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Open AccessArticle Moringa Leaves Prevent Hepatic Lipid Accumulation and Inflammation in Guinea Pigs by Reducing the Expression of Genes Involved in Lipid Metabolism

by Manal Mused Almatrafi, Marcela Vergara-Jimenez, Ana Gabriela Murillo, Gregory H. Norris, Christopher N. Blesso and Maria Luz Fernandez

Int. J. Mol. Sci. 2017, 18(7), 1330; doi:10.3390/ijms18071330

Received: 18 May 2017 / Revised: 14 June 2017 / Accepted: 15 June 2017 / Published: 22 June 2017

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Abstract

To investigate the mechanisms by which Moringa oleifera leaves (ML) modulate hepatic lipids, guinea pigs were allocated to either control (0% ML), 10% Low Moringa (LM) or 15% High Moringa (HM) diets with 0.25% dietary cholesterol to induce hepatic steatosis. After 6 weeks,

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To investigate the mechanisms by which Moringa oleifera leaves (ML) modulate hepatic lipids, guinea pigs were allocated to either control (0% ML), 10% Low Moringa (LM) or 15% High Moringa (HM) diets with 0.25% dietary cholesterol to induce hepatic steatosis. After 6 weeks, guinea pigs were sacrificed and liver and plasma were collected to determine plasma lipids, hepatic lipids, cytokines and the expression of genes involved in hepatic cholesterol (CH) and triglyceride (TG) metabolism. There were no differences in plasma lipids among groups. A dose-response effect of ML was observed in hepatic lipids (CH and TG) with the lowest concentrations in the HM group (p < 0.001), consistent with histological evaluation of lipid droplets. Hepatic gene expression of diglyceride acyltransferase-2 and peroxisome proliferator activated receptor-γ, as well as protein concentrations interleukin (IL)-1β and interferon-γ, were lowest in the HM group (p < 0.005). Hepatic gene expression of cluster of differentiation-68 and sterol regulatory element binding protein-1c were 60% lower in both the LM and HM groups compared to controls (p < 0.01). This study demonstrates that ML may prevent hepatic steatosis by affecting gene expression related to hepatic lipids synthesis resulting in lower concentrations of cholesterol and triglycerides and reduced inflammation in the liver. Full article

(This article belongs to the Special Issue Natural Anti-Inflammatory Agents)

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Open AccessArticle Seabuckthorn Leaves Extract and Flavonoid Glycosides Extract from Seabuckthorn Leaves Ameliorates Adiposity, Hepatic Steatosis, Insulin Resistance, and Inflammation in Diet-Induced Obesity

by Eun-Young Kwon, Jeonghyeon Lee, Ye Jin Kim, Ara Do, Ji-Young Choi, Su-Jung Cho, Un Ju Jung, Mi-Kyung Lee, Yong Bok Park and Myung-Sook Choi

Nutrients 2017, 9(6), 569; doi:10.3390/nu9060569

Received: 26 April 2017 / Revised: 26 May 2017 / Accepted: 31 May 2017 / Published: 2 June 2017

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Abstract

The aim of the current study was to elucidate the effect of seabuckthorn leaves (SL) extract and flavonoid glycosides extract from seabuckthorn leaves (SLG) on diet-induced obesity and related metabolic disturbances, and additionally, to identify whether flavonoid glycosides and other components in SL

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The aim of the current study was to elucidate the effect of seabuckthorn leaves (SL) extract and flavonoid glycosides extract from seabuckthorn leaves (SLG) on diet-induced obesity and related metabolic disturbances, and additionally, to identify whether flavonoid glycosides and other components in SL can exert a possible interaction for the prevention of metabolic diseases by comparing the effect of SL and SLG. C57BL/6J mice were fed a normal diet (ND, AIN-93G purified diet), high-fat diet (HFD, 60 kcal% fat), HFD + 1.8% (w/w) SL (SL), and HFD + 0.04% (w/w) SLG (SLG) for 12 weeks. In high fat-fed mice, SL and SLG decreased the adiposity by suppressing lipogenesis in adipose tissue, while increasing the energy expenditure. SL and SLG also improved hepatic steatosis by suppressing hepatic lipogenesis and lipid absorption, whilst also enhancing hepatic fatty acid oxidation, which may be linked to the improvement in dyslipidemia. Moreover, SL and SLG improved insulin sensitivity by suppressing the levels of plasma GIP that were modulated by secreted resistin and pro-inflammatory cytokine, and hepatic glucogenic enzyme activities. SL, especially its flavonoid glycosides (SLG), can protect against the deleterious effects of diet-induced obesity (DIO) and its metabolic complications such as adiposity, dyslipidemia, inflammation, hepatic steatosis, and insulin resistance. Full article

(This article belongs to the Special Issue Effects of Polyphenol-Rich Foods on Human Health)

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Open AccessArticle Vitis vinifera Extract Ameliorate Hepatic and Renal Dysfunction Induced by Dexamethasone in Albino Rats

by Nabil A. Hasona, Ahmed A. Alrashidi, Thamer Z. Aldugieman, Ali M. Alshdokhi and Mohammed Q. Ahmed

Toxics 2017, 5(2), 11; doi:10.3390/toxics5020011

Received: 9 March 2017 / Revised: 5 April 2017 / Accepted: 6 April 2017 / Published: 11 April 2017

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Abstract

This study was conducted to evaluate the biochemical effects of grape seed extract against dexamethasone-induced hepatic and renal dysfunction in a female albino rat. Twenty-eight adult female rats were divided randomly into four equal groups: Group 1: animals were injected subcutaneously with saline

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This study was conducted to evaluate the biochemical effects of grape seed extract against dexamethasone-induced hepatic and renal dysfunction in a female albino rat. Twenty-eight adult female rats were divided randomly into four equal groups: Group 1: animals were injected subcutaneously with saline and consider as normal control one. Group 2: animals were injected subcutaneously with dexamethasone in a dose of 0.1 mg/kg body weight. Group 3: animals were injected subcutaneously with 0.1 mg/kg body weight of dexamethasone, and then treated with a grape seed extract in a dose of 200 mg/kg body weight by oral gavage. Group 4: animals were injected subcutaneously with 0.1 mg/kg body weight of dexamethasone, and then treated with a grape seed extract in a dose of 400 mg/kg body weight by oral gavage. After 4 weeks, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) activities, albumin, uric acid, creatinine, and glucose levels were assayed. Hepatic reduced glutathione (GSH), total protein content, and catalase and glucose-6-phosphate dehydrogenase activities were also assayed. Dexamethasone administration caused elevation of serum levels of glucose, uric acid, creatinine, ALT, AST activities, and a decrease in other parameters such as hepatic glutathione, total protein levels, and catalase enzyme activity. Treatment with Vitis vinifera L. seed extract showed a significant increase in the body weight of rats in the group treated with Vitis vinifera L. seed extract orally compared with the dexamethasone control group. An increase in GSH and catalase activity in response to oral treatment with Vitis vinifera L. seed extract was observed after treatment. Grape seed extract positively affects glucocorticoid-induced hepatic and renal alteration in albino rats. Full article

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Open AccessArticle Anticancer Dose Adjustment for Patients with Renal and Hepatic Dysfunction: From Scientific Evidence to Clinical Application

by Tomi Hendrayana, André Wilmer, Verena Kurth, Ingo GH Schmidt-Wolf and Ulrich Jaehde

Sci. Pharm. 2017, 85(1), 8; doi:10.3390/scipharm85010008

Received: 22 December 2016 / Revised: 4 February 2017 / Accepted: 20 February 2017 / Published: 27 February 2017

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Abstract

Most anticancer agents exhibit a narrow therapeutic index, i.e., a small change in plasma concentrations can lead to a less efficacious treatment or an unacceptable degree of toxicity. This study aimed at providing health professionals with a feasible and time-saving tool to adapt

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Most anticancer agents exhibit a narrow therapeutic index, i.e., a small change in plasma concentrations can lead to a less efficacious treatment or an unacceptable degree of toxicity. This study aimed at providing health professionals with a feasible and time-saving tool to adapt the dose of anticancer agents for patients with renal or hepatic dysfunction. A guideline for anticancer agents was developed based on a literature search. An algorithm was generated to enhance the efficiency of the dose adaptation process. Finally, the dosing guideline was converted into an easy-to-use Excel^TM tool. The concept was applied to a total of 105 adult patients at the Centre for Integrated Oncology, Bonn, Germany. In total, 392 recommendations for dose adaptation were made and 320 (81.6%) recommendations were responded to by the oncologists. 98.4% of the recommendations were accepted. The algorithm simplifies the decision and screening process for high-risk patients. Moreover, it provides the possibility to quickly decide which laboratory tests are required and whether a dose adjustment for a particular anticancer drug is needed. The Excel^TM tool provides a recommended individual dose for patients with renal or hepatic dysfunction. The effectiveness of this strategy to reduce toxicity should be investigated in further studies before being adopted for routine use. Full article

(This article belongs to the Special Issue Selected Papers from the International Seminar on Pharmacology and Clinical Pharmacy (ISPCP-ITB 2016))

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Open AccessReview Hepatic Retinyl Ester Hydrolases and the Mobilization of Retinyl Ester Stores

by Lukas Grumet, Ulrike Taschler and Achim Lass

Nutrients 2017, 9(1), 13; doi:10.3390/nu9010013

Received: 28 October 2016 / Revised: 12 December 2016 / Accepted: 21 December 2016 / Published: 27 December 2016

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Abstract

For mammals, vitamin A (retinol and metabolites) is an essential micronutrient that is required for the maintenance of life. Mammals cannot synthesize vitamin A but have to obtain it from their diet. Resorbed dietary vitamin A is stored in large quantities in the

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For mammals, vitamin A (retinol and metabolites) is an essential micronutrient that is required for the maintenance of life. Mammals cannot synthesize vitamin A but have to obtain it from their diet. Resorbed dietary vitamin A is stored in large quantities in the form of retinyl esters (REs) in cytosolic lipid droplets of cells to ensure a constant supply of the body. The largest quantities of REs are stored in the liver, comprising around 80% of the body’s total vitamin A content. These hepatic vitamin A stores are known to be mobilized under times of insufficient dietary vitamin A intake but also under pathological conditions such as chronic alcohol consumption and different forms of liver diseases. The mobilization of REs requires the activity of RE hydrolases. It is astounding that despite their physiological significance little is known about their identities as well as about factors or stimuli which lead to their activation and consequently to the mobilization of hepatic RE stores. In this review, we focus on the recent advances for the understanding of hepatic RE hydrolases and discuss pathological conditions which lead to the mobilization of hepatic RE stores. Full article

(This article belongs to the Special Issue Vitamin A Update 2016)

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Open AccessArticle Troxerutin Attenuates Enhancement of Hepatic Gluconeogenesis by Inhibiting NOD Activation-Mediated Inflammation in High-Fat Diet-Treated Mice

by Zifeng Zhang, Xin Wang, Guihong Zheng, Qun Shan, Jun Lu, Shaohua Fan, Chunhui Sun, Dongmei Wu, Cheng Zhang, Weitong Su, Junwen Sui and Yuanlin Zheng

Int. J. Mol. Sci. 2017, 18(1), 31; doi:10.3390/ijms18010031

Received: 4 November 2016 / Revised: 13 December 2016 / Accepted: 21 December 2016 / Published: 25 December 2016

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Abstract

Recent evidence suggests that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, exhibits beneficial effects on diabetes-related symptoms. Here we investigated the effects of troxerutin on the enhancement of hepatic gluconeogenesis in high-fat diet (HFD)-treated mice and the mechanisms underlying these effects. Mice

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Recent evidence suggests that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, exhibits beneficial effects on diabetes-related symptoms. Here we investigated the effects of troxerutin on the enhancement of hepatic gluconeogenesis in high-fat diet (HFD)-treated mice and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + Troxerutin group, and Troxerutin group. Troxerutin was treated by daily oral administration at doses of 150 mg/kg/day for 20 weeks. Tauroursodeoxycholic acid (TUDCA) was used to inhibit endoplasmic reticulum stress (ER stress). Our results showed that troxerutin effectively improved obesity and related metabolic parameters, and liver injuries in HFD-treated mouse. Furthermore, troxerutin significantly attenuated enhancement of hepatic gluconeogenesis in HFD-fed mouse. Moreover, troxerutin notably suppressed nuclear factor-κB (NF-κB) p65 transcriptional activation and release of inflammatory cytokines in HFD-treated mouse livers. Mechanismly, troxerutin dramatically decreased Nucleotide oligomerization domain (NOD) expression, as well as interaction between NOD1/2 with interacting protein-2 (RIP2), by abating oxidative stress-induced ER stress in HFD-treated mouse livers, which was confirmed by TUDCA treatment. These improvement effects of troxerutin on hepatic glucose disorders might be mediated by its anti-obesity effect. In conclusion, troxerutin markedly diminished HFD-induced enhancement of hepatic gluconeogenesis via its inhibitory effects on ER stress-mediated NOD activation and consequent inflammation, which might be mediated by its anti-obesity effect. Full article

(This article belongs to the Special Issue Gene-Diet Interactions in Chronic Diseases)

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Open AccessArticle Ameliorative Effect of Curcumin-Encapsulated Hyaluronic Acid–PLA Nanoparticles on Thioacetamide-Induced Murine Hepatic Fibrosis

by Yu-Nong Chen, Shih-Lan Hsu, Ming-Yuan Liao, Yi-Ting Liu, Chien-Hung Lai, Ji-Feng Chen, Mai-Huong Thi Nguyen, Yung-Hsiang Su, Shang-Ting Chen and Li-Chen Wu

