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Zinc supplementation attenuates ethanol- and acetaldehyde-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS) production and by influencing intracellular signaling.
Biochem Pharmacol. 2009 Aug 01; 78(3):301-14.BP

Abstract

BACKGROUND/AIMS

Zinc has been reported to prevent and reverse liver fibrosis in vivo; however, the mechanisms of its action are poorly understood. We therefore aimed to determine the antifibrotic potential of zinc.

METHODS

Assessed was the influence of preincubation of rat HSCs with 30 microM ZnCl2 on ethanol- (in the presence of 4-methyl pyrazole (4-MP)) or acetaldehyde-induced toxicity, apoptosis, migration, expression of smooth muscle alpha-actin (alpha-SMA) and procollagen I, release of reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-alpha), tumor growth factor-beta1 (TGF-beta1), metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases (TIMPs) production. Intracellular signals such as nuclear factor-kappaB (NFkappaB), C-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) induced by ethanol and its metabolite were also assessed.

RESULTS

30 microM zinc protected HSCs against ethanol and acetaldehyde toxicity and inhibited their apoptosis. Zinc inhibited the production of ROS by HSCs treated with ethanol and acetaldehyde and inhibited their migration. Zinc also inhibited ethanol- and acetaldehyde-induced TGF-beta1 and TNF-alpha production. Zinc down-regulated ethanol- and acetaldehyde-induced production of TIMP-1 and TIMP-2 and decreased the activity of MMP-2. In ethanol- and acetaldehyde-induced HSCs, zinc inhibited the activation of the p38 MAPK as well as the JNK transduction pathways and phosphorylation of IkappaB and Smad 3.

CONCLUSION

The results indicated that zinc supplementation inhibited ethanol- and acetaldehyde-induced activation of HSCs on different levels, acting as an antioxidant and inhibitor of MAPK, TGF-beta and NFkappaB/IkappaB transduction signaling. The remarkable inhibition of several markers of HCS activation makes zinc a promising agent for antifibrotic combination therapies.

Authors+Show Affiliations

Department of Virology and Immunology, Maria Curie-Skłodowska University, Agnieszka Szuster-Ciesielska, Akademicka 19, 20-033 Lublin, Poland. szustera@hektor.umcs.lublin.plNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19376089

Citation

Szuster-Ciesielska, Agnieszka, et al. "Zinc Supplementation Attenuates Ethanol- and Acetaldehyde-induced Liver Stellate Cell Activation By Inhibiting Reactive Oxygen Species (ROS) Production and By Influencing Intracellular Signaling." Biochemical Pharmacology, vol. 78, no. 3, 2009, pp. 301-14.
Szuster-Ciesielska A, Plewka K, Daniluk J, et al. Zinc supplementation attenuates ethanol- and acetaldehyde-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS) production and by influencing intracellular signaling. Biochem Pharmacol. 2009;78(3):301-14.
Szuster-Ciesielska, A., Plewka, K., Daniluk, J., & Kandefer-Szerszeń, M. (2009). Zinc supplementation attenuates ethanol- and acetaldehyde-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS) production and by influencing intracellular signaling. Biochemical Pharmacology, 78(3), 301-14. https://doi.org/10.1016/j.bcp.2009.04.009
Szuster-Ciesielska A, et al. Zinc Supplementation Attenuates Ethanol- and Acetaldehyde-induced Liver Stellate Cell Activation By Inhibiting Reactive Oxygen Species (ROS) Production and By Influencing Intracellular Signaling. Biochem Pharmacol. 2009 Aug 1;78(3):301-14. PubMed PMID: 19376089.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Zinc supplementation attenuates ethanol- and acetaldehyde-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS) production and by influencing intracellular signaling. AU - Szuster-Ciesielska,Agnieszka, AU - Plewka,Krzysztof, AU - Daniluk,Jadwiga, AU - Kandefer-Szerszeń,Martyna, Y1 - 2009/04/17/ PY - 2009/02/04/received PY - 2009/04/09/revised PY - 2009/04/09/accepted PY - 2009/4/21/entrez PY - 2009/4/21/pubmed PY - 2009/6/23/medline SP - 301 EP - 14 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 78 IS - 3 N2 - BACKGROUND/AIMS: Zinc has been reported to prevent and reverse liver fibrosis in vivo; however, the mechanisms of its action are poorly understood. We therefore aimed to determine the antifibrotic potential of zinc. METHODS: Assessed was the influence of preincubation of rat HSCs with 30 microM ZnCl2 on ethanol- (in the presence of 4-methyl pyrazole (4-MP)) or acetaldehyde-induced toxicity, apoptosis, migration, expression of smooth muscle alpha-actin (alpha-SMA) and procollagen I, release of reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-alpha), tumor growth factor-beta1 (TGF-beta1), metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases (TIMPs) production. Intracellular signals such as nuclear factor-kappaB (NFkappaB), C-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) induced by ethanol and its metabolite were also assessed. RESULTS: 30 microM zinc protected HSCs against ethanol and acetaldehyde toxicity and inhibited their apoptosis. Zinc inhibited the production of ROS by HSCs treated with ethanol and acetaldehyde and inhibited their migration. Zinc also inhibited ethanol- and acetaldehyde-induced TGF-beta1 and TNF-alpha production. Zinc down-regulated ethanol- and acetaldehyde-induced production of TIMP-1 and TIMP-2 and decreased the activity of MMP-2. In ethanol- and acetaldehyde-induced HSCs, zinc inhibited the activation of the p38 MAPK as well as the JNK transduction pathways and phosphorylation of IkappaB and Smad 3. CONCLUSION: The results indicated that zinc supplementation inhibited ethanol- and acetaldehyde-induced activation of HSCs on different levels, acting as an antioxidant and inhibitor of MAPK, TGF-beta and NFkappaB/IkappaB transduction signaling. The remarkable inhibition of several markers of HCS activation makes zinc a promising agent for antifibrotic combination therapies. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/19376089/Zinc_supplementation_attenuates_ethanol__and_acetaldehyde_induced_liver_stellate_cell_activation_by_inhibiting_reactive_oxygen_species__ROS__production_and_by_influencing_intracellular_signaling_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(09)00295-0 DB - PRIME DP - Unbound Medicine ER -