α2-Adrenergic Receptor in Liver Fibrosis: Implications for the Adrenoblocker Mesedin

The noradrenergic system is proposed to play a prominent role in the pathogenesis of liver fibrosis. While α1- and β-adrenergic receptors (ARs) are suggested to be involved in a multitude of profibrogenic actions, little is known about α2-AR-mediated effects and their expression pattern during liver fibrosis and cirrhosis. We explored the expression of α2-AR in two models of experimental liver fibrosis. We further evaluated the capacity of the α2-AR blocker mesedin to deactivate hepatic stellate cells (HSCs) and to increase the permeability of human liver sinusoidal endothelial cells (hLSECs). The mRNA of α2a-, α2b-, and α2c-AR subtypes was uniformly upregulated in carbon tetrachloride-treated mice vs the controls, while in bile duct-ligated mice, only α2b-AR increased in response to liver injury. In murine HSCs, mesedin led to a decrease in α-smooth muscle actin, transforming growth factor-β and α2a-AR expression, which was indicated by RT-qPCR, immunocytochemistry, and Western blot analyses. In a hLSEC line, an increased expression of endothelial nitric oxide synthase was detected along with downregulated transforming growth factor-β. In conclusion, we suggest that the α2-AR blockade alleviates the activation of HSCs and may increase the permeability of liver sinusoids during liver injury.

Download Full-text

Hepatoprotective Effect of the Fruits of Polygonum orientale L. Against Carbon Tetrachloride-Induced Liver Fibrosis in Mice

Natural Product Communications ◽

10.1177/1934578x20971501 ◽

2020 ◽

Vol 15 (11) ◽

pp. 1934578X2097150

Author(s):

Yung-Jia Chiu ◽

Kun-Chang Wu ◽

Jen-Chieh Tsai ◽

Chun-Pin Kao ◽

Jung Chao ◽

...

Keyword(s):

Carbon Tetrachloride ◽

Growth Factor ◽

Liver Injury ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Transforming Growth Factor Β ◽

Serum Levels ◽

Hepatoprotective Activity ◽

Tissue Growth ◽

Factor Α

The aim of this study was to evaluate the hepatoprotective effects of the fruits of Polygonum orientale L. (POE) against fibrosis in carbon tetrachloride (CCl4)-induced liver injury. Bioactive components of POE were identified using liquid chromatography (LC)-mass spectrometry (MS)/MS by comparison with standards. Treatment with either silymarin (200 mg/kg) or POE (0.5 and 1.0 g/kg) caused significant decreases in the serum levels of enzymes and reduced the extent of liver lesions and fibrosis in histological analysis. POE (0.5 and 1.0 g/kg) decreased the levels of malondialdehyde, nitric oxide, proinflammatory cytokines (ie, tumor necrosis factor-α, interleukin [IL]-1β, and IL-6), an inflammatory cytokine (ie, cyclooxygenase-2), a profibrotic cytokine (ie, transforming growth factor-β), and fibrosis-related proteins (ie, connective tissue growth factor and α-smooth muscle actin) in the liver and enhanced the activities of the antioxidative enzymes superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. Quantitative analysis of the active constituents in POE revealed an extract composition of 3.4 mg/g of protocatechuic acid, 20.8 mg/g of taxifolin, and 5.6 mg/g of quercetin. We have demonstrated that the hepatoprotective mechanisms of POE are likely to be associated with the decrease in inflammatory cytokines by increasing the activities of antioxidant enzymes. Our findings provide evidence that POE possesses a hepatoprotective activity to ameliorate chronic liver injury.

Download Full-text

Piceatannol increases the expression of hepatocyte growth factor and IL-10 thereby protecting hepatocytes in thioacetamide-induced liver fibrosis

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2016-0001 ◽

2016 ◽

Vol 94 (7) ◽

pp. 779-787 ◽

Cited By ~ 6

Author(s):

Hazem Abd-Elgawad ◽

Nashwa Abu-Elsaad ◽

Amr El-Karef ◽

Tarek Ibrahim

Keyword(s):