Int. J. Environ. Res. Public Health 2017, 14(1), 11; doi:10.3390/ijerph14010011

Received: 30 September 2016 / Revised: 21 November 2016 / Accepted: 15 December 2016 / Published: 24 December 2016

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Abstract

In this study, we developed curcumin-encapsulated hyaluronic acid–polylactide nanoparticles (CEHPNPs) to be used for liver fibrosis amelioration. CD44, the hyaluronic acid (HA) receptor, is upregulated on the surface of cancer cells and on activated hepatic stellate cells (aHSCs) rather than normal cells. CEHPNPs

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In this study, we developed curcumin-encapsulated hyaluronic acid–polylactide nanoparticles (CEHPNPs) to be used for liver fibrosis amelioration. CD44, the hyaluronic acid (HA) receptor, is upregulated on the surface of cancer cells and on activated hepatic stellate cells (aHSCs) rather than normal cells. CEHPNPs could bind to CD44 and be internalized effectively through endocytosis to release curcumin, a poor water-soluble liver protective agent. Thus, CEHPNPs were potentially not only improving drug efficiency, but also targeting aHSCs. HA and polylactide (PLA) were crosslinked by adipic acid dihydrazide (ADH). The synthesis of HA–PLA was monitored by Fourier-transform infrared (FTIR) and Nuclear Magnetic Resonance (NMR). The average particle size was approximately 60–70 nm as determined by dynamic light scattering (DLS) and scanning electron microscope (SEM). Zeta potential was around −30 mV, which suggested a good stability of the particles. This drug delivery system induced significant aHSC cell death without affecting quiescent HSCs, hepatic epithelial, and parenchymal cells. This system reduced drug dosage without sacrificing therapeutic efficacy. The cytotoxicity IC₅₀ (inhibitory concentration at 50%) value of CEHPNPs was approximately 1/30 to that of the free drug treated group in vitro. Additionally, the therapeutic effects of CEHPNPs were as effective as the group treated with the same curcumin dose intensity in vivo. CEHPNPs significantly reduced serum aspartate transaminase/alanine transaminase (ALT/AST) significantly, and attenuated tissue collagen production and cell proliferation as revealed by liver biopsy. Conclusively, the advantages of superior biosafety and satisfactory therapeutic effect mean that CEHPNPs hold great potential for treating hepatic fibrosis. Full article

(This article belongs to the Special Issue Nanomaterials-Based New Techniques, New Drugs, and Antibacterial Reagents)

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Open AccessArticle Maternal Food Restriction during Pregnancy and Lactation Adversely Affect Hepatic Growth and Lipid Metabolism in Three-Week-Old Rat Offspring

by Sangmi Lee, Young-Ah You, Eun Jin Kwon, Sung-Chul Jung, Inho Jo and Young Ju Kim

Int. J. Mol. Sci. 2016, 17(12), 2115; doi:10.3390/ijms17122115

Received: 26 October 2016 / Revised: 2 December 2016 / Accepted: 11 December 2016 / Published: 15 December 2016

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Abstract

Maternal malnutrition influences the early development of foetal adaptive changes for survival. We explored the effects of maternal undernutrition during gestation and lactation on hepatic growth and function. Sprague-Dawley rats were fed a normal or a food-restricted (FR) diet during gestation and/or lactation.

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Maternal malnutrition influences the early development of foetal adaptive changes for survival. We explored the effects of maternal undernutrition during gestation and lactation on hepatic growth and function. Sprague-Dawley rats were fed a normal or a food-restricted (FR) diet during gestation and/or lactation. We performed analyses of covariance (adjusting for the liver weight/body weight ratio) to compare hepatic growth and lipid metabolism among the offspring. Maternal FR during gestation triggered the development of wide spaces between hepatic cells and increased the expression of mammalian target of rapamycin (mTOR) in three-week-old male offspring compared with controls (both p < 0.05). Offspring nursed by FR dams exhibited wider spaces between hepatic cells and a lower liver weight/body weight ratio than control offspring, and increased mTOR expression (p < 0.05). Interestingly, the significant decrease in expression of lipogenic-related genes was dependent on carbohydrate-responsive element-binding protein, despite the increased expression of sterol regulatory element-binding protein 1 (SREBP1) (p < 0.05). This study demonstrated increased expression of key metabolic regulators (mTOR and SREBP1), alterations in lipid metabolism, and deficits in hepatic growth in the offspring of FR-treated dams. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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Open AccessArticle Regressive Effect of Myricetin on Hepatic Steatosis in Mice Fed a High-Fat Diet

by Shu-Fang Xia, Guo-Wei Le, Peng Wang, Yu-Yu Qiu, Yu-Yu Jiang and Xue Tang

Nutrients 2016, 8(12), 799; doi:10.3390/nu8120799

Received: 9 October 2016 / Revised: 4 December 2016 / Accepted: 5 December 2016 / Published: 11 December 2016

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Abstract

Myricetin is an effective antioxidant in the treatment of obesity and obesity-related metabolic disorders. The objective of this study was to explore the regressive effect of myricetin on pre-existing hepatic steatosis induced by high-fat diet (HFD). C57BL/6 mice were fed either a standard

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Myricetin is an effective antioxidant in the treatment of obesity and obesity-related metabolic disorders. The objective of this study was to explore the regressive effect of myricetin on pre-existing hepatic steatosis induced by high-fat diet (HFD). C57BL/6 mice were fed either a standard diet or a HFD for 12 weeks and then half of the mice were treated with myricetin (0.12% in the diet, w/w) while on their respective diets for further 12 weeks. Myricetin treatment significantly alleviated HFD-induced steatosis, decreased hepatic lipid accumulation and thiobarbituric acid reactive substance (TBARS) levels, and increased antioxidative enzyme activities, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Microarray analysis of hepatic gene expression profiles showed that myricetin significantly altered the expression profiles of 177 genes which were involved in 12 biological pathways, including the peroxisome proliferator activated receptor (PPAR) signaling pathway and peroxisome. Further research indicated that myricetin elevated hepatic nuclear Nrf2 translocation, increased the protein expression of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), reduced the protein expression of PPARγ, and normalized the expressions of genes that were involved in peroxisome and the PPAR signaling pathway. Our data indicated that myricetin might represent an effective therapeutic agent to treat HFD-induced hepatic steatosis via activating the Nrf2 pathway and the PPAR signaling pathway. Full article

(This article belongs to the Special Issue Antioxidants in Health and Disease)

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Open AccessArticle Correlations of Hepatic Hemodynamics, Liver Function, and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus

Int. J. Mol. Sci. 2016, 17(9), 1545; doi:10.3390/ijms17091545

Received: 30 June 2016 / Revised: 1 September 2016 / Accepted: 8 September 2016 / Published: 14 September 2016

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Abstract

The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue

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The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue blood flow (TBF). Xenon computed tomography (Xe-CT) was performed in 139 patients with NAFLD and 152 patients with CHC (including liver cirrhosis (LC)). The cutoff values for fibrosis markers were compared between NAFLD and CHC, and correlations between hepatic TBF and liver function tests were examined at each fibrosis stage. The cutoff values for detection of the advanced fibrosis stage were lower in NAFLD than in CHC. Although portal venous TBF (PVTBF) correlated with liver function tests, PVTBF in initial LC caused by nonalcoholic steatohepatitis (NASH-LC) was significantly lower than that in hepatitis C virus (C-LC) (p = 0.014). Conversely, the liver function tests in NASH-LC were higher than those in C-LC (p < 0.05). It is important to recognize the difference between NAFLD and CHC. We concluded that changes in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD; therefore, patients with NAFLD need to be followed carefully. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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Open AccessArticle How Does the Severity of Injury Vary between Motorcycle and Automobile Accident Victims Who Sustain High-Grade Blunt Hepatic and/or Splenic Injuries? Results of a Retrospective Analysis

by Ting-Min Hsieh, Tsung-Cheng Tsai, Yueh-Wei Liu and Ching-Hua Hsieh

Int. J. Environ. Res. Public Health 2016, 13(7), 739; doi:10.3390/ijerph13070739

Received: 8 June 2016 / Revised: 13 July 2016 / Accepted: 19 July 2016 / Published: 21 July 2016

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Abstract

Background: High-grade blunt hepatic and/or splenic injuries (BHSI) remain a great challenge for trauma surgeons. The main aim of this study was to investigate the characteristics, mortality rates, and outcomes of high-grade BHSI in motorcyclists and car occupants hospitalized for treatment of

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Background: High-grade blunt hepatic and/or splenic injuries (BHSI) remain a great challenge for trauma surgeons. The main aim of this study was to investigate the characteristics, mortality rates, and outcomes of high-grade BHSI in motorcyclists and car occupants hospitalized for treatment of traumatic injuries in a Level I trauma center in southern Taiwan. Methods: High-grade BHSI are defined as grade III-VI blunt hepatic injuries and grade III-V blunt splenic injuries. This retrospective study reviewed the data of 101 motorcyclists and 32 car occupants who experienced a high-grade BHSI from 1 January 2011 to 31 December 2013. Two-sided Fisher’s exact or Pearson’s chi-square tests were used to compare categorical data, unpaired Student’s t-test was used to analyze normally distributed continuous data, and Mann–Whitney’s U test was used to compare non-normally distributed data. Results: In this study, the majority (76%, 101/133) of high-grade BHSI were due to motorcycle crashes. Car occupants had a significantly higher injury severity score (ISS; 26.8 ± 10.9 vs. 20.7 ± 10.4, respectively, p = 0.005) and organ injured score (OIS; 3.8 ± 1.0 vs. 3.4 ± 0.6, respectively, p = 0.033), as well as a significantly longer hospital length of stay (LOS; 21.2 days vs. 14.6 days, respectively, p = 0.038) than did motorcyclists. Car occupants with high-grade BHSI also had worse clinical presentations than their motorcyclist counterparts, including a significantly higher incidence of hypotension, hyperpnea, tube thoracostomy, blood transfusion >4 units, LOS in intensive care unit >5 days, and complications. However, there were no differences in the percentage of angiography or laparotomy performed or mortality rate between these two groups of patients. Conclusions: This study demonstrated that car occupants with high-grade BHSI were injured more severely, had a higher incidence of worse clinical presentation, had a longer hospital LOS, and had a higher incidence of complications than motorcyclists. The results also implied that specific attention should be paid to those car occupants with high-grade BHSI, whose critical condition should not be underestimated because of the concept that the patients within in a car are much safer. Full article

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Open AccessArticle Niemann-Pick Type C2 Protein Mediates Hepatic Stellate Cells Activation by Regulating Free Cholesterol Accumulation

by Yuh-Ching Twu, Tzong-Shyuan Lee, Yun-Lian Lin, Shih-Ming Hsu, Yuan-Hsi Wang, Chia-Yu Liao, Chung-Kwe Wang, Yu-Chih Liang and Yi-Jen Liao

Int. J. Mol. Sci. 2016, 17(7), 1122; doi:10.3390/ijms17071122

Received: 23 May 2016 / Revised: 26 June 2016 / Accepted: 7 July 2016 / Published: 13 July 2016

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Abstract

In chronic liver diseases, regardless of their etiology, the development of fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. Hepatic stellate cells (HSCs) are the main profibrogenic cells that promote the pathogenesis of liver fibrosis, and

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In chronic liver diseases, regardless of their etiology, the development of fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. Hepatic stellate cells (HSCs) are the main profibrogenic cells that promote the pathogenesis of liver fibrosis, and so it is important to identify the molecules that regulate HSCs activation and liver fibrosis. Niemann-Pick type C2 (NPC2) protein plays an important role in the regulation of intracellular cholesterol homeostasis by directly binding with free cholesterol. However, the roles of NPC2 in HSCs activation and liver fibrosis have not been explored in detail. Since a high-cholesterol diet exacerbates liver fibrosis progression in both rodents and humans, we propose that the expression of NPC2 affects free cholesterol metabolism and regulates HSCs activation. In this study, we found that NPC2 is decreased in both thioacetamide- and carbon tetrachloride-induced liver fibrosis tissues. In addition, NPC2 is expressed in quiescent HSCs, but its activation status is down-regulated. Knockdown of NPC2 in HSC-T6 cells resulted in marked increases in transforming growth factor-β1 (TGF-β1)-induced collagen type 1 α1 (Col1a1), α-smooth muscle actin (α-SMA) expression, and Smad2 phosphorylation. In contrast, NPC2 overexpression decreased TGF-β1-induced HSCs activation. We further demonstrated that NPC2 deficiency significantly increased the accumulation of free cholesterol in HSCs, increasing Col1a1 and α-SMA expression and activating Smad2, and leading to sensitization of HSCs to TGF-β1 activation. In contrast, overexpression of NPC2 decreased U18666A-induced free cholesterol accumulation and inhibited the subsequent HSCs activation. In conclusion, our study has demonstrated that NPC2 plays an important role in HSCs activation by regulating the accumulation of free cholesterol. NPC2 overexpression may thus represent a new treatment strategy for liver fibrosis. Full article

(This article belongs to the collection Molecular Mechanisms of Human Liver Diseases)

Open AccessArticle Total Flavonoids from Rosa laevigata Michx Fruit Ameliorates Hepatic Ischemia/Reperfusion Injury through Inhibition of Oxidative Stress and Inflammation in Rats

by Xufeng Tao, Xiance Sun, Lina Xu, Lianhong Yin, Xu Han, Yan Qi, Youwei Xu, Yanyan Zhao, Changyuan Wang and Jinyong Peng

Nutrients 2016, 8(7), 418; doi:10.3390/nu8070418

Received: 1 May 2016 / Revised: 29 June 2016 / Accepted: 4 July 2016 / Published: 8 July 2016

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Abstract

The effects of total flavonoids (TFs) from Rosa laevigata Michx fruit against liver damage and cerebral ischemia/reperfusion (I/R) injury have been reported, but its action on hepatic I/R injury remains unknown. In this work, the effects and possible mechanisms of TFs against hepatic

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The effects of total flavonoids (TFs) from Rosa laevigata Michx fruit against liver damage and cerebral ischemia/reperfusion (I/R) injury have been reported, but its action on hepatic I/R injury remains unknown. In this work, the effects and possible mechanisms of TFs against hepatic I/R injury were examined using a 70% partial hepatic warm ischemia rat model. The results demonstrated TFs decreased serum aspartate transaminase (AST), alanine aminotransferase (ALT), myeloperoxidase (MPO), and lactate dehydrogenase (LDH) activities, improved liver histopathology and ultrastructure through hematoxylin-eosin (HE) staining and electron microscope observation. In addition, TFs significantly decreased malondialdehyde (MDA) and increased the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), which indicated that TFs alleviated oxidative stress caused by I/R injury. RT-PCR results proved that TFs downregulated the gene levels of inflammatory factors including interleukin-1 beta (IL-1β), interleukin-1 (IL-6), and tumor necrosis factor alpha (TNF-α). Further research indicated that TF-induced hepatoprotection was completed through inhibiting TLR4/MyD88 and activating Sirt1/Nrf2 signaling pathways. Blockade of the TLR4 pathway by TFs inhibited NF-κB and AP-1 transcriptional activities and inflammatory reaction. Activation of Sirt1/Nrf2 pathway by TFs increased the protein levels of HO-1 and GST to improve oxidative stress. Collectively, these findingsconfirmed the potent effects of TFs against hepatic I/R injury, which should be developed as a candidate for the prevention of this disease. Full article

(This article belongs to the Special Issue Health-Promoting Components of Fruits and Vegetables in Human Health)

Open AccessArticle MicroRNA-146a-5p Negatively Regulates Pro-Inflammatory Cytokine Secretion and Cell Activation in Lipopolysaccharide Stimulated Human Hepatic Stellate Cells through Inhibition of Toll-Like Receptor 4 Signaling Pathways

by Yuhan Chen, Zhaochong Zeng, Xiaoyun Shen, Zhifeng Wu, Yinying Dong and Jason Chia-Hsien Cheng

Int. J. Mol. Sci. 2016, 17(7), 1076; doi:10.3390/ijms17071076

Received: 30 May 2016 / Revised: 20 June 2016 / Accepted: 28 June 2016 / Published: 7 July 2016

Abstract

Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this

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Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this study, we found that TLR4 and α-smooth muscle actin (α-SMA) were up-regulated and miR-146a-5p was down-regulated in human hepatic stellate cell (HSC) line LX2 after LPS stimulation. Overexpression of miR-146a-5p inhibited LPS induced pro-inflammatory cytokines secretion through down-regulating the expression levels of TLR-4, IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor associated factor-6 (TRAF6) and phosphorylation of nuclear factor-kappa B (NF-κB). Knockdown of IRAK1 and TRAF6 also suppressed pro-inflammatory cytokine production by inhibiting NF-κB phosphorylation. In addition, miR-146a-5p mimic blocked LPS induced TRAF6 dependent c-Jun N-terminal kinase (JNK) and Smad2 activation as well as α-SMA production. Taken together, these results suggest that miR-146a-5p suppresses pro-inflammatory cytokine secretion and cell activation of HSC through inhibition of TLR4/NF-κB and TLR4/TRAF6/JNK pathway. Full article

(This article belongs to the collection Regulation by Non-Coding RNAs)

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Open AccessArticle Demethyleneberberine Protects against Hepatic Fibrosis in Mice by Modulating NF-κB Signaling

by Yongchen Wang, Zheng Zhao, Yan Yan, Xiaoyan Qiang, Cuisong Zhou, Ruiyan Li, Huan Chen and Yubin Zhang

Int. J. Mol. Sci. 2016, 17(7), 1036; doi:10.3390/ijms17071036

Received: 12 May 2016 / Revised: 17 June 2016 / Accepted: 23 June 2016 / Published: 30 June 2016

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Abstract

Demethyleneberberine (DMB) is an essential metabolite of Berberine (BBR) in vivo. Recent reports have revealed multiple novel therapeutic applications of BBR. However, the pharmacological activities of DMB remain to be elucidated. This study aimed to demonstrate the hepatoprotective and anti-fibrotic effects of DMB

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Demethyleneberberine (DMB) is an essential metabolite of Berberine (BBR) in vivo. Recent reports have revealed multiple novel therapeutic applications of BBR. However, the pharmacological activities of DMB remain to be elucidated. This study aimed to demonstrate the hepatoprotective and anti-fibrotic effects of DMB both in vitro and in vivo. Here we showed that DMB protects against thioacetamide (TAA)-induced hepatic fibrosis in mice and exhibits a higher safety profile as compared to BBR. Flow cytometry and Western blotting analysis showed that DMB is able to suppress the activation of hepatic stellate cells (HSCs) and induce cell apoptosis through the nuclear factor-κB (NF-κB) cascade. Immunohistochemical (IHC) and quantitative polymerase chain reaction (qPCR) analysis indicated that DMB also has inhibitory effects on collagen synthesis and is able to increase collagen degradation by blocking the transforming growth factor β 1 (TGF-β1)-Smad signaling and reducing the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs). These findings indicate that DMB has the potential to attenuate hepatic fibrosis via suppressing HSC activation. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Open AccessArticle Beneficial Effect of Synbiotic Supplementation on Hepatic Steatosis and Anthropometric Parameters, But Not on Gut Permeability in a Population with Nonalcoholic Steatohepatitis

by Silvia M. Ferolla, Cláudia A. Couto, Luciana Costa-Silva, Geyza N. A. Armiliato, Cristiano A. S. Pereira, Flaviano S. Martins, Maria de Lourdes A. Ferrari, Eduardo G. Vilela, Henrique O. G. Torres, Aloísio S. Cunha and Teresa C. A. Ferrari

Nutrients 2016, 8(7), 397; doi:10.3390/nu8070397

Received: 9 May 2016 / Revised: 10 June 2016 / Accepted: 20 June 2016 / Published: 28 June 2016

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Abstract

Nonalcoholic fatty liver disease is the most prevalent chronic liver disease in Western countries; it can progress to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocarcinoma. The importance of gut-liver-adipose tissue axis has become evident and treatments targeting gut microbiota may improve inflammatory and metabolic

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Nonalcoholic fatty liver disease is the most prevalent chronic liver disease in Western countries; it can progress to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocarcinoma. The importance of gut-liver-adipose tissue axis has become evident and treatments targeting gut microbiota may improve inflammatory and metabolic parameters in NASH patients. In a randomized, controlled clinical trial, involving 50 biopsy-proven NASH patients, we investigated the effects of synbiotic supplementation on metabolic parameters, hepatic steatosis, intestinal permeability, small intestinal bacterial overgrowth (SIBO) and lipopolysaccharide (LPS) serum levels. Patients were separated into two groups receiving Lactobacillus reuteri with guar gum and inulin for three months and healthy balanced nutritional counseling versus nutritional counseling alone. Before and after the intervention we assessed steatosis by magnetic resonance imaging, intestinal permeability by lactulose/mannitol urinary excretion and SIBO by glucose breath testing. NASH patients presented high gut permeability, but low prevalence of SIBO. After the intervention, only the synbiotic group presented a reduction in steatosis, lost weight, diminished BMI and waist circumference measurement. Synbiotic did not improve intestinal permeability or LPS levels. We concluded that synbiotic supplementation associated with nutritional counseling seems superior to nutritional counseling alone for NASH treatment as it attenuates steatosis and may help to achieve weight loss. Full article

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Open AccessArticle Trans-Fatty Acids Aggravate Obesity, Insulin Resistance and Hepatic Steatosis in C57BL/6 Mice, Possibly by Suppressing the IRS1 Dependent Pathway

by Xiaona Zhao, Cheng Shen, Hong Zhu, Cong Wang, Xiangwei Liu, Xiaolei Sun, Shasha Han, Peng Wang, Zhen Dong, Xin Ma, Kai Hu, Aijun Sun and Junbo Ge

Molecules 2016, 21(6), 705; doi:10.3390/molecules21060705

Received: 23 March 2016 / Revised: 12 May 2016 / Accepted: 19 May 2016 / Published: 30 May 2016

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Abstract

Trans-fatty acid consumption has been reported as a risk factor for metabolic disorders and targeted organ damages. Nonetheless, little is known about the roles and mechanisms of trans-fatty acids in obesity, insulin resistance (IR) and hepatic steatosis. Adult C57BL/6 male mice

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Trans-fatty acid consumption has been reported as a risk factor for metabolic disorders and targeted organ damages. Nonetheless, little is known about the roles and mechanisms of trans-fatty acids in obesity, insulin resistance (IR) and hepatic steatosis. Adult C57BL/6 male mice were fed with four different diets for 20 weeks: normal diet (ND), high fat diet (HFD), low trans-fatty acids diet (LTD) and high trans-fatty acid diet (HTD). The diet-induced metabolic disorders were assessed by evaluating body weight, glucose tolerance test, hepatic steatosis and plasma lipid profiles post 20-week diet. Histological (H&E, Oil-Red-O) staining and western blot analysis were employed to assess liver steatosis and potential signaling pathways. After 20-weeks of diet, the body weights of the four groups were 29.61 ± 1.89 g (ND), 39.04 ± 4.27 g (HFD), 34.09 ± 2.62 g (LTD) and 43.78 ± 4.27 g (HTD) (p < 0.05), respectively. HFD intake significantly impaired glucose tolerance, which was impaired further in the mice consuming the HTD diet. The effect was further exacerbated by HTD diet. Moreover, the HTD group exhibited significantly more severe liver steatosis compared with HFD group possibly through regulating adipose triglyceride lipase. The group consuming the HTD also exhibited significantly reduced levels of IRS1, phosphor-PKC and phosphor-AKT. These results support our hypothesis that consumption of a diet high in trans-fatty acids induces higher rates of obesity, IR and hepatic steatosis in male C57BL/6 mice, possibly by suppressing the IRS1dependent pathway. Full article

(This article belongs to the Special Issue Natural Products in Anti-Obesity Therapy)

Open AccessArticle Apigenin Ameliorates Dyslipidemia, Hepatic Steatosis and Insulin Resistance by Modulating Metabolic and Transcriptional Profiles in the Liver of High-Fat Diet-Induced Obese Mice

by Un Ju Jung, Yun-Young Cho and Myung-Sook Choi

Nutrients 2016, 8(5), 305; doi:10.3390/nu8050305

Received: 27 April 2016 / Revised: 10 May 2016 / Accepted: 13 May 2016 / Published: 19 May 2016

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Abstract

Several in vitro and in vivo studies have reported the anti-inflammatory, anti-diabetic and anti-obesity effects of the flavonoid apigenin. However, the long-term supplementary effects of low-dose apigenin on obesity are unclear. Therefore, we investigated the protective effects of apigenin against obesity and related

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Several in vitro and in vivo studies have reported the anti-inflammatory, anti-diabetic and anti-obesity effects of the flavonoid apigenin. However, the long-term supplementary effects of low-dose apigenin on obesity are unclear. Therefore, we investigated the protective effects of apigenin against obesity and related metabolic disturbances by exploring the metabolic and transcriptional responses in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed an HFD or apigenin (0.005%, w/w)-supplemented HFD for 16 weeks. In HFD-fed mice, apigenin lowered plasma levels of free fatty acid, total cholesterol, apolipoprotein B and hepatic dysfunction markers and ameliorated hepatic steatosis and hepatomegaly, without altering food intake and adiposity. These effects were partly attributed to upregulated expression of genes regulating fatty acid oxidation, tricarboxylic acid cycle, oxidative phosphorylation, electron transport chain and cholesterol homeostasis, downregulated expression of lipolytic and lipogenic genes and decreased activities of enzymes responsible for triglyceride and cholesterol ester synthesis in the liver. Moreover, apigenin lowered plasma levels of pro-inflammatory mediators and fasting blood glucose. The anti-hyperglycemic effect of apigenin appeared to be related to decreased insulin resistance, hyperinsulinemia and hepatic gluconeogenic enzymes activities. Thus, apigenin can ameliorate HFD-induced comorbidities via metabolic and transcriptional modulations in the liver. Full article

(This article belongs to the Special Issue Health-Promoting Components of Fruits and Vegetables in Human Health)

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Open AccessLetter Ionone Derivatives from the Mycelium of Phellinus linteus and the Inhibitory Effect on Activated Rat Hepatic Stellate Cells

by Shiow-Chyn Huang, Ping-Chung Kuo, Hsin-Yi Hung, Tai-Long Pan, Fu-An Chen and Tian-Shung Wu

Int. J. Mol. Sci. 2016, 17(5), 681; doi:10.3390/ijms17050681

Received: 26 February 2016 / Revised: 22 April 2016 / Accepted: 26 April 2016 / Published: 6 May 2016

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Abstract

Three new γ-ionylideneacetic acid derivatives, phellinulins A–C (1–3), were characterized from the mycelium extract of Phellinus linteus. The chemical structures were established based on the spectroscopic analysis. In addition, phellinulin A (1) was subjected to the examination of effects on activated rat

