Browsing by Subject "liver damage"

Now showing 1 - 3 of 3
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    Melatonin receptor 1A, but not 1B, knockout decreases biliary damage and liver fibrosis during cholestatic liver injury
    (Wiley, 2021) Wu, Nan; Carpino, Guido; Ceci, Ludovica; Baiocchi, Leonardo; Francis, Heather; Kennedy, Lindsey; Zhou, Tianhao; Chen, Lixian; Sato, Keisaku; Kyritsi, Konstantina; Meadows, Vik; Ekser, Burcin; Franchitto, Antonio; Mancinelli, Romina; Onori, Onori; Gaudio, Eugenio; Glaser, Shannon; Alpini, Gianfranco; Medicine, School of Medicine
    Background and Aims Melatonin reduces biliary damage and liver fibrosis in cholestatic models by interaction with melatonin receptors 1A (MT1) and 1B (MT2). MT1 and MT2 can form heterodimers and homodimers, but MT1 and MT2 can heterodimerize with the orphan receptor G protein–coupled receptor 50 (GPR50). MT1/GPR50 dimerization blocks melatonin binding, but MT2/GPR50 dimerization does not affect melatonin binding. GPR50 can dimerize with TGFβ receptor type I (TGFβRI) to activate this receptor. We aimed to determine the differential roles of MT1 and MT2 during cholestasis. Approach and Results Wild-type (WT), MT1 knockout (KO), MT2KO, and MT1/MT2 double KO (DKO) mice underwent sham or bile duct ligation (BDL); these mice were also treated with melatonin. BDL WT and multidrug resistance 2 KO (Mdr2−/−) mice received mismatch, MT1, or MT2 Vivo-Morpholino. Biliary expression of MT1 and GPR50 increases in cholestatic rodents and human primary sclerosing cholangitis (PSC) samples. Loss of MT1 in BDL and Mdr2−/− mice ameliorated biliary and liver damage, whereas these parameters were enhanced following loss of MT2 and in DKO mice. Interestingly, melatonin treatment alleviated BDL-induced biliary and liver injury in BDL WT and BDL MT2KO mice but not in BDL MT1KO or BDL DKO mice, demonstrating melatonin’s interaction with MT1. Loss of MT2 or DKO mice exhibited enhanced GPR50/TGFβR1 signaling, which was reduced by loss of MT1. Conclusions Melatonin ameliorates liver phenotypes through MT1, whereas down-regulation of MT2 promotes liver damage through GPR50/TGFβR1 activation. Blocking GPR50/TGFβR1 binding through modulation of melatonin signaling may be a therapeutic approach for PSC.
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    Noninvasive monitoringn of CCl4 induced acute and chronic liver damage in rat by single quantum and triple quantum filtered 23Na magnetic resonance imaging
    (2008) Gao, Yong; Bansal, Navin; Babsky, Andriy M.; Kempson, Stephen A.; Basile, David P.
    In present study, single quantum (SQ) and triple quantum filtered (TQF) 23Na magnetic resonance imaging (MRI) was used to monitor the severity and progression of CCl4 induced acute and chronic liver damage in rat model. SQ 23Na MRI was proposed to measure the 23Na signal intensity (SI) of total tissue sodium ions, and TQF 23Na MRI was proposed to measure the SI of intracellular sodium ions. In addition, shift reagent aided 23Na and 31P magnetic resonance spectroscopy (MRS) was used to measure in vivo intracellular sodium concentration ([Na+i]), total tissue sodium concentration ([Na+t]) and relative extracellular space (rECS) of liver in the same model. In acute high dose CCl4 intoxication, 24 hours after single dose of CCl4 in 5ml per kg body weight of mixture of CCl4 and oil in 1:1 ratio, SQ 23Na SI increased by 83% and TQF 23Na SI increased by 174% compared to the baseline level. According to SR-aided 23Na and 31P MRS, [Na+i] increased by 188% and [Na+t] increased by 43%. In addition, there was significant decrease in cellular energetic level, represented by ATP/Pi ratio. Histology examination showed pronounced inflammatory response in centrilobular regions, with neutrophiles infiltration, fatty accumulation and swollen hepatocytes. In chronic 8-week experiment, chronic damage was induced by biweekly administration of CCl4 in a dosage of 0.5 ml per kg body weight. From week 1 to week 6, SQ 23Na SI remained relatively constant, and then increased by 15% from week 6 to week 8. TQF 23Na SI progressively increased from week 1 to week 8, totally by 56%. Both SQ and TQF 23Na SI showed significant difference between treated group and control at every week. SR-aided 23Na and 31P MRS experiment showed that, at the end of 8-week CCl4 intoxication, both [Na+t] and rECS were higher than control, by 49% and 47% respectively; however, there was no significant difference for [Na+i] between two groups. Histology examination showed excessive deposition of extracellular matrix. In conclusion, SQ and TQF 23Na MRI appears valuable in the functional assessment of liver in noninvasive approach, and could be a promising diagnostic modality for liver diseases in clinical area.
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    Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis
    (Wiley, 2019-06-28) Kennedy, Lindsey; Francis, Heather; Invernizzi, Pietro; Venter, Julie; Wu, Nan; Carbone, Marco; Gershwin, M. Eric; Bernuzzi, Francesca; Franchitto, Antonio; Alvaro, Domenico; Marzioni, Marco; Onori, Paolo; Gaudio, Eugenio; Sybenga, Amelia; Fabris, Luca; Meng, Fanyin; Glaser, Shannon; Alpini, Gianfranco; Medicine, School of Medicine
    Primary biliary cholangitis (PBC) primarily targets cholangiocytes and is characterized by liver fibrosis and biliary proliferation. Activation of the secretin (Sct)/secretin receptor (SR) axis, expressed only by cholangiocytes, increases biliary proliferation, liver fibrosis, and bicarbonate secretion. We evaluated the effectiveness of SR antagonist treatment for early-stage PBC. Male and female dominant-negative TGF-β receptor II (dnTGF-βRII) (model of PBC) and wild-type mice at 12 wk of age were treated with saline or the SR antagonist, Sec 5–27, for 1 wk. dnTGF-βRII mice expressed features of early-stage PBC along with enhanced Sct/SR axis activation and Sct secretion. dnTGF-βRII mice had increased biliary proliferation or senescence, inflammation, and liver fibrosis. In dnTGF-βRII mice, there was increased microRNA-125b/TGF-β1/TGF-β receptor 1/VEGF-A signaling. Human early-stage PBC patients had an increase in hepatobiliary Sct and SR expression and serum Sct levels. Increased biliary Sct/SR signaling promotes biliary and hepatic damage during early-stage PBC.—Kennedy, L., Francis, H., Invernizzi, P., Venter, J., Wu, N., Carbone, M., Gershwin, M. E., Bernuzzi, F., Franchitto, A., Alvaro, D., Marzioni, M., Onori, P., Gaudio, E., Sybenga, A., Fabris, L., Meng, F., Glaser, S., Alpini, G. Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis.