Placental extract ameliorates liver fibrosis in a methionine- and choline-deficient diet-induced mouse model of non-alcoholic steatohepatitis

Abstract

Non-alcoholic steatohepatitis (NASH) is a severe form of fatty liver disease that is defined by the presence of inflammation and fibrosis, which ultimately leads to cirrhosis and hepatocellular carcinoma. We previously showed that human placental extract (hPE) was intramuscularly injected to ameliorates liver injury in a methionine-and choline-deficient (MCD) diet-induced NASH model. In the present study, we investigated the effects of hPE using dB/dB mice which exhibit obesity and insulin resistance and are thought to reproduce the pathological background of NASH. The MCD-diet induced liver atrophy accompanied by fibrosis around the liver sinusoids. hPE dosedependently reduced the perivascular fibrosis. Moreover, αSMA-positive activated hepatic stellate cells increased in number in mice on the MCD diet, with this effect reversed by hPE treatment. hPE significantly decreased expression of Acta2, Col1a1, and Tgfb1 genes in hepatic stellate cells, and inhibited Smad phosphorylation. Moreover, hPE treatment increased the expression of the antioxidative genes Hmox1, Nqo1, Cat, and Sod1, and significantly enhanced nuclear factor erythroid 2-related factor 2 activity. Furthermore, hPE decreased the expression of Nox4 and attenuated the levels of intracellular reactive oxygen species. These results, along with our previous study, suggest that hPE effectively ameliorates liver fibrosis in NASH. This beneficial effect may, in part, be due to suppression of hepatic stellate cell activation.

Human placental extract ameliorates methotrexate-induced hepatotoxicity in rats via regulating antioxidative and anti-inflammatory responses

“…This suggests that reductions in oxidative stress and inflammation are key beneficial effects of HPE. These results are in accordance with [ 68 ]. Our observed results of HPE acting in concert with MTX matches closely with the recent study by Cataldi et al of a new avenue for treatment and prevention of drug-induced steatosis and steatohepatitis [ 69 ], where they noted promising work in in vitro and animal studies of combining a hepatotoxic drug with a second molecule that aimed to antagonize liver toxicity as well as enhance the pharmacological activity of the drug.…”

Experimental medicinal hepatitis. Hepatoprotective effects of the drug Laennec in models of toxic liver injury with paracetamol or alcohol

“…ГПЧ значительно снижал экспрессию генов Acta2, Col1a1 и Tgfb 1 в звездчатых клетках печени и ингибировал профибротические молекулярные пути (фосфорилирование сигнальных белков Smad). Кроме того, ГПЧ увеличивал экспрессию антиоксидантных генов Hmox1, Nqo1, Cat и Sod1 и снижал уровни внутриклеточных активных форм кислорода, что способствует снижению профибротических изменений печени при НАСГ [12].…”

Protective Effect and Mechanism of Placenta Extract on Liver

“…The histological structures are the most intuitive indicators to evaluate the liver health status. PE has been reported to possess hepatoprotective effects against chemical factors (drugs, alcohol) [ 42 , 62 , 63 ], physical factors (partial hepatectomy) [ 64 ], and nutritional disorders (methionine and choline deficiency, high salt intake) that induce liver histological structure damage [ 50 , 65 ]. For example, PE could improve the vacuolar degeneration and steatosis of hepatocytes [ 42 , 51 , 64 ], inhibit the process of hepatocyte apoptosis and necrosis [ 51 , 66 ], and restore normal cellularity, including a typical polygonal morphology, normal cytoplasm and nucleus, and clear cell edges [ 62 ].…”

“…For the interstitial changes in the liver, PE reduces the dilatation and congestion of hepatic sinusoids and central veins and inhibits lipogenesis and inflammatory cell infiltration [ 62 ]. Further, PE attenuates the proliferation of fibrosis tissue, collagen, and fat deposition in the damaged liver [ 65 , 67 ] and inhibits pseudolobule formation [ 64 ], ultimately alleviating liver fibrosis and the fatty liver process [ 42 , 50 , 68 ]. In addition, a hepatoprotective agent with the placenta as the adjuvant and the transplantation of chorionic plate-derived mesenchymal stem cells (CP-MSCs) can also reduce hepatocyte necrosis, inflammatory cell infiltration, and collagen and fat deposition [ 63 ].…”

“…PE exerts antioxidant effects mainly through activating the Nrf2 pathway, increasing the antioxidant enzymes’ (SOD, CAT, GSH-Px) [ 51 , 62 , 74 ] and phase II detoxification enzymes’ (HO-1, NQO1) [ 51 , 65 ] activity, and reducing the generation of MDA and ROS in the liver [ 63 , 65 , 76 ]. Furthermore, PE reduces the expression of liver Nox4, p22phox, p67phox, and 4-hydroxy-2-nonenal (4HNE, a product of lipid peroxidation) and decreases the intracellular redox potential.…”