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Three new γ-ionylideneacetic acid derivatives, phellinulins A–C (1–3), were characterized from the mycelium extract of Phellinus linteus. The chemical structures were established based on the spectroscopic analysis. In addition, phellinulin A (1) was subjected to the examination of effects on activated rat hepatic stellate cells and exhibited significant inhibition of hepatic fibrosis. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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Open AccessArticle TFE3 Alleviates Hepatic Steatosis through Autophagy-Induced Lipophagy and PGC1α-Mediated Fatty Acid β-Oxidation

by Jie Xiong, Kezhou Wang, Jiangping He, Guangya Zhang, Dandan Zhang and Fengling Chen

Int. J. Mol. Sci. 2016, 17(3), 387; doi:10.3390/ijms17030387

Received: 13 February 2016 / Revised: 6 March 2016 / Accepted: 7 March 2016 / Published: 18 March 2016

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Abstract

Autophagy flux deficiency is closely related to the development of hepatic steatosis. Transcription factor E3 (TFE3) is reported to be a crucial gene that regulates autophagy flux and lysosome function. Therefore, we investigated the role of TFE3 in a cell model

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Autophagy flux deficiency is closely related to the development of hepatic steatosis. Transcription factor E3 (TFE3) is reported to be a crucial gene that regulates autophagy flux and lysosome function. Therefore, we investigated the role of TFE3 in a cell model of hepatic steatosis. We constructed L02 hepatocyte lines that stably over-expressed or knocked down the expression of TFE3. Subsequently, the effects of TFE3 on hepatocellular lipid metabolism were determined by autophagy flux assay, lipid oil red O (ORO) staining, immunofluorescence staining, and mitochondrial β-oxidation assessment. Finally, we analyzed whether peroxisome proliferative activated receptor gamma coactivator 1α (PGC1α) was the potential target gene of TFE3 in the regulation of hepatic steatosis using a chromatin immunoprecipitation (CHIP) assay and a luciferase reporter system. We found that overexpression of TFE3 markedly alleviated hepatocellular steatosis. On the contrary, downregulation of TFE3 resulted in an aggravated steatosis. The mechanistic studies revealed that the TFE3-manipulated regulatory effects on hepatocellular steatosis are dependent on autophagy-induced lipophagy and PGC1α-mediated fatty acid β-oxidation because blocking these pathways with an Atg5 small interfering RNA (siRNA) or PGC1α siRNA dramatically blunted the TFE3-mediated regulation of steatosis. In conclusion, TFE3 gene provides a novel insight into the treatment of hepatic steatosis and other metabolic disease. Full article

(This article belongs to the Special Issue Molecule- and Cell-Targeted Drug Design and Screening and Identification of Natural Product)

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Open AccessReview Hepatic Stellate Cells and microRNAs in Pathogenesis of Liver Fibrosis

by Mio Kitano and P. Mark Bloomston

J. Clin. Med. 2016, 5(3), 38; doi:10.3390/jcm5030038

Received: 20 November 2015 / Revised: 23 February 2016 / Accepted: 7 March 2016 / Published: 16 March 2016

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Abstract

microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by either blocking translation or inducing degradation of target mRNA. miRNAs play essential roles in diverse biological and pathological processes, including development of hepatic fibrosis. Hepatic stellate cells (HSCs) play a central role

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microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by either blocking translation or inducing degradation of target mRNA. miRNAs play essential roles in diverse biological and pathological processes, including development of hepatic fibrosis. Hepatic stellate cells (HSCs) play a central role in development of hepatic fibrosis and there are intricate regulatory effects of miRNAs on their activation, proliferation, collagen production, migration, and apoptosis. There are multiple differentially expressed miRNAs in activated HSCs, and in this review we aim to summarize current data on miRNAs that participate in the development of hepatic fibrosis. Based on this review, miRNAs may serve as biomarkers for diagnosis of liver disease, as well as markers of disease progression. Most importantly, dysregulated miRNAs may potentially be targeted by novel therapies to treat and reverse progression of hepatic fibrosis. Full article

(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers for Liver Diseases)

Open AccessArticle Silymarin-Loaded Nanoparticles Based on Stearic Acid-Modified Bletilla striata Polysaccharide for Hepatic Targeting

by Yanni Ma, Shaolong He, Xueqin Ma, Tongtong Hong, Zhifang Li, Kinam Park and Wenping Wang

Molecules 2016, 21(3), 265; doi:10.3390/molecules21030265

Received: 18 January 2016 / Revised: 15 February 2016 / Accepted: 22 February 2016 / Published: 29 February 2016

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Abstract

Silymarin has been widely used as a hepatoprotective drug in the treatment of various liver diseases, yet its effectiveness is affected by its poor water solubility and low bioavailability after oral administration, and there is a need for the development of intravenous products,

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Silymarin has been widely used as a hepatoprotective drug in the treatment of various liver diseases, yet its effectiveness is affected by its poor water solubility and low bioavailability after oral administration, and there is a need for the development of intravenous products, especially for liver-targeting purposes. In this study, silymarin was encapsulated in self-assembled nanoparticles of Bletilla striata polysaccharide (BSP) conjugates modified with stearic acid and the physicochemical properties of the obtained nanoparticles were characterized. The silymarin-loaded micelles appeared as spherical particles with a mean diameter of 200 nm under TEM. The encapsulation of drug molecules was confirmed by DSC thermograms and XRD diffractograms, respectively. The nanoparticles exhibited a sustained-release profile for nearly 1 week with no obvious initial burst. Compared to drug solutions, the drug-loaded nanoparticles showed a lower viability and higher uptake intensity on HepG2 cell lines. After intravenous administration of nanoparticle formulation for 30 min to mice, the liver became the most significant organ enriched with the fluorescent probe. These results suggest that BSP derivative nanoparticles possess hepatic targeting capability and are promising nanocarriers for delivering silymarin to the liver. Full article

(This article belongs to the Section Medicinal Chemistry)

Open AccessArticle 1-Deoxynojirimycin Alleviates Liver Injury and Improves Hepatic Glucose Metabolism in db/db Mice

by Qingpu Liu, Xuan Li, Cunyu Li, Yunfeng Zheng, Fang Wang, Hongyang Li and Guoping Peng

Molecules 2016, 21(3), 279; doi:10.3390/molecules21030279

Received: 3 January 2016 / Revised: 21 February 2016 / Accepted: 23 February 2016 / Published: 27 February 2016

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Abstract

The present study investigated the effect of 1-Deoxynojirimycin (DNJ) on liver injury and hepatic glucose metabolism in db/db mice. Mice were divided into five groups: normal control, db/db control, DNJ-20 (DNJ 20 mg·kg⁻¹·day⁻¹), DNJ-40 (DNJ

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The present study investigated the effect of 1-Deoxynojirimycin (DNJ) on liver injury and hepatic glucose metabolism in db/db mice. Mice were divided into five groups: normal control, db/db control, DNJ-20 (DNJ 20 mg·kg⁻¹·day⁻¹), DNJ-40 (DNJ 40 mg·kg⁻¹·day⁻¹) and DNJ-80 (DNJ 80 mg·kg⁻¹·day⁻¹). All doses were treated intravenously by tail vein for four weeks. DNJ was observed to significantly reduce the levels of serum triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and liver TG, as well as activities of serum alanine aminotransferase (ALT), and aspartate transaminase (AST); DNJ also alleviated macrovesicular steatosis and decreased tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6) levels in liver tissue. Furthermore, DNJ treatment significantly increased hepatic glycogen content, the activities of hexokinase (HK), pyruvate kinase (PK) in liver tissue, and decreased the activities of glucose-6-phosphatase (G6Pase), glycogen phosphorylase (GP), and phosphoenolpyruvate carboxykinase (PEPCK). Moreover, DNJ increased the phosphorylation of phosphatidylinositol 3 kinase (PI3K) on p85, protein kinase B (PKB) on Ser473, glycogen synthase kinase 3β (GSK-3β) on Ser9, and inhibited phosphorylation of glycogen synthase (GS) on Ser645 in liver tissue of db/db mice. These results demonstrate that DNJ can increase hepatic insulin sensitivity via strengthening of the insulin-stimulated PKB/GSK-3β signal pathway and by modulating glucose metabolic enzymes in db/db mice. Moreover, DNJ also can improve lipid homeostasis and attenuate hepatic steatosis in db/db mice. Full article

(This article belongs to the Section Medicinal Chemistry)

Open AccessArticle Solanum nigrum Protects against Hepatic Fibrosis via Suppression of Hyperglycemia in High-Fat/Ethanol Diet-Induced Rats

by Cheng-Jeng Tai, Chen-Yen Choong, Yeu-Ching Shi, Yu-Chun Lin, Chia-Woei Wang, Bao-Hong Lee and Chen-Jei Tai

Molecules 2016, 21(3), 269; doi:10.3390/molecules21030269

Received: 19 December 2015 / Revised: 17 February 2016 / Accepted: 19 February 2016 / Published: 25 February 2016

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Abstract

Background: Advanced glycation end products (AGEs) signal through the receptor for AGE (RAGE), which can lead to hepatic fibrosis in hyperglycemia and hyperlipidemia. We investigated the inhibitory effect of aqueous extracts from Solanum nigrum (AESN) on AGEs-induced RAGE signaling and activation of hepatic

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Background: Advanced glycation end products (AGEs) signal through the receptor for AGE (RAGE), which can lead to hepatic fibrosis in hyperglycemia and hyperlipidemia. We investigated the inhibitory effect of aqueous extracts from Solanum nigrum (AESN) on AGEs-induced RAGE signaling and activation of hepatic stellate cells (HSCs) and hyperglycemia induced by high-fat diet with ethanol. Methods: An animal model was used to evaluate the anti-hepatic fibrosis activity of AESN in rats fed a high-fat diet (HFD; 30%) with ethanol (10%). Male Wistar rats (4 weeks of age) were randomly divided into four groups (n = 6): (1) control (basal diet); (2) HFD (30%) + ethanol (10%) (HFD/ethanol); (3) HFD/ethanol + AESN (100 mg/kg, oral administration); and (4) HFD/ethanol + pioglitazone (10 mg/kg, oral administration) and treated with HFD for 6 months in the presence or absence of 10% ethanol in dietary water. Results: We found that AESN improved insulin resistance and hyperinsulinemia, and downregulated lipogenesis via regulation of the peroxisome proliferator-activated receptor α (PPARα), PPARγ co-activator (PGC-1α), carbohydrate response element-binding protein (ChREBP), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) mRNA levels in the liver of HFD/ethanol-treated rats. In turn, AESN may delay and inhibit the progression of hepatic fibrosis, including α-smooth muscle actin (α-SMA) inhibition and MMP-2 production. Conclusions: These results suggest that AESN may be further explored as a novel anti-fibrotic strategy for the prevention of liver disease. Full article

(This article belongs to the Section Natural Products)

Open AccessArticle Korean Pine Nut Oil Attenuated Hepatic Triacylglycerol Accumulation in High-Fat Diet-Induced Obese Mice

by Soyoung Park, Sunhye Shin, Yeseo Lim, Jae Hoon Shin, Je Kyung Seong and Sung Nim Han

Nutrients 2016, 8(1), 59; doi:10.3390/nu8010059

Received: 16 November 2015 / Revised: 6 January 2016 / Accepted: 15 January 2016 / Published: 21 January 2016

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Abstract

Korean pine nut oil (PNO) has been reported to influence weight gain and lipid metabolism. We examined whether PNO replacement in a high-fat diet (HFD) can ameliorate HFD-induced hepatic steatosis. Five-week-old male C57BL mice were fed control diets containing 10% of the energy

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Korean pine nut oil (PNO) has been reported to influence weight gain and lipid metabolism. We examined whether PNO replacement in a high-fat diet (HFD) can ameliorate HFD-induced hepatic steatosis. Five-week-old male C57BL mice were fed control diets containing 10% of the energy from fat from PNO or soybean oil (SBO) (PC, SC) or HFDs with 45% of the energy from fat, with 10% from PNO or SBO and 35% from lard (PHFD, SHFD), for 12 weeks. Body weight gain and amount of white adipose tissue were lower in PHFD (10% and 18% lower, respectively) compared with SHFD. Hepatic triacylglycerol (TG) level was significantly lower in PHFD than the SHFD (26% lower). PNO consumption upregulated hepatic ACADL mRNA levels. The hepatic PPARG mRNA level was lower in the PC than in the SC. Expression of the sirtuin (SIRT) 3 protein in white adipose tissue was down-regulated in the SHFD and restored in the PHFD to the level in the lean control mice. SIRT 3 was reported to be upregulated under conditions of caloric restriction (CR) and plays a role in regulating mitochondrial function. PNO consumption resulted in lower body fat and hepatic TG accumulation in HFD-induced obesity, which seemed to be associated with the CR-mimetic response. Full article

(This article belongs to the Special Issue Fatty Acids in Obesity and Type 2 Diabetes)

Open AccessArticle Phenylethanol Glycosides from Cistanche tubulosa Suppress Hepatic Stellate Cell Activation and Block the Conduction of Signaling Pathways in TGF-β₁/smad as Potential Anti-Hepatic Fibrosis Agents

by Shu-Ping You, Long Ma, Jun Zhao, Shi-Lei Zhang and Tao Liu

Molecules 2016, 21(1), 102; doi:10.3390/molecules21010102

Received: 25 November 2015 / Revised: 11 January 2016 / Accepted: 13 January 2016 / Published: 18 January 2016

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Abstract

Cistanche tubulosa is a traditional Chinese herbal medicine widely used for regulating immunity and phenylethanol glycosides (CPhGs) are among the primary components responsible for this activity. Previous studies have indicated the preventive and therapeutic effects of CPhGs on bovine serum albumin (BSA)-induced hepatic