Growth Factor ◽

Liver Fibrosis ◽

Liver Function ◽

Hepatocyte Growth Factor ◽

Transforming Growth Factor ◽

Histopathological Examination ◽

Smooth Muscle Actin ◽

Interleukin 10 ◽

Hepatocyte Growth ◽

Inflammatory Effect

Piceatannol is a polyphenolic analog of resveratrol that selectively inhibits the non-receptor tyrosine kinase-Syk. This study investigates the potential ability of piceatannol to attenuate liver fibrosis and protect hepatocytes from injury. Thioacetamide was injected in adult male mice (100 mg/kg, i.p., 3 times/week) for 8 weeks. Piceatannol (1 or 5 mg/kg per day) was administered by oral gavage during the last 4 weeks. Liver function biomarkers, tissue malondialdehyde (MDA), cytokeratin-18 (CK18), hepatocyte growth factor (HGF), and interleukin-10 (IL-10) were measured. Necroinflammation, fibrosis, expression of transforming growth factor (TGF)-β1, and α-smooth muscle actin (SMA) were scored by histopathological examination and immunohistochemistry. Obtained results showed ability of piceatannol (1 mg/kg) to restore liver function and reduce inflammation. It significantly (p < 0.001) reduced MDA, CK18, TGF-β1, and α-SMA expression, and increased HGF and IL-10. It can be concluded that piceatannol at low dose can inhibit TGF-β1 induced hepatocytes apoptosis and exerts an anti-inflammatory effect attenuating fibrosis progression.

Download Full-text

Overexpression of angiotensin type 2 receptor ameliorates glomerular injury in a mouse remnant kidney model

AJP Renal Physiology ◽

10.1152/ajprenal.00294.2003 ◽

2004 ◽

Vol 286 (3) ◽

pp. F516-F525 ◽

Cited By ~ 45

Author(s):

Naoko Hashimoto ◽

Yohei Maeshima ◽

Minoru Satoh ◽

Masahiro Odawara ◽

Hitoshi Sugiyama ◽

...

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Transforming Growth Factor Β ◽

Glomerular Injury ◽

Wild Mice ◽

Angiotensin Type 2 Receptor ◽

Glomerular Size ◽

Nitric Oxide Metabolites

Angiotensin II mediates the progression of renal disease through the type 1 receptor (AT1R). Recent studies have suggested that type 2 receptor (AT2R)-mediated signaling inhibits cell proliferation by counteracting the actions of AT1R. The aim of the present study was to determine the effect of AT2R overexpression on glomerular injury induced by ⅚ nephrectomy (⅚Nx). AT2R transgenic mice (AT2-Tg), overexpressing AT2R under the control of α-smooth muscle actin (α-SMA) promoter, and control wild-type mice (Wild) were subjected to ⅚Nx. In AT2-Tg mice, the glomerular expression of AT2R was upregulated after ⅚Nx. Urinary albumin excretion at 12 wk after ⅚Nx was decreased by 33.7% in AT2-Tg compared with Wild mice. Glomerular size in AT2-Tg mice was significantly smaller than in Wild mice after ⅚Nx (93.1 ± 3.0 vs. 103.3 ± 1.8 μm; P < 0.05). Immunohistochemistry revealed significant decreases in glomerular expression of platelet-derived growth factor-BB chain (PDGF-BB) and transforming growth factor-β1 (TGF-β1) in AT2-Tg with ⅚Nx compared with Wild mice. Urinary excretion of nitric oxide metabolites was increased 2.5-fold in AT2-Tg compared with Wild mice. EMSA showed that activation of early growth response gene-1, which induces the transcription of PDGF-BB and TGF-β1, was decreased in AT2-Tg mice. These changes in AT2-Tg mice at 12 wk after ⅚Nx were blocked by the AT2R antagonist PD-123319. Taken together, our findings suggest that AT2R-mediated signaling may protect from glomerular injuries induced by ⅚Nx and that overexpression of AT2R may serve as a potential therapeutic strategy for glomerular disorders.

