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The generally accepted hypothesis for the pathogenesis of alcoholic liver disease (ALD) is the two-hit model, which proposes that fat accumulation in the liver increases the sensitivity of the liver to a second hit that leads to inflammatory liver cell damage. In this study we evaluated the effects of Magnolia officinalis (MO), which contains honokiol and magnolol as the primary pharmacological components, to eradicate fatty liver in rats fed an ethanol diet. In vitro studies showed that MO was able to protect RAW 264.7 cells from ethanol-induced production of tumor necrosis factor-alpha, reactive oxygen species, and superoxide anion radicals; the activation of NADPH oxidase; and subsequent cell death. We also investigated the therapeutic effects of MO on alcoholic fatty liver in Lieber-DeCarli ethanol diet-fed rats. MO treatment of the rats for the last 2 weeks of ethanol feeding completely reversed all the serum, hepatic parameters, and fatty liver changes. The increased maturation of sterol regulatory element-binding protein-1c in the liver by ethanol treatment was completely inhibited by treatment with MO. Therefore, MO may be a promising candidate for development as a therapeutic agent for ALD.

The generally accepted hypothesis for the pathogenesis of alcoholic liver disease (ALD) is the two-hit model, which proposes that fat accumulation in the liver increases the sensitivity of the liver to a second hit that leads to inflammatory liver cell damage. In this study we evaluated the effects of Magnolia officinalis (MO), which contains honokiol and magnolol as the primary pharmacological components, to eradicate fatty liver in rats fed an ethanol diet. In vitro studies showed that MO was able to protect RAW 264.7 cells from ethanol-induced production of tumor necrosis factor-alpha, reactive oxygen species, and superoxide anion radicals; the activation of NADPH oxidase; and subsequent cell death. We also investigated the therapeutic effects of MO on alcoholic fatty liver in Lieber-DeCarli ethanol diet-fed rats. MO treatment of the rats for the last 2 weeks of ethanol feeding completely reversed all the serum, hepatic parameters, and fatty liver changes. The increased maturation of sterol regulatory element-binding protein-1c in the liver by ethanol treatment was completely inhibited by treatment with MO. Therefore, MO may be a promising candidate for development as a therapeutic agent for ALD.

Casearia sylvestris Sw. is widely used in popular medicine to treat inflammatory conditions.To investigate the anti-inflammatory and antioxidant properties of hydroalcoholic crude extract (HCE) taken from Casearia sylvestris Sw. (Salicaceae).The effect of the HCE from this plant (3-300 mg/kg) on the reduction of inflammatory response to carrageenan was investigated in pleurisy in rats (intrapleural, 2% in 0.2 mL) or paw edema in mice (intraplantar, 300 μg/20 μL, right hind paw). The plant anti-inflammatory action was assessed by its capability in inhibiting cell migration, enzymatic activity of myeloperoxidase (MPO) and production of nitrite/nitrate or edema. The in vitro antioxidant activity of this extract against lipid peroxidation and damage to proteins was assessed as possible pathways to contribute as anti-inflammatory mechanisms. Carrageenan-induced hind paw edema (739.3 ± 11.9 μm) was reduced by HCE (30 mg/kg: 462.8 ± 28.38 μm) to similar extents as dexametasone (365.1 ± 16.7). In pleurisy, treatment of the animals with HCE (100mg/kg: 0.010 ± 0.001 mU/mg of protein) also reduced MPO activity augmented by carrageenan (0.020 ± 0.001 mU/mg of protein) as well as leukocytes migration (carrageenan: 17.8890 ± 2.3900 leukocytes/mL, HCE 100mg/kg: 7.0880 ± 9631 leukocytes/mL). Significant effects were also observed in animals treated with different doses of HCE in biochemical tests for oxidative stress analysis.The anti-inflammatory and antioxidant effects of HCE from Casearia sylvestris Sw. suggests a potential therapeutic benefit of this plant in treatment of inflammatory conditions.

Casearia sylvestris Sw. is widely used in popular medicine to treat inflammatory conditions.To investigate the anti-inflammatory and antioxidant properties of hydroalcoholic crude extract (HCE) taken from Casearia sylvestris Sw. (Salicaceae).The effect of the HCE from this plant (3-300 mg/kg) on the reduction of inflammatory response to carrageenan was investigated in pleurisy in rats (intrapleural, 2% in 0.2 mL) or paw edema in mice (intraplantar, 300 μg/20 μL, right hind paw). The plant anti-inflammatory action was assessed by its capability in inhibiting cell migration, enzymatic activity of myeloperoxidase (MPO) and production of nitrite/nitrate or edema. The in vitro antioxidant activity of this extract against lipid peroxidation and damage to proteins was assessed as possible pathways to contribute as anti-inflammatory mechanisms. Carrageenan-induced hind paw edema (739.3 ± 11.9 μm) was reduced by HCE (30 mg/kg: 462.8 ± 28.38 μm) to similar extents as dexametasone (365.1 ± 16.7). In pleurisy, treatment of the animals with HCE (100mg/kg: 0.010 ± 0.001 mU/mg of protein) also reduced MPO activity augmented by carrageenan (0.020 ± 0.001 mU/mg of protein) as well as leukocytes migration (carrageenan: 17.8890 ± 2.3900 leukocytes/mL, HCE 100mg/kg: 7.0880 ± 9631 leukocytes/mL). Significant effects were also observed in animals treated with different doses of HCE in biochemical tests for oxidative stress analysis.The anti-inflammatory and antioxidant effects of HCE from Casearia sylvestris Sw. suggests a potential therapeutic benefit of this plant in treatment of inflammatory conditions.