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Cistanche tubulosa is a traditional Chinese herbal medicine widely used for regulating immunity and phenylethanol glycosides (CPhGs) are among the primary components responsible for this activity. Previous studies have indicated the preventive and therapeutic effects of CPhGs on bovine serum albumin (BSA)-induced hepatic fibrosis in rats. The aim of the study was to evaluate the anti-hepatic fibrosis effect of CPhGs and the monomers echinacoside and acteoside by inhibiting hepatic stellate cell (HSC) activation, blocking the conduction of signaling pathways in transforming growth factor-β₁ (TGF-β₁)/smad, and determine their in vitro hepatoprotective activity. HSC proliferation was obviously inhibited after treatment with CPhGs (100, 50 μg/mL)/echinacoside (500, 250, 125 μg/mL)/acteoside (6, 3 μg/mL), with IC₅₀ values of 119.125, 520.345 and 6.999 μg/mL, respectively, in the MTT assay. Different concentrations of CPhGs/echinacoside/acteoside did not affect the cellular toxicity on HSC according to lactate dehydrogenase (LDH) measurements. Different concentrations of CPhGs/echinacoside/acteoside increased the mRNA level and protein expression of smad7, and decreased the mRNA levels of smad2, smad3 and the protein expression of smad2, phospho-smad2 (p-smad2), smad3, phospho-smad3 (p-smad3) in HSC. In summary, these results demonstrate that CPhGs/echinacoside/acteoside can block the conduction of the signaling pathways in TGF-β₁/smad, and inhibit the activation of HSC, suggesting that C. tubulosa may thus be a potential herbal medicine for the treatment of liver fibrosis. Full article

(This article belongs to the Section Medicinal Chemistry)

Open AccessReview Reversible Human TGF-β Signal Shifting between Tumor Suppression and Fibro-Carcinogenesis: Implications of Smad Phospho-Isoforms for Hepatic Epithelial-Mesenchymal Transitions

by Katsunori Yoshida, Miki Murata, Takashi Yamaguchi, Koichi Matsuzaki and Kazuichi Okazaki

J. Clin. Med. 2016, 5(1), 7; doi:10.3390/jcm5010007

Received: 18 November 2015 / Revised: 16 December 2015 / Accepted: 4 January 2016 / Published: 12 January 2016

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Abstract

Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are observed during both physiological liver wound healing and the pathological fibrotic/carcinogenic (fibro-carcinogenetic) process. TGF-β and pro-inflammatory cytokine are considered to be the major factors accelerating liver fibrosis and promoting liver carcinogenesis. Smads, consisting of intermediate

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Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are observed during both physiological liver wound healing and the pathological fibrotic/carcinogenic (fibro-carcinogenetic) process. TGF-β and pro-inflammatory cytokine are considered to be the major factors accelerating liver fibrosis and promoting liver carcinogenesis. Smads, consisting of intermediate linker regions connecting Mad homology domains, act as the intracellular mediators of the TGF-β signal transduction pathway. As the TGF-β receptors, c-Jun N-terminal kinase and cyclin-dependent kinase, differentially phosphorylate Smad2/3, we have generated numerous antibodies against linker (L) and C-terminal (C) phosphorylation sites in Smad2/3 and identified four types of phosphorylated forms: cytostatic COOH-terminally-phosphorylated Smad3 (pSmad3C), mitogenic pSmad3L (Ser-213) signaling, fibrogenic pSmad2L (Ser-245/250/255)/C signaling and migratory pSmad2/3L (Thr-220/179)/C signaling. After acute liver injury, TGF-β upregulates pSmad3C signaling and terminates pSmad3L (Ser-213)-mediated hepatocyte proliferation. TGF-β and pro-inflammatory cytokines cooperatively enhance collagen synthesis by upregulating pSmad2L (Thr-220)/C and pSmad3L (Thr-179)/C pathways in activated hepatic stellate cells. During chronic liver injuries, hepatocytes persistently affected by TGF-β and pro-inflammatory cytokines eventually become pre-neoplastic hepatocytes. Both myofibroblasts and pre-neoplastic hepatocyte exhibit the same carcinogenic (mitogenic) pSmad3L (Ser-213) and fibrogenic pSmad2L (Ser-245/250/255)/C signaling, with acquisition of fibro-carcinogenic properties and increasing risk of hepatocellular carcinoma (HCC). Firstly, we review phospho-Smad-isoform signalings in epithelial and mesenchymal cells in physiological and pathological conditions and then consider Smad linker phosphorylation as a potential target for pathological EMT during human fibro-carcinogenesis, because human Smad phospho-isoform signals can reverse from fibro-carcinogenesis to tumor-suppression in a process of MET after therapy. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)

Open AccessFeature PaperArticle Targeted Sterically Stabilized Phospholipid siRNA Nanomedicine for Hepatic and Renal Fibrosis

by Fatima Khaja, Dulari Jayawardena, Antonina Kuzmis and Hayat Önyüksel

Nanomaterials 2016, 6(1), 8; doi:10.3390/nano6010008

Received: 16 October 2015 / Revised: 23 December 2015 / Accepted: 28 December 2015 / Published: 5 January 2016

Abstract

Since its discovery, small interfering RNA (siRNA) has been considered a potent tool for modulating gene expression. It has the ability to specifically target proteins via selective degradation of messenger RNA (mRNA) not easily accessed by conventional drugs. Hence, RNA interference (RNAi) therapeutics

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Since its discovery, small interfering RNA (siRNA) has been considered a potent tool for modulating gene expression. It has the ability to specifically target proteins via selective degradation of messenger RNA (mRNA) not easily accessed by conventional drugs. Hence, RNA interference (RNAi) therapeutics have great potential in the treatment of many diseases caused by faulty protein expression such as fibrosis and cancer. However, for clinical application siRNA faces a number of obstacles, such as poor in vivo stability, and off-target effects. Here we developed a unique targeted nanomedicine to tackle current siRNA delivery issues by formulating a biocompatible, biodegradable and relatively inexpensive nanocarrier of sterically stabilized phospholipid nanoparticles (SSLNPs). This nanocarrier is capable of incorporating siRNA in its core through self-association with a novel cationic lipid composed of naturally occuring phospholipids and amino acids. This overall assembly protects and delivers sufficient amounts of siRNA to knockdown over-expressed protein in target cells. The siRNA used in this study, targets connective tissue growth factor (CTGF), an important regulator of fibrosis in both hepatic and renal cells. Furthermore, asialoglycoprotein receptors are targeted by attaching the galactosamine ligand to the nanocarries which enhances the uptake of nanoparticles by hepatocytes and renal tubular epithelial cells, the major producers of CTGF in fibrosis. On animals this innovative nanoconstruct, small interfering RNA in sterically stabilized phospholipid nanoparticles (siRNA-SSLNP), showed favorable pharmacokinetic properties and accumulated mostly in hepatic and renal tissues making siRNA-SSLNP a suitable system for targeting liver and kidney fibrotic diseases. Full article

(This article belongs to the Special Issue Nanoparticles Assisted Drug Delivery)

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Open AccessReview Pathogenesis of Type 2 Epithelial to Mesenchymal Transition (EMT) in Renal and Hepatic Fibrosis

by Anusha H. Tennakoon, Takeshi Izawa, Mitsuru Kuwamura and Jyoji Yamate

J. Clin. Med. 2016, 5(1), 4; doi:10.3390/jcm5010004

Received: 30 November 2015 / Revised: 22 December 2015 / Accepted: 24 December 2015 / Published: 30 December 2015

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Abstract

Epithelial to mesenchymal transition (EMT), particularly, type 2 EMT, is important in progressive renal and hepatic fibrosis. In this process, incompletely regenerated renal epithelia lose their epithelial characteristics and gain migratory mesenchymal qualities as myofibroblasts. In hepatic fibrosis (importantly, cirrhosis), the process also

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Epithelial to mesenchymal transition (EMT), particularly, type 2 EMT, is important in progressive renal and hepatic fibrosis. In this process, incompletely regenerated renal epithelia lose their epithelial characteristics and gain migratory mesenchymal qualities as myofibroblasts. In hepatic fibrosis (importantly, cirrhosis), the process also occurs in injured hepatocytes and hepatic progenitor cells (HPCs), as well as ductular reaction-related bile epithelia. Interestingly, the ductular reaction contributes partly to hepatocarcinogenesis of HPCs, and further, regenerating cholangiocytes after injury may be derived from hepatic stellate cells via mesenchymal to epithelia transition, a reverse phenomenon of type 2 EMT. Possible pathogenesis of type 2 EMT and its differences between renal and hepatic fibrosis are reviewed based on our experimental data. Full article

(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)

Open AccessReview Oxidative Stress and Inflammation in Hepatic Diseases: Therapeutic Possibilities of N-Acetylcysteine

by Kívia Queiroz de Andrade, Fabiana Andréa Moura, John Marques dos Santos, Orlando Roberto Pimentel de Araújo, Juliana Célia de Farias Santos and Marília Oliveira Fonseca Goulart

Int. J. Mol. Sci. 2015, 16(12), 30269-30308; doi:10.3390/ijms161226225

Received: 10 October 2015 / Revised: 2 December 2015 / Accepted: 4 December 2015 / Published: 18 December 2015

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Abstract

Liver disease is highly prevalent in the world. Oxidative stress (OS) and inflammation are the most important pathogenetic events in liver diseases, regardless the different etiology and natural course. N-acetyl-l-cysteine (the active form) (NAC) is being studied in diseases characterized

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Liver disease is highly prevalent in the world. Oxidative stress (OS) and inflammation are the most important pathogenetic events in liver diseases, regardless the different etiology and natural course. N-acetyl-l-cysteine (the active form) (NAC) is being studied in diseases characterized by increased OS or decreased glutathione (GSH) level. NAC acts mainly on the supply of cysteine for GSH synthesis. The objective of this review is to examine experimental and clinical studies that evaluate the antioxidant and anti-inflammatory roles of NAC in attenuating markers of inflammation and OS in hepatic damage. The results related to the supplementation of NAC in any form of administration and type of study are satisfactory in 85.5% (n = 59) of the cases evaluated (n = 69, 100%). Within this percentage, the dosage of NAC utilized in studies in vivo varied from 0.204 up to 2 g/kg/day. A standard experimental design of protection and treatment as well as the choice of the route of administration, with a broader evaluation of OS and inflammation markers in the serum or other biological matrixes, in animal models, are necessary. Clinical studies are urgently required, to have a clear view, so that, the professionals can be sure about the effectiveness and safety of NAC prescription. Full article

(This article belongs to the Special Issue Antioxidant 2.0——Redox Modulation by Food and Drugs)

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Open AccessArticle Protective Effects of Alisma orientale Extract against Hepatic Steatosis via Inhibition of Endoplasmic Reticulum Stress

by Min-Kyung Jang, Yu-Ran Han, Jeong Soo Nam, Chang Woo Han, Byung Joo Kim, Han-Sol Jeong, Ki-Tae Ha and Myeong Ho Jung

Int. J. Mol. Sci. 2015, 16(11), 26151-26165; doi:10.3390/ijms161125944

Received: 4 September 2015 / Revised: 9 October 2015 / Accepted: 21 October 2015 / Published: 2 November 2015

Abstract

Endoplasmic reticulum (ER) stress is associated with the pathogenesis of hepatic steatosis. Alisma orientale Juzepzuk is a traditional medicinal herb for diuretics, diabetes, hepatitis, and inflammation. In this study, we investigated the protective effects of methanol extract of the tuber of Alisma orientale

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Endoplasmic reticulum (ER) stress is associated with the pathogenesis of hepatic steatosis. Alisma orientale Juzepzuk is a traditional medicinal herb for diuretics, diabetes, hepatitis, and inflammation. In this study, we investigated the protective effects of methanol extract of the tuber of Alisma orientale (MEAO) against ER stress-induced hepatic steatosis in vitro and in vivo. MEAO inhibited the tunicamycin-induced increase in luciferase activity of ER stress-reporter constructs containing ER stress response element and ATF6 response element. MEAO significantly inhibited tunicamycin-induced ER stress marker expression including GRP78, CHOP, and XBP-1 in tunicamycin-treated Human hepatocellular carcinoma (HepG2) cells and the livers of tunicamycin-injected mice. It also inhibited tunicamycin-induced accumulation of cellular triglyceride. Similar observations were made under physiological ER stress conditions such as in palmitate (PA)-treated HepG2 cells and the livers of high-fat diet (HFD)-induced obese mice. MEAO repressed hepatic lipogenic gene expression in PA-treated HepG2 cells and the livers of HFD obese mice. Furthermore, MEAO repressed very low-density lipoprotein receptor (VLDLR) expression and improved ApoB secretion in the livers of tunicamycin-injected mice or HFD obese mice as well as in tunicamycin or PA-treated HepG2 cells. Alismol, a guaiane-type sesquiterpenes in Alisma orientale, inhibited GRP78 expression in tunicamycin-treated HepG2 cells. In conclusion, MEAO attenuates ER stress and prevents hepatic steatosis pathogenesis via inhibition of expression of the hepatic lipogenic genes and VLDLR, and enhancement of ApoB secretion. Full article

(This article belongs to the Special Issue The Mechanism of Action of Food Components in Disease Prevention)

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Open AccessArticle Ameliorative Effect of Gallic Acid on Cyclophosphamide-Induced Oxidative Injury and Hepatic Dysfunction in Rats

by Ebenezer Tunde Olayinka, Ayokanmi Ore, Olaniyi Solomon Ola and Oluwatobi Adewumi Adeyemo

