Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Crespo, Irene; San‐Miguel, Beatriz; Fernández, Antonio José Díaz; Urbina, Juan Ortiz de; González‐Gallego, Javier; Tuñón, María J.

doi:10.1016/j.trsl.2014.10.003

Cited by 43 publications

(54 citation statements)

References 48 publications

(65 reference statements)

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“…These results are in agreement with the recent findings of Crespo et al (2015) and Liang et al (2015) where CCl 4 -induced liver fibrosis in mice is associated with increased transcription of MMP-9. In addition, the expression of genes encoding MMP-9 was enhanced and TIMP-2 was decreased.…”

Section: Discussionsupporting

confidence: 93%

Inflammation, oxidative stress and apoptosis cascade implications in bisphenol A‐induced liver fibrosis in male rats

Elswefy

Abdallah

Atteia

et al. 2016

Int J Experimental Path

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Bisphenol A (BPA) is a key monomer in the production of plastics. It has been shown to be hepatotoxic. Inflammation and oxidative stress are closely linked with liver fibrosis, the major contributing factor to hepatic failure. Therefore, the aim of this study was to evaluate the impact of chronic exposure to BPA on the development of hepatic fibrosis in male rats and to determine the cross-talk between the hepatic cytokine network, oxidative stress and apoptosis. For this purpose, 30 male Wistar albino rats were divided into three equal groups as follows: the first group was given no treatment (normal control group); the second group was given corn oil once daily by oral gavage for 8 weeks (vehicle control group); and the third group received BPA (50 mg/kg body weight/day, p.o.) for 8 weeks. BPA administration induced liver fibrosis as reflected in an increase in serum hepatic enzymes activities, hepatic hydroxyproline content and histopathological changes particularly increased collagen fibre deposition around the portal tract. In addition, there was inflammation (as reflected in increase in interleukin-1beta 'IL-1β', decrease in interleukin-10 'IL-10' serum levels and increase in IL-1β/IL-10 ratio), oxidative stress (as reflected in increase in malondialdehyde (MDA) level, reduction in reduced glutathione (GSH) content and inhibition of catalase (CAT) activity) and apoptosis [as reflected in an increase in caspase-3 level and a decrease in numbers of B-cell lymphoma 2 (BCL2)-immunopositive hepatocytes]. Interestingly, BPA had an upregulating effect on an extracellular matrix turnover gene [as reflected in matrix metalloproteinase-9 (MMP-9)] and a downregulating effect on its inhibitor gene [as reflected in tissue inhibitor of matrix metalloproteinase-2 (TIMP-2)] expression. Thus, the mechanism by which BPA induced liver fibrosis seems to be related to stimulation of the inflammatory response, along with oxidative stress, the apoptotic pathway and activation of extracellular matrix turnover.

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Section: Discussionsupporting

confidence: 93%

Inflammation, oxidative stress and apoptosis cascade implications in bisphenol A‐induced liver fibrosis in male rats

Elswefy

Abdallah

Atteia

et al. 2016

Int J Experimental Path

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“…It is known that the indole abrogates activation of HSCs induced in vitro , and different authors have demonstrated that melatonin attenuates multiple profibrogenic pathways in rats or mice with fibrosis induced by CCl 4 , bile duct ligation, dymethylnitrosamine or thioacetamide . Although in most studies only preventive effects before the onset of liver toxicity have been shown, we have recently demonstrated that delayed melatonin treatment allowing initial activation of HSCs ameliorates fibrosis in CCl 4 ‐treated mice, with a downregulated expression of profibrogenic factors which associates to inhibition of endoplasmic reticulum stress and autophagy .…”

Section: Introductionmentioning

confidence: 87%

Inhibition of the SphK1/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells

et al. 2016

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The sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) system is involved in different pathological processes, including fibrogenesis. Melatonin abrogates activation of hepatic stellate cells (HSCs) and attenuates different profibrogenic pathways in animal models of fibrosis, but it is unknown if protection associates with its inhibitory effect on the SphK1/S1P axis. Mice in treatment groups received carbon tetrachloride (CCl 4 ) 5 µL/g body wt i.p. twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg/kg/day i.p, beginning two weeks after the start of CCl 4 administration. At both 4 and 6 weeks following CCl 4 treatment, liver mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased significantly. S1P production, and expression of S1P receptor (S1PR)1, S1PR3 and acid sphingomyelinase (ASMase) were significantly elevated. However, there was a decreased expression of S1PR2 and S1P lyase (S1PL). Melatonin attenuated liver fibrosis, as shown by a significant inhibition of the expression of α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β and collagen (Col) Ι. Furthermore, melatonin inhibited S1P production, lowered expression of SphK1, S1PR1, SP1R3 and ASMase, and increased expression of S1PL. Melatonin induced a reversal of activated human HSCs cell line LX2, as evidenced by a reduction in α-SMA, TGF-β, and Col I expression. Melatonin-treated cells also exhibited an inhibition of the SphK1/S1P axis. Antifibrogenic effect of SphK1 inhibition was confirmed by treatment of LX2 cells with PF543. Abrogation of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in liver fibrogenesis.

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“…Several studies have suggested that melatonin might be developed into a promising treatment for liver fibrosis. In addition, some studies demonstrated that melatonin attenuated liver fibrosis via limiting the expression of profibrogenic genes [143], directly suppressing hepatic stellate cells activation [144], and so on.…”

Section: Protective Effects Of Melatonin On Liver Fibrosismentioning

confidence: 99%

Effects of Melatonin on Liver Injuries and Diseases

Zhang

Meng

et al. 2017

IJMS

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Liver injuries and diseases are serious health problems worldwide. Various factors, such as chemical pollutants, drugs, and alcohol, could induce liver injuries. Liver diseases involve a wide range of liver pathologies, including hepatic steatosis, fatty liver, hepatitis, fibrosis, cirrhosis, and hepatocarcinoma. Despite all the studies performed up to now, therapy choices for liver injuries and diseases are very few. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries and diseases remains a priority. Melatonin is a well-known natural antioxidant, and has many bioactivities. There are numerous studies investigating the effects of melatonin on liver injuries and diseases, and melatonin could regulate various molecular pathways, such as inflammation, proliferation, apoptosis, metastasis, and autophagy in different pathophysiological situations. Melatonin could be used for preventing and treating liver injuries and diseases. Herein, we conduct a review summarizing the potential roles of melatonin in liver injuries and diseases, paying special attention to the mechanisms of action.

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Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

Cited by 43 publications

References 48 publications

Inflammation, oxidative stress and apoptosis cascade implications in bisphenol A‐induced liver fibrosis in male rats

Inflammation, oxidative stress and apoptosis cascade implications in bisphenol A‐induced liver fibrosis in male rats

Inhibition of the SphK1/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells

Effects of Melatonin on Liver Injuries and Diseases

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