Download Full-text

Hierarchical Coculture of Hepatocyte and Hepatic Non-Parenchymal Cells for Liver Fibrosis Studies in vitro

10.20944/preprints202010.0409.v1 ◽

2020 ◽

Author(s):

Qiao You Lau ◽

Fuad Gandhi Torizal ◽

Marie Shinohara ◽

Yasuyuki Sakai

Keyword(s):

Growth Factor ◽

Liver Fibrosis ◽

Oxygen Tension ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Liver Sinusoidal Endothelial Cell ◽

Type I ◽

Parenchymal Cells

During chronic liver injury, inflammation leads to the development of liver fibrosis— particularly due to the activation of hepatic stellate cells (HSCs). However, the involvement of inflammatory cytokines in HSC activation is unclear. Many existing in vitro liver models do not include these non-parenchymal cells (NPCs), and hence, do not represent the physiological relevance found in vivo. Herein, we demonstrated the hierarchical coculture of primary rat hepatocytes with NPCs such as the human-derived HSC line (LX-2) and the human-derived liver sinusoidal endothelial cell line (TMNK-1). The coculture tissue had higher albumin production and hepatic cytochrome P450 3A4 activity compared to the monoculture. We then further studied the effects of stimulation by both oxygen tension and key pro-fibrogenic cytokines, such as the transforming growth factor beta (TGF-β), on HSC activation. Gene expression analysis revealed that lower oxygen tension and TGF-β1 stimulation enhanced collagen type I, III, and IV, alpha-smooth muscle actin, platelet-derived growth factor, and matrix metallopeptidase expression from LX-2 cells in the hierarchical coculture after fibrogenesis induction. This hierarchical in vitro cocultured liver tissue could, therefore, provide an improved platform as a disease model for elucidating the interactions of various liver cell types and biochemical signals in liver fibrosis studies.

Download Full-text

Smad3 Mediates Transforming Growth Factor-β–Induced α-Smooth Muscle Actin Expression

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/rcmb.2003-0063oc ◽

2003 ◽

Vol 29 (3) ◽

pp. 397-404 ◽

Cited By ~ 203

Author(s):

Biao Hu ◽

Zhe Wu ◽

Sem H. Phan

Keyword(s):

Smooth Muscle ◽

Growth Factor ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Transforming Growth Factor Β ◽

Muscle Actin ◽

Actin Expression

Download Full-text

A histone deacetylase inhibitor, largazole, decreases liver fibrosis and angiogenesis by inhibiting transforming growth factor-β and vascular endothelial growth factor signalling

Liver International ◽

10.1111/liv.12034 ◽

2012 ◽

Vol 33 (4) ◽

pp. 504-515 ◽

Cited By ~ 57

Author(s):

Yuqing Liu ◽

Zhuo Wang ◽

Jianing Wang ◽

Wingchi Lam ◽

Shuqin Kwong ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Liver Fibrosis ◽

Histone Deacetylase Inhibitor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Vascular Endothelial ◽

Deacetylase Inhibitor ◽

Growth Factor Signalling ◽

Endothelial Growth Factor

Download Full-text

Antifibrotic Effects of Amyloid-Beta and Its Loss in Cirrhotic Liver

Cells ◽

10.3390/cells9020452 ◽

2020 ◽

Vol 9 (2) ◽

pp. 452 ◽

Cited By ~ 2

Author(s):

Gayane Hrachia Buniatian ◽

Ralf Weiskirchen ◽

Thomas S. Weiss ◽

Ute Schwinghammer ◽

Martin Fritz ◽

...

Keyword(s):

Amyloid Beta ◽

Potential Role ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Transforming Growth Factor Β ◽

Cirrhotic Liver ◽

Liver Sinusoidal Endothelial Cells ◽

Beta Secretase ◽

Diseased Liver

The function and regulation of amyloid-beta (Aβ) in healthy and diseased liver remains unexplored. Because Aβ reduces the integrity of the blood-brain barrier we have examined its potential role in regulating the sinusoidal permeability of normal and cirrhotic liver. Aβ and key proteins that generate (beta-secretase 1 and presenilin-1) and degrade it (neprilysin and myelin basic protein) were decreased in human cirrhotic liver. In culture, activated hepatic stellate cells (HSC) internalized Aβ more efficiently than astrocytes and HSC degraded Aβ leading to suppressed expression of α-smooth muscle actin (α-SMA), collagen 1 and transforming growth factor β (TGFβ). Aβ also upregulated sinusoidal permeability marker endothelial NO synthase (eNOS) and decreased TGFβ in cultured human liver sinusoidal endothelial cells (hLSEC). Liver Aβ levels also correlate with the expression of eNOS in transgenic Alzheimer’s disease mice and in human and rodent cirrhosis/fibrosis. These findings suggest a previously unexplored role of Aβ in the maintenance of liver sinusoidal permeability and in protection against cirrhosis/fibrosis via attenuation of HSC activation.

Download Full-text