Med. Sci. 2015, 3(3), 78-92; doi:10.3390/medsci3030078

Received: 9 August 2015 / Revised: 27 August 2015 / Accepted: 1 September 2015 / Published: 8 September 2015

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Abstract

Cyclophosphamide (CP), a bifunctional alkylating agent used in chemotherapy has been reported to induce organ toxicity mediated by generation of reactive oxygen species and oxidative stress. Gallic acid (GA), a phenolic substance, is a natural antioxidant with proven free radical scavenging activity and

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Cyclophosphamide (CP), a bifunctional alkylating agent used in chemotherapy has been reported to induce organ toxicity mediated by generation of reactive oxygen species and oxidative stress. Gallic acid (GA), a phenolic substance, is a natural antioxidant with proven free radical scavenging activity and offers protection against oxidative damage. This research study was designed to investigate the ameliorative effect of GA against CP-induced toxicity in rats. Twenty-five male Wistar rats (180–200 g) were randomized into five treatment groups: (A) control, (B) CP, 2 mg/kg body weight (b.w.), (C) pre-treatment with GA (20 mg/kg b.w.) for seven days followed by CP (2 mg/kg b.w.) for seven days, (D) co-treatment with GA (20 mg/kg b.w) and CP (2 mg/kg b.w.) for seven days, and (E) GA (20 mg/kg b.w.) for seven days. CP induced marked renal and hepatic damages as plasma levels of urea, creatinine, bilirubin and activities of AST, ALT, ALP and GGT were significantly elevated (p < 0.05) in the CP-treated group relative to control. In addition, hepatic levels of GSH, vitamin C and activities of SOD, catalase and GST significantly reduced in the CP-treated group when compared with control. This was accompanied with a significant increase in hepatic lipid peroxidation. The restoration of the markers of renal and hepatic damages as well as antioxidant indices and lipid peroxidation by pre- and co-treatment with GA clearly shows that GA offers ameliorative effect by scavenging the reactive oxygen species generated by CP. This protective effect may be attributed to the antioxidant property of gllic acid. Full article

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Open AccessArticle Apple Polyphenols Decrease Atherosclerosis and Hepatic Steatosis in ApoE^−/− Mice through the ROS/MAPK/NF-κB Pathway

by Zhe-Rong Xu, Jin-You Li, Xin-Wei Dong, Zhong-Ju Tan, Wei-Zhen Wu, Qiang-Min Xie and Yun-Mei Yang

Nutrients 2015, 7(8), 7085-7105; doi:10.3390/nu7085324

Received: 16 July 2015 / Revised: 7 August 2015 / Accepted: 13 August 2015 / Published: 24 August 2015

Abstract

In this study, we examined the effects of apple polyphenols (APs) on hyperlipidemia, atherosclerosis, hepatic steatosis and endothelial function and investigated the potential mechanisms. ApoE^−/− mice were fed a western-type diet and orally treated with APs (100 mg/kg) or atorvastatin (10 mg/kg)

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In this study, we examined the effects of apple polyphenols (APs) on hyperlipidemia, atherosclerosis, hepatic steatosis and endothelial function and investigated the potential mechanisms. ApoE^−/− mice were fed a western-type diet and orally treated with APs (100 mg/kg) or atorvastatin (10 mg/kg) for 12 weeks. Hyperlipidemia and atherosclerosis in the aortic sinuses and, and hepatic lipidosis were measured. The treatment with APs or atorvastatin induced a remarkable reduction in the atherosclerotic lesions and hepatic steatosis and decreased the levels of low-density lipoprotein, triglyceride, CCL-2 and VCAM-1 levels in the plasma. Conversely, the APs significantly increased the plasma levels of high-density lipoprotein (HDL) cholesterol and markedly up-regulated the glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) levels in liver tissues. Moreover, the APs treatment modulated lipid metabolism by up-regulating the transcription of associated hepatic genes including PPARα, while down-regulating the transcription of SCAP and its downstream genes associated with lipid synthesis in the liver. Histological assessment showed that the APs treatment also reduced the macrophage infiltration in the aortic root plaque and the inflammatory cells infiltrations to the liver tissues. Moreover, we confirmed that the APs treatment greatly reduced the ox-LDL-induced endothelial dysfunction and monocyte adhesion to rat aortic endothelial cells (RAECs). Mechanistically, the APs treatment suppressed the ROS/MAPK/NF-κB signaling pathway, and consequently, reduced CCL-2, ICAM-1 and VCAM-1 expression. Our results suggest that the APs are a beneficial nutritional supplement for the attenuation of atherosclerosis. Full article

Open AccessArticle Novel Radiolytic Rotenone Derivative, Rotenoisin B with Potent Anti-Carcinogenic Activity in Hepatic Cancer Cells

by Srilatha Badaboina, Hyoung-Woo Bai, Yun Hee Na, Chul-Hong Park, Tae Hoon Kim, Tae-Hoon Lee and Byung Yeoup Chung

Int. J. Mol. Sci. 2015, 16(8), 16806-16815; doi:10.3390/ijms160816806

Received: 28 May 2015 / Revised: 15 July 2015 / Accepted: 16 July 2015 / Published: 24 July 2015

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Abstract

Rotenone, isolated from roots of derris plant, has been shown to possess various biological activities, which lead to attempting to develop a potent drug against several diseases. However, recent studies have demonstrated that rotenone has the potential to induce several adverse effects such

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Rotenone, isolated from roots of derris plant, has been shown to possess various biological activities, which lead to attempting to develop a potent drug against several diseases. However, recent studies have demonstrated that rotenone has the potential to induce several adverse effects such as a neurodegenerative disease. Radiolytic transformation of the rotenone with gamma-irradiation created a new product, named rotenoisin B. The present work was designed to investigate the anticancer activity of rotenoisin B with low toxicity and its molecular mechanism in hepatic cancer cells compared to a parent compound, rotenone. Our results showed rotenoisin B inhibited hepatic cancer cells’ proliferation in a dose dependent manner and increased in apoptotic cells. Interestingly, rotenoisin B showed low toxic effects on normal cells compared to rotenone. Mitochondrial transmembrane potential has been decreased, which leads to cytochrome c release. Down regulation of anti-apoptotic Bcl-2 levels as well as the up regulation of proapoptotic Bax levels were observed. The cleaved PARP (poly ADP-ribose polymerase) level increased as well. Moreover, phosphorylation of extracellular signal regulated kinase (ERK) and p38 slightly up regulated and intracellular reactive oxygen species (ROS) increased as well as cell cycle arrest predominantly at the G₂/M phase observed. These results suggest that rotenoisin B might be a potent anticancer candidate similar to rotenone in hepatic cancer cells with low toxicity to normal cells even at high concentrations compared to rotenone. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Chemical-Induced Toxicity and Carcinogenesis)

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Open AccessArticle Astaxanthin Pretreatment Attenuates Hepatic Ischemia Reperfusion-Induced Apoptosis and Autophagy via the ROS/MAPK Pathway in Mice

by Jingjing Li, Fan Wang, Yujing Xia, Weiqi Dai, Kan Chen, Sainan Li, Tong Liu, Yuanyuan Zheng, Jianrong Wang, Wenxia Lu, Yuqing Zhou, Qin Yin, Jie Lu, Yingqun Zhou and Chuanyong Guo

Mar. Drugs 2015, 13(6), 3368-3387; doi:10.3390/md13063368

Received: 23 March 2015 / Revised: 16 May 2015 / Accepted: 19 May 2015 / Published: 27 May 2015

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Abstract

Background: Hepatic ischemia reperfusion (IR) is an important issue in complex liver resection and liver transplantation. The aim of the present study was to determine the protective effect of astaxanthin (ASX), an antioxidant, on hepatic IR injury via the reactive oxygen species/mitogen-activated protein

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Background: Hepatic ischemia reperfusion (IR) is an important issue in complex liver resection and liver transplantation. The aim of the present study was to determine the protective effect of astaxanthin (ASX), an antioxidant, on hepatic IR injury via the reactive oxygen species/mitogen-activated protein kinase (ROS/MAPK) pathway. Methods: Mice were randomized into a sham, IR, ASX or IR + ASX group. The mice received ASX at different doses (30 mg/kg or 60 mg/kg) for 14 days. Serum and tissue samples at 2 h, 8 h and 24 h after abdominal surgery were collected to assess alanine aminotransferase (ALT), aspartate aminotransferase (AST), inflammation factors, ROS, and key proteins in the MAPK family. Results: ASX reduced the release of ROS and cytokines leading to inhibition of apoptosis and autophagy via down-regulation of the activated phosphorylation of related proteins in the MAPK family, such as P38 MAPK, JNK and ERK in this model of hepatic IR injury. Conclusion: Apoptosis and autophagy caused by hepatic IR injury were inhibited by ASX following a reduction in the release of ROS and inflammatory cytokines, and the relationship between the two may be associated with the inactivation of the MAPK family. Full article

Open AccessArticle Bisdemethoxycurcumin Induces Apoptosis in Activated Hepatic Stellate Cells via Cannabinoid Receptor 2

by Phil Jun Lee, Seung Je Woo, Jun-Goo Jee, Sang Hyun Sung and Hong Pyo Kim

Molecules 2015, 20(1), 1277-1292; doi:10.3390/molecules20011277

Received: 21 November 2014 / Accepted: 9 January 2015 / Published: 14 January 2015

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Abstract

Activated Hepatic Stellate Cells (HSCs), major fibrogenic cells in the liver, undergo apoptosis when liver injuries cease, which may contribute to the resolution of fibrosis. Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin with anti-inflammatory and anti-cancer activities. The therapeutic potential of BDMC

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Activated Hepatic Stellate Cells (HSCs), major fibrogenic cells in the liver, undergo apoptosis when liver injuries cease, which may contribute to the resolution of fibrosis. Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin with anti-inflammatory and anti-cancer activities. The therapeutic potential of BDMC in hepatic fibrosis has not been studied thus far in the context of the apoptosis in activated HSCs. In the current study, we compared the activities of BDMC and curcumin in the HSC-T6 cell line and demonstrated that BDMC relatively induced a potent apoptosis. BDMC-induced apoptosis was mediated by a combinatory inhibition of cytoprotective proteins, such as Bcl₂ and heme oxygenase-1 and increased generation of reactive oxygen species. Intriguingly, BDMC-induced apoptosis was reversed with co-treatment of sr144528, a cannabinoid receptor (CBR) 2 antagonist, which was confirmed with genetic downregulation of the receptor using siCBR2. Additionally, incubation with BDMC increased the formation of death-induced signaling complex in HSC-T6 cells. Treatment with BDMC significantly diminished total intracellular ATP levels and upregulated ATP inhibitory factor-1. Collectively, the results demonstrate that BDMC induces apoptosis in activated HSCs, but not in hepatocytes, by impairing cellular energetics and causing a downregulation of cytoprotective proteins, likely through a mechanism that involves CBR2. Full article

(This article belongs to the Special Issue Curcumin, Inflammation, and Chronic Diseases: How are They Linked?)

Open AccessArticle Profiling of Concanavalin A-Binding Glycoproteins in Human Hepatic Stellate Cells Activated with Transforming Growth Factor-β1

by Yannan Qin, Yaogang Zhong, Ganglong Yang, Tianran Ma, Liyuan Jia, Chen Huang and Zheng Li

Molecules 2014, 19(12), 19845-19867; doi:10.3390/molecules191219845

Received: 27 September 2014 / Revised: 18 November 2014 / Accepted: 24 November 2014 / Published: 28 November 2014

Abstract

Glycoproteins play important roles in maintaining normal cell functions depending on their glycosylations. Our previous study indicated that the abundance of glycoproteins recognized by concanavalin A (ConA) was increased in human hepatic stellate cells (HSCs) following activation by transforming growth factor-β1 (TGF-β1); however,

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Glycoproteins play important roles in maintaining normal cell functions depending on their glycosylations. Our previous study indicated that the abundance of glycoproteins recognized by concanavalin A (ConA) was increased in human hepatic stellate cells (HSCs) following activation by transforming growth factor-β1 (TGF-β1); however, little is known about the ConA-binding glycoproteins (CBGs) of HSCs. In this study, we employed a targeted glycoproteomics approach using lectin-magnetic particle conjugate-based liquid chromatography-tandem mass spectrometry to compare CBG profiles between LX-2 HSCs with and without activation by TGF-β1, with the aim of discovering novel CBGs and determining their possible roles in activated HSCs. A total of 54 and 77 proteins were identified in the quiescent and activated LX-2 cells, respectively. Of the proteins identified, 14.3% were glycoproteins and 73.3% were novel potential glycoproteins. Molecules involved in protein processing in the endoplasmic reticulum (e.g., calreticulin) and calcium signaling (e.g., 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase β-2 [PLCB2]) were specifically identified in activated LX-2 cells. Additionally, PLCB2 expression was upregulated in the cytoplasm of the activated LX-2 cells, as well as in the hepatocytes and sinusoidal cells of liver cirrhosis tissues. In conclusion, the results of this study may aid future investigations to find new molecular mechanisms involved in HSC activation and antifibrotic therapeutic targets. Full article

(This article belongs to the collection Advances in Carbohydrate Chemistry)

Open AccessArticle Integrated Computational Model of Intracellular Signaling and microRNA Regulation Predicts the Network Balances and Timing Constraints Critical to the Hepatic Stellate Cell Activation Process

by Lakshmi Kuttippurathu, Austin Parrish and Rajanikanth Vadigepalli

Processes 2014, 2(4), 773-794; doi:10.3390/pr2040773

Received: 29 August 2014 / Revised: 26 September 2014 / Accepted: 8 October 2014 / Published: 17 October 2014

