeding. The activities of ALT and AST in serum were assessed as well as the level of GSH and the activity of SOD in the liver. The expression of CYP2E1 and proteins in the NRF2-ARE signaling pathway including NRF2, GCLC, GCLM, HO-1 were measured, and the effect of WZ on NRF2 transcriptional activity was determined. We found that both models resulted in liver steatosis accompanied by increased transaminase activities, but that liver injury was significantly attenuated by WZ. WZ administration also inhibited CYP2E1 expression induced by alcohol, and elevated the level of GSH and the activity of SOD in the liver. Moreover, the NRF2-ARE signaling pathway was activated by WZ and the target genes were all upregulated. Furthermore, WZ significantly activated NRF2 transcriptional activity. Collectively, our study demonstrates that WZ protected against alcohol-induced liver injury by reducing oxidative stress and improving antioxidant defense, possibly by activating the NRF2-ARE pathway.

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Schisandra sphenanthera Extract Facilitates Liver Regeneration after Partial Hepatectomy in Mice

Cited by 22 publications

References 35 publications

GDF8 Contributes to the Adverse Effects of Liver Injury on Skeletal Muscle Homeostasis and Regeneration

GDF8 Contributes to the Adverse Effects of Liver Injury on Skeletal Muscle Homeostasis and Regeneration

Metabolic mapping of Schisandra sphenanthera extract and its active lignans using a metabolomic approach based on ultra high performance liquid chromatography with high‐resolution mass spectrometry

Schisandra sphenanthera extract (Wuzhi Tablet) protects against chronic-binge and acute alcohol-induced liver injury by regulating the NRF2-ARE pathway in mice

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