AbstractEfferocytosis is a unique phagocytic process for macrophages to remove apoptotic cells in inflammatory loci. This event is maintained by milk fat globule-EGF factor 8 (MFG-E8), but attenuated by high mobility group box 1 (HMGB1). Alcohol abuse causes injury and inflammation in multiple tissues. It alters efferocytosis, but precise molecular mechanisms for this effect remain largely unknown. Here, we showed that acute exposure of macrophages to alcohol (25 mmol/L) inhibited MFG-E8 gene expression and impaired efferocytosis. The effect was mimicked by hydrogen peroxide. Moreover, N-acetylcysteine (NAC), a potent antioxidant, blocked acute alcohol effect on inhibition of macrophage MFG-E8 gene expression and efferocytosis. In addition, recombinant MFG-E8 rescued the activity of alcohol-treated macrophages in efferocytosis. Together, the data suggest that acute alcohol exposure impairs macrophage efferocytosis via inhibition of MFG-E8 gene expression through a reactive oxygen species dependent mechanism. Alcohol has been found to suppress or exacerbate immune cell activities depending on the length of alcohol exposure. Thus, we further examined the role of chronic alcohol exposure on macrophage efferocytosis. Interestingly, treatment of macrophages with alcohol for seven days in vitro enhanced MFG-E8 gene expression and efferocytosis. However, chronic feeding of mice with alcohol caused increase in HMGB1 levels in serum. Furthermore, HMGB1 diminished efferocytosis by macrophages that were treated chronically with alcohol, suggesting that HMGB1 might attenuate the direct effect of chronic alcohol on macrophage efferocytosis in vivo. Therefore, we speculated that the balance between MFG-E8 and HMGB1 levels determines pathophysiological effects of chronic alcohol exposure on macrophage efferocytosis in vivo.

AbstractEfferocytosis is a unique phagocytic process for macrophages to remove apoptotic cells in inflammatory loci. This event is maintained by milk fat globule-EGF factor 8 (MFG-E8), but attenuated by high mobility group box 1 (HMGB1). Alcohol abuse causes injury and inflammation in multiple tissues. It alters efferocytosis, but precise molecular mechanisms for this effect remain largely unknown. Here, we showed that acute exposure of macrophages to alcohol (25 mmol/L) inhibited MFG-E8 gene expression and impaired efferocytosis. The effect was mimicked by hydrogen peroxide. Moreover, N-acetylcysteine (NAC), a potent antioxidant, blocked acute alcohol effect on inhibition of macrophage MFG-E8 gene expression and efferocytosis. In addition, recombinant MFG-E8 rescued the activity of alcohol-treated macrophages in efferocytosis. Together, the data suggest that acute alcohol exposure impairs macrophage efferocytosis via inhibition of MFG-E8 gene expression through a reactive oxygen species dependent mechanism. Alcohol has been found to suppress or exacerbate immune cell activities depending on the length of alcohol exposure. Thus, we further examined the role of chronic alcohol exposure on macrophage efferocytosis. Interestingly, treatment of macrophages with alcohol for seven days in vitro enhanced MFG-E8 gene expression and efferocytosis. However, chronic feeding of mice with alcohol caused increase in HMGB1 levels in serum. Furthermore, HMGB1 diminished efferocytosis by macrophages that were treated chronically with alcohol, suggesting that HMGB1 might attenuate the direct effect of chronic alcohol on macrophage efferocytosis in vivo. Therefore, we speculated that the balance between MFG-E8 and HMGB1 levels determines pathophysiological effects of chronic alcohol exposure on macrophage efferocytosis in vivo.

Background and Aims: Alcohol-associated liver disease (ALD) accounts for 70% of liver-related deaths in Europe, with no effective approved therapies. Although mitochondrial dysfunction is one of the earliest manifestations of alcohol-induced injury, restoring mitochondrial activity remains a problematic strategy due to oxidative stress. Here, we identify methylation-controlled J protein (MCJ) as a mediator for ALD progression and hypothesize that targeting MCJ may help in recovering mitochondrial fitness without collateral oxidative damage. Approach and Results: C57BL/6 mice [wild-type (Wt)] Mcj knockout and Mcj liver-specific silencing (MCJ-LSS) underwent the NIAAA dietary protocol (Lieber-DeCarli diet containing 5% (vol/vol) ethanol for 10 days, plus a single binge ethanol feeding at day 11). To evaluate the impact of a restored mitochondrial activity in ALD, the liver, gut, and pancreas were characterized, focusing on lipid metabolism, glucose homeostasis, intestinal permeability, and microbiota composition. MCJ, a protein acting as an endogenous negative regulator of mitochondrial respiration, is downregulated in the early stages of ALD and increases with the severity of the disease. Whole-body deficiency of MCJ is detrimental during ALD because it exacerbates the systemic effects of alcohol abuse through altered intestinal permeability, increased endotoxemia, and dysregulation of pancreatic function, which overall worsens liver injury. On the other hand, liver-specific Mcj silencing prevents main ALD hallmarks, that is, mitochondrial dysfunction, steatosis, inflammation, and oxidative stress, as it restores the NAD+/NADH ratio and SIRT1 function, hence preventing de novo lipogenesis and improving lipid oxidation. Conclusions: Improving mitochondrial respiration by liver-specific Mcj silencing might become a novel therapeutic approach for treating ALD.