Abstract

Activation and deactivation of hepatic stellate cells (HSCs) is an important mechanism contributing to both healthy liver function and development of liver diseases, which relies on the interplay between numerous signaling pathways. There is accumulating evidence for the regulatory role of microRNAs that

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Activation and deactivation of hepatic stellate cells (HSCs) is an important mechanism contributing to both healthy liver function and development of liver diseases, which relies on the interplay between numerous signaling pathways. There is accumulating evidence for the regulatory role of microRNAs that are downstream from these pathways in HSC activation. However, the relative contribution of these pathways and interacting microRNA regulators to the activation process is unknown. We pursued a computational modeling approach to explore the timing and regulatory balances that are critical to HSC activation and quiescence. We developed an integrated model incorporating three signaling pathways with crosstalk (NF-κB, STAT3 and TGF-β) and two microRNAs (miR-146a, miR-21) that are differentially regulated by these pathways. Simulations demonstrated that TGF-β-mediated regulation of microRNAs is critical to drive the HSC phenotypic switch from quiescence (miR-146a^high miR-21^l^ow) to an activated state (miR-146a^l^ow miR-21^high). We found that the relative timing between peak NF-κB and STAT3 activation plays a key role driving the initial dynamics of miR-146a. We observed re-quiescence from the activated HSC state upon termination of cytokine stimuli. Our integrated model of signaling and microRNA regulation provides a new computational platform for investigating the mechanisms driving HSC molecular state phenotypes in normal and pathological liver physiology. Full article

(This article belongs to the Special Issue Modeling and Analysis of Signal Transduction Networks) Printed Edition available

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Open AccessArticle The Beneficial Effects of Combined Grape Pomace and Omija Fruit Extracts on Hyperglycemia, Adiposity and Hepatic Steatosis in db/db Mice: A Comparison with Major Index Compounds

by Su-Jung Cho, Hae-Jin Park, Un Ju Jung, Hye-Jin Kim, Byoung Seok Moon and Myung-Sook Choi

Int. J. Mol. Sci. 2014, 15(10), 17778-17789; doi:10.3390/ijms151017778

Received: 8 August 2014 / Revised: 17 September 2014 / Accepted: 18 September 2014 / Published: 30 September 2014

Abstract

This study investigated the effects of combined grape pomace and omija fruit extracts (GO) on diabetes-related metabolic changes in type 2 diabetic db/db mice. The effects of GO were compared with those of a resveratrol and schizandrin mixture (RS), which is

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This study investigated the effects of combined grape pomace and omija fruit extracts (GO) on diabetes-related metabolic changes in type 2 diabetic db/db mice. The effects of GO were compared with those of a resveratrol and schizandrin mixture (RS), which is a mixture of major components of GO. Mice were fed a normal diet with RS (0.005% resveratrol and 0.02% schizandrin in diet, w/w) or GO (0.3% grape pomace ethanol extract and 0.05% omija fruit ethanol extract in diet, w/w) for seven weeks. RS and GO not only lowered the levels of blood and plasma glucose, HbA_1c, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) with a simultaneous decrease in hepatic gluconeogenic enzymes activities and adiposity, but also improved preservation of the pancreatic β-cells. Plasma leptin and resistin levels were lower while the plasma adiponectin level was higher in the RS and GO groups than in the control group. Especially, GO increased hepatic glucokinase activity and gene expression and improved hepatic steatosis by elevating fatty acid oxidation compared to RS. These findings suggest that GO ameliorates hyperglycemia, adiposity and hepatic steatosis in type 2 diabetic mice. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

Open AccessArticle Reducing Liver Fat by Low Carbohydrate Caloric Restriction Targets Hepatic Glucose Production in Non-Diabetic Obese Adults with Non-Alcoholic Fatty Liver Disease

by Haoyong Yu, Weiping Jia and ZengKui Guo

J. Clin. Med. 2014, 3(3), 1050-1063; doi:10.3390/jcm3031050

Received: 2 July 2014 / Revised: 4 September 2014 / Accepted: 12 September 2014 / Published: 22 September 2014

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Abstract

Non-alcoholic fatty liver disease (NAFLD) impairs liver functions, the organ responsible for the regulation of endogenous glucose production and thus plays a key role in glycemic homeostasis. Therefore, interventions designed to normalize liver fat content are needed to improve glucose metabolism in patients

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Non-alcoholic fatty liver disease (NAFLD) impairs liver functions, the organ responsible for the regulation of endogenous glucose production and thus plays a key role in glycemic homeostasis. Therefore, interventions designed to normalize liver fat content are needed to improve glucose metabolism in patients affected by NAFLD such as obesity. Objective: this investigation is designed to determine the effects of caloric restriction on hepatic and peripheral glucose metabolism in obese humans with NAFLD. Methods: eight non-diabetic obese adults were restricted for daily energy intake (800 kcal) and low carbohydrate (<10%) for 8 weeks. Body compositions, liver fat and hepatic glucose production (HGP) and peripheral glucose disposal before and after the intervention were determined. Results: the caloric restriction reduced liver fat content by 2/3 (p = 0.004). Abdominal subcutaneous and visceral fat, body weight, BMI, waist circumference and fasting plasma triglyceride and free fatty acid concentrations all significantly decreased (p < 0.05). The suppression of post-load HGP was improved by 22% (p = 0.002) whereas glucose disposal was not affected (p = 0.3). Fasting glucose remained unchanged and the changes in the 2-hour plasma glucose and insulin concentration were modest and statistically insignificant (p > 0.05). Liver fat is the only independent variable highly correlated to HGP after the removal of confounders. Conclusion: NAFLD impairs HGP but not peripheral glucose disposal; low carbohydrate caloric restriction effectively lowers liver fat which appears to directly correct the HGP impairment. Full article

(This article belongs to the Special Issue Obesity, Diabetes and Metabolic Syndrome)

Open AccessArticle The Effects of Choline on Hepatic Lipid Metabolism, Mitochondrial Function and Antioxidative Status in Human Hepatic C3A Cells Exposed to Excessive Energy Substrates

by Jie Zhu, Yang Wu, Qingya Tang, Yan Leng and Wei Cai

Nutrients 2014, 6(7), 2552-2571; doi:10.3390/nu6072552

Received: 23 April 2014 / Revised: 12 June 2014 / Accepted: 18 June 2014 / Published: 9 July 2014

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Abstract

Choline plays a lipotropic role in lipid metabolism as an essential nutrient. In this study, we investigated the effects of choline (5, 35 and 70 μM) on DNA methylation modifications, mRNA expression of the critical genes and their enzyme activities involved in hepatic

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Choline plays a lipotropic role in lipid metabolism as an essential nutrient. In this study, we investigated the effects of choline (5, 35 and 70 μM) on DNA methylation modifications, mRNA expression of the critical genes and their enzyme activities involved in hepatic lipid metabolism, mitochondrial membrane potential (Δψm) and glutathione peroxidase (GSH-Px) in C3A cells exposed to excessive energy substrates (lactate, 10 mM; octanoate, 2 mM and pyruvate, 1 mM; lactate, octanoate and pyruvate-supplemented medium (LOP)). Thirty five micromole or 70 μM choline alone, instead of a low dose (5 μM), reduced hepatocellular triglyceride (TG) accumulation, protected Δψm from decrement and increased GSH-Px activity in C3A cells. The increment of TG accumulation, reactive oxygen species (ROS) production and Δψm disruption were observed under LOP treatment in C3A cells after 72 h of culture, which were counteracted by concomitant treatment of choline (35 μM or 70 μM) partially via reversing the methylation status of the peroxisomal proliferator-activated receptor alpha (PPARα) gene promoter, upregulating PPARα, carnitine palmitoyl transferase-I (CPT-I) and downregulating fatty acid synthase (FAS) gene expression, as well as decreasing FAS activity and increasing CPT-I and GSH-Px activities. These findings provided a novel insight into the lipotropic role of choline as a vital methyl-donor in the intervention of chronic metabolic diseases. Full article

(This article belongs to the Special Issue Nutrition and Liver Disease)

Open AccessArticle Sasa borealis Stem Extract Attenuates Hepatic Steatosis in High-Fat Diet-induced Obese Rats

by Yuno Song, Soo-Jung Lee, Sun-Hee Jang, Ji Hee Ha, Young Min Song, Yeoung-Gyu Ko, Hong-Duck Kim, Wongi Min, Suk Nam Kang and Jae-Hyeon Cho

Nutrients 2014, 6(6), 2179-2195; doi:10.3390/nu6062179

Received: 15 April 2014 / Revised: 12 May 2014 / Accepted: 26 May 2014 / Published: 5 June 2014

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Abstract

The aim of the current study is to examine the improving effect of Sasa borealis stem (SBS) extract extracts on high-fat diet (HFD)-induced hepatic steatosis in rats. To determine the hepatoprotective effect of SBS, we fed rats a normal regular diet (ND),

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The aim of the current study is to examine the improving effect of Sasa borealis stem (SBS) extract extracts on high-fat diet (HFD)-induced hepatic steatosis in rats. To determine the hepatoprotective effect of SBS, we fed rats a normal regular diet (ND), HFD, and HFD supplemented with 150 mg/kg body weight (BW) SBS extracts for five weeks. We found that the body weight and liver weight of rats in the HFD + SBS group were significantly lower than those in the HFD group. Significantly lower serum total cholesterol (TC) and triglyceride (TG) concentrations were observed in the SBS-supplemented group compared with the HFD group. We also found that the HFD supplemented with SBS group showed dramatically reduced hepatic lipid accumulation compared to the HFD alone group, and administration of SBS resulted in dramatic suppression of TG, TC in the HFD-induced fatty liver. In liver gene expression within the SBS treated group, PPARα was significantly increased and SREBP-1c was significantly suppressed. SBS induced a significant decrease in the hepatic mRNA levels of PPARγ, FAS, ACC1, and DGAT2. In conclusion, SBS improved cholesterol metabolism, decreased lipogenesis, and increased lipid oxidation in HFD-induced hepatic steatosis in rats, implying a potential application in treatment of non-alcoholic fatty liver disease. Full article

(This article belongs to the Special Issue Nutrition and Liver Disease)

Open AccessArticle Evaluation of Hepatic Tissue Blood Flow Using Xenon Computed Tomography with Fibrosis Progression in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis C

by Ryuta Shigefuku, Hideaki Takahashi, Masaki Kato, Yoshihito Yoshida, Keigo Suetani, Yohei Noguchi, Moriaki Hatsugai, Kazunari Nakahara, Hiroki Ikeda, Minoru Kobayashi, Kotaro Matsunaga, Nobuyuki Matsumoto, Chiaki Okuse, Fumio Itoh, Shiro Maeyama, Shigeru Sase and Michihiro Suzuki

Int. J. Mol. Sci. 2014, 15(1), 1026-1039; doi:10.3390/ijms15011026

Received: 6 November 2013 / Revised: 24 December 2013 / Accepted: 27 December 2013 / Published: 14 January 2014

Cited by 5 | Viewed by 1769 | PDF Full-text (1510 KB) | HTML Full-text | XML Full-text

Abstract

Aims: The present study evaluated the utility of xenon computed tomography (Xe-CT) as a noninvasive diagnostic procedure for the measurement of hepatic tissue blood flow (TBF) in patients with nonalcoholic fatty liver disease (NAFLD) or chronic hepatitis C (CH-C). Methods: Xe-CT was performed

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Aims: The present study evaluated the utility of xenon computed tomography (Xe-CT) as a noninvasive diagnostic procedure for the measurement of hepatic tissue blood flow (TBF) in patients with nonalcoholic fatty liver disease (NAFLD) or chronic hepatitis C (CH-C). Methods: Xe-CT was performed in 93 patients with NAFLD and in 109 patients with CH-C. Subjects were classified into one of three groups, based on fibrosis stage: group 1, no bridging fibrosis; group 2, bridging fibrosis; and group 3, liver cirrhosis. Correlations between hepatic TBFs in each fibrosis stage were examined. Results: In group 1, portal venous TBF (PVTBF), hepatic arterial (HATBF), and total hepatic TBF (THTBF) were significantly lower in patients with in nonalcoholic steatohepatitis (NASH) than in those with CH-C (p < 0.001, p < 0.05, p < 0.001, respectively). In group 2, PVTBF and THTBF were significantly lower in patients with in NASH than in those with CH-C (p < 0.001, p < 0.05, respectively). In group 3, hepatic TBFs were not significantly different when comparing patients with NASH and those with CH-C. Conclusions: PVTBF decreased due to fat infiltration. Therefore, hemodynamic changes occur relatively earlier in NAFLD than in CH-C. Patients with NASH should be monitored carefully for portal hypertensive complications in the early fibrosis stage. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)

Open AccessReview Role of Hepatic Progenitor Cells in Nonalcoholic Fatty Liver Disease Development: Cellular Cross-Talks and Molecular Networks

by Guido Carpino, Anastasia Renzi, Paolo Onori and Eugenio Gaudio

Int. J. Mol. Sci. 2013, 14(10), 20112-20130; doi:10.3390/ijms141020112

Received: 6 August 2013 / Revised: 18 September 2013 / Accepted: 18 September 2013 / Published: 9 October 2013

Cited by 20 | Viewed by 3137 | PDF Full-text (1007 KB) | HTML Full-text | XML Full-text

Abstract

Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases ranging from simple fatty liver to nonalcoholic steatohepatitis, (NASH) which may progress to cirrhosis and hepatocellular carcinoma. NASH has been independently correlated with atherosclerosis progression and cardiovascular risk. NASH development is characterized by

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Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases ranging from simple fatty liver to nonalcoholic steatohepatitis, (NASH) which may progress to cirrhosis and hepatocellular carcinoma. NASH has been independently correlated with atherosclerosis progression and cardiovascular risk. NASH development is characterized by intricate interactions between resident and recruited cells that enable liver damage progression. The increasing general agreement is that the cross-talk between hepatocytes, hepatic stellate cells (HSCs) and macrophages in NAFLD has a main role in the derangement of lipid homeostasis, insulin resistance, danger recognition, immune tolerance response and fibrogenesis. Moreover, several evidences have suggested that hepatic stem/progenitor cell (HPCs) activation is a component of the adaptive response of the liver to oxidative stress in NAFLD. HPC activation determines the appearance of a ductular reaction. In NASH, ductular reaction is independently correlated with progressive portal fibrosis raising the possibility of a periportal fibrogenetic pathway for fibrogenesis that is parallel to the deposition of subsinusoidal collagen in zone 3 by HSCs. Recent evidences indicated that adipokines, a class of circulating factors, have a key role in the cross-talk among HSCs, HPCs and liver macrophages. This review will be focused on cellular cross-talk and the relative molecular networks which are at the base of NASH progression and fibrosis. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research)

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Open AccessArticle Protective Effect of N-Acetylserotonin against Acute Hepatic Ischemia-Reperfusion Injury in Mice

by Shuna Yu, Jie Zheng, Zhengchen Jiang, Caixing Shi, Jin Li, Xiaodong Du, Hailiang Wang, Jiying Jiang and Xin Wang

Int. J. Mol. Sci. 2013, 14(9), 17680-17693; doi:10.3390/ijms140917680

Received: 19 July 2013 / Revised: 29 July 2013 / Accepted: 9 August 2013 / Published: 29 August 2013

Cited by 7 | Viewed by 1875 | PDF Full-text (763 KB) | HTML Full-text | XML Full-text

Abstract

The purpose of this study was to investigate the possible protective effect of N-acetylserotonin (NAS) against acute hepatic ischemia-reperfusion (I/R) injury in mice. Adult male mice were randomly divided into three groups: sham, I/R, and I/R + NAS. The hepatic I/R injury

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The purpose of this study was to investigate the possible protective effect of N-acetylserotonin (NAS) against acute hepatic ischemia-reperfusion (I/R) injury in mice. Adult male mice were randomly divided into three groups: sham, I/R, and I/R + NAS. The hepatic I/R injury model was generated by clamping the hepatic artery, portal vein, and common bile duct with a microvascular bulldog clamp for 30 min, and then removing the clamp and allowing reperfusion for 6 h. Morphologic changes and hepatocyte apoptosis were evaluated by hematoxylin-eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, respectively. Activated caspase-3 expression was evaluated by immunohistochemistry and Western blot. The activation of aspartate aminotransferase (AST), malondialdehyde (MDA), and superoxide dismutase (SOD) was evaluated by enzyme-linked immunosorbent assay (ELISA). The data show that NAS rescued hepatocyte morphological damage and dysfunction, decreased the number of apoptotic hepatocytes, and reduced caspase-3 activation. Our work demonstrates that NAS ameliorates hepatic IR injury. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

Open AccessReview Contributions of Microdialysis to New Alternative Therapeutics for Hepatic Encephalopathy

by Liliana Rivera-Espinosa, Esaú Floriano-Sánchez, José Pedraza-Chaverrí, Elvia Coballase-Urrutia, Aristides III Sampieri, Daniel Ortega-Cuellar, Noemí Cárdenas-Rodríguez and Liliana Carmona-Aparicio

Int. J. Mol. Sci. 2013, 14(8), 16184-16206; doi:10.3390/ijms140816184

Received: 15 July 2013 / Revised: 24 July 2013 / Accepted: 29 July 2013 / Published: 5 August 2013

Cited by 4 | Viewed by 2455 | PDF Full-text (1432 KB) | HTML Full-text | XML Full-text

Abstract

Hepatic encephalopathy (HE) is a common complication of cirrhosis, of largely reversible impairment of brain function occurring in patients with acute or chronic liver failure or when the liver is bypassed by portosystemic shunts. The mechanisms causing this brain dysfunction are still largely

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Hepatic encephalopathy (HE) is a common complication of cirrhosis, of largely reversible impairment of brain function occurring in patients with acute or chronic liver failure or when the liver is bypassed by portosystemic shunts. The mechanisms causing this brain dysfunction are still largely unclear. The need to avoid complications caused by late diagnosis has attracted interest to understand the mechanisms underlying neuronal damage in order to find markers that will allow timely diagnosis and to propose new therapeutic alternatives to improve the care of patients. One of the experimental approaches to study HE is microdialysis; this technique allows evaluation of different chemical substances in several organs through the recollection of samples in specific places by semi-permeable membranes. In this review we will discuss the contributions of microdialysis in the understanding of the physiological alterations in human hepatic encephalopathy and experimental models and the studies to find novel alternative therapies for this disease. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

Open AccessArticle Improvement of Carbon Tetrachloride-Induced Acute Hepatic Failure by Transplantation of Induced Pluripotent Stem Cells without Reprogramming Factor c-Myc

by Hua-Ming Chang, Yi-Wen Liao, Chih-Hung Chiang, Yi-Jen Chen, Ying-Hsiu Lai, Yuh-Lih Chang, Hen-Li Chen, Shaw-Yeu Jeng, Jung-Hung Hsieh, Chi-Hsien Peng, Hsin-Yang Li, Yueh Chien, Szu-Yu Chen, Liang-Kung Chen and Teh-Ia Huo

Int. J. Mol. Sci. 2012, 13(3), 3598-3617; doi:10.3390/ijms13033598

Received: 16 January 2012 / Revised: 13 February 2012 / Accepted: 28 February 2012 / Published: 16 March 2012

Cited by 8 | Viewed by 2812 | PDF Full-text (920 KB) | HTML Full-text | XML Full-text

Abstract

The only curative treatment for hepatic failure is liver transplantation. Unfortunately, this treatment has several major limitations, as for example donor organ shortage. A previous report demonstrated that transplantation of induced pluripotent stem cells without reprogramming factor c-Myc (3-genes iPSCs) attenuates thioacetamide-induced hepatic

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The only curative treatment for hepatic failure is liver transplantation. Unfortunately, this treatment has several major limitations, as for example donor organ shortage. A previous report demonstrated that transplantation of induced pluripotent stem cells without reprogramming factor c-Myc (3-genes iPSCs) attenuates thioacetamide-induced hepatic failure with minimal incidence of tumorigenicity. In this study, we investigated whether 3-genes iPSC transplantation is capable of rescuing carbon tetrachloride (CCl₄)-induced fulminant hepatic failure and hepatic encephalopathy in mice. Firstly, we demonstrated that 3-genes iPSCs possess the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) that exhibit biological functions and express various hepatic specific markers. 3-genes iPSCs also exhibited several antioxidant enzymes that prevented CCl₄-induced reactive oxygen species production and cell death. Intraperitoneal transplantation of either 3-genes iPSCs or 3-genes iPSC-Heps significantly reduced hepatic necrotic areas, improved hepatic functions, and survival rate in CCl₄-treated mice. CCl₄-induced hepatic encephalopathy was also improved by 3-genes iPSC transplantation. Hoechst staining confirmed the successful engraftment of both 3-genes iPSCs and 3-genes iPSC-Heps, indicating the homing properties of these cells. The most pronounced hepatoprotective effect of iPSCs appeared to originate from the highest antioxidant activity of 3-gene iPSCs among all transplanted cells. In summary, our findings demonstrated that 3-genes iPSCs serve as an available cell source for the treatment of an experimental model of acute liver diseases. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

Open AccessCase Report Primary Hepatic Gastrinoma Causing Zollinger-Ellison Syndrome: A Rare and Challenging Diagnosis

by Adrian Harvey, Janice L. Pasieka, Hassan Al-Bisher and Elijah Dixon

Cancers 2012, 4(1), 130-140; doi:10.3390/cancers4010130

Received: 6 December 2011 / Revised: 23 January 2012 / Accepted: 30 January 2012 / Published: 14 February 2012

Cited by 3 | Viewed by 2510 | PDF Full-text (1202 KB) | HTML Full-text | XML Full-text

Abstract

The majority of gastrinomas causing Zollinger-Ellison syndrome (ZES) are located in the duodenum or the pancreas. Primary hepatic gastrinomas (PHG) are extremely rare and difficult to diagnose because the liver is the commonest site of metastatic disease and gastrinomas can be very small.

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The majority of gastrinomas causing Zollinger-Ellison syndrome (ZES) are located in the duodenum or the pancreas. Primary hepatic gastrinomas (PHG) are extremely rare and difficult to diagnose because the liver is the commonest site of metastatic disease and gastrinomas can be very small. Furthermore, gastrinomas are typically slow-growing thus a missed, occult primary tumour may not become evident for many years. The diagnosis of PHG is therefore dependent on a careful search for a primary and long-term biochemical follow-up following curative hepatic resection. We report a case of a 7 cm PHG in a 48 year old man with ZES. Preoperatively, both a basal and stimulated gastrin levels were elevated. Surgical exploration including intraoperative ultrasound and duodenotomy, failed to reveal a primary. Patient underwent a right hepatectomy. Yearly, gastrin and secretin stimulation tests remain normal 6 years following surgery. He remains symptom free off all medication. An additional 26 cases of PHG were found. Including this case, 21 had at least 1 year follow-up, however only eight had greater than 5 years (median 24 months). Post-op gastrin levels were reported in 25, however provocative testing was done in only 10. Persistence and recurrence occurred in one and four, respectively. PHG causing ZES is extremely rare. Although the current literature claims to include 26 additional cases of PHG, without a thorough search for the primary and long-term follow-up data including provocative testing, this diagnosis remains a challenge. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors)

Open AccessArticle Inhibitory Effects of Ecklonia cava Extract on High Glucose-Induced Hepatic Stellate Cell Activation

by Kumiko Yokogawa, Isao Matsui-Yuasa, Akiko Tamura, Masaki Terada and Akiko Kojima-Yuasa

Mar. Drugs 2011, 9(12), 2793-2808; doi:10.3390/md9122793

Received: 10 November 2011 / Revised: 9 December 2011 / Accepted: 13 December 2011 / Published: 20 December 2011

Cited by 11 | Viewed by 3001 | PDF Full-text (336 KB) | HTML Full-text | XML Full-text

Abstract

Nonalcoholic steatohepatitis (NASH) is a disease closely associated with obesity and diabetes. A prevalence of type 2 diabetes and a high body mass index in cryptogenic cirrhosis may imply that obesity leads to cirrhosis. Here, we examined the effects of an extract of

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Nonalcoholic steatohepatitis (NASH) is a disease closely associated with obesity and diabetes. A prevalence of type 2 diabetes and a high body mass index in cryptogenic cirrhosis may imply that obesity leads to cirrhosis. Here, we examined the effects of an extract of Ecklonia cava, a brown algae, on the activation of high glucose-induced hepatic stellate cells (HSCs), key players in hepatic fibrosis. Isolated HSCs were incubated with or without a high glucose concentration. Ecklonia cava extract (ECE) was added to the culture simultaneously with the high glucose. Treatment with high glucose stimulated expression of type I collagen and α-smooth muscle actin, which are markers of activation in HSCs, in a dose-dependent manner. The activation of high glucose-treated HSCs was suppressed by the ECE. An increase in the formation of intracellular reactive oxygen species (ROS) and a decrease in intracellular glutathione levels were observed soon after treatment with high glucose, and these changes were suppressed by the simultaneous addition of ECE. High glucose levels stimulated the secretion of bioactive transforming growth factor-β (TGF-β) from the cells, and the stimulation was also suppressed by treating the HSCs with ECE. These results suggest that the suppression of high glucose-induced HSC activation by ECE is mediated through the inhibition of ROS and/or GSH and the downregulation of TGF-β secretion. ECE is useful for preventing the development of diabetic liver fibrosis. Full article

(This article belongs to the Special Issue Marine Functional Food)

Open AccessArticle Specific siRNA Targeting the Receptor for Advanced Glycation End Products Inhibits Experimental Hepatic Fibrosis in Rats

by Jin-Rong Xia, Nai-Feng Liu and Nai-Xun Zhu

Int. J. Mol. Sci. 2008, 9(4), 638-661; doi:10.3390/ijms9040638

Received: 13 January 2008 / Revised: 17 August 2008 / Accepted: 22 April 2008 / Published: 24 April 2008

Cited by 28 | Viewed by 5914 | PDF Full-text (3984 KB) | HTML Full-text | XML Full-text

Abstract

Receptor for advanced glycation end products (RAGE) was studied in different stages of carbon tetrachloride induced hepatic fibrosis (HF), and effect of its gene silencing in the HF development was evaluated in rats. Silencing RAGE expression by specific siRNA effectively suppressed NF-κB activity,

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Receptor for advanced glycation end products (RAGE) was studied in different stages of carbon tetrachloride induced hepatic fibrosis (HF), and effect of its gene silencing in the HF development was evaluated in rats. Silencing RAGE expression by specific siRNA effectively suppressed NF-κB activity, hepatic stellate cell activation, and accumulation of extracellular matrix proteins in the fibrotic liver, and also greatly improved the histopathology and the ultra-structure of liver cells. These effects may be partially mediated by the inhibition on IκBα degradation. RAGE gene silencing effectively prevented liver from fibrosis, therefore it offers a potential pharmacological tool for anti-HF gene therapy. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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