Iron is an essential element for all organisms. Iron‐containing proteins play critical roles in cellular functions. The biological importance of iron is largely attributable to its chemical ...properties as a transitional metal. However, an excess of ‘free’ reactive iron damages the macromolecular components of cells and cellular DNA through the production of harmful free radicals. On the contrary, most of the body’s excess iron is stored in the liver. Not only hereditary haemochromatosis but also some liver diseases with mild‐to‐moderate hepatic iron accumulation, such as chronic hepatitis C, alcoholic liver disease and nonalcoholic steatohepatitis, are associated with a high risk for liver cancer development. These findings have attracted attention to the causative and promotive roles of iron in the development of liver cancer. In the last decade, accumulating evidence regarding molecules regulating iron metabolism or iron‐related cell death programmes such as ferroptosis has shed light on the relationship between hepatic iron accumulation and hepatocarcinogenesis. In this review, we briefly present the current molecular understanding of iron regulation in the liver. Next, we describe the mechanisms underlying dysregulated iron metabolism depending on the aetiology of liver diseases. Finally, we discuss the causative and promotive roles of iron in cancer development.
Dysregulated iron homeostasis induced by various factors such as mutations in haemochromatosis genes, reactive oxygen species and hypoxia causes mild‐to‐severe iron accumulation in the liver, which in turn triggers hepatocarcinogenesis through activation of cell proliferation, ferroptosis, dysregulation of p53 and mitochondrial iron accumulation. Once hepatocellular carcinoma has been developed, cancer cells adapt to the iron‐associated cellular responses mainly through activation of nuclear factor erythroid 2‐related factor 2.
Background
Accurately evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) is important for identifying those who may develop complications. The aims of this study ...were (1) to measure serum
Wisteria floribunda
agglutinin-positive Mac-2 binding protein (WFA
+
-M2BP) using the glycan sugar chain-based immunoassay and (2) to compare the results with clinical assessments of fibrosis.
Methods
Serum WFA
+
-M2BP values were retrospectively evaluated in 289 patients with NAFLD who had undergone liver biopsy. Histological findings were evaluated by three blinded, experienced liver-specific pathologists.
Results
For stages 0 (
n
= 35), 1 (
n
= 113), 2 (
n
= 49), 3 (
n
= 41), and 4 (
n
= 51) of liver fibrosis, the serum WFA
+
-M2BP cutoff indexes were 0.57, 0.70, 1.02, 1.57, and 2.96, respectively. Multivariate regression analysis showed that serum WFA
+
-M2BP values were associated with the stage of fibrosis (≥stage 2). The areas under the receiver operating characteristic curve (AUROC), sensitivity, and specificity of serum WFA
+
-M2BP were 0.876, 85.9, and 74.6 %, respectively, for severe fibrosis (≥stage 3) and were 0.879, 74.6, and 87.0 %, respectively, for cirrhosis. When compared with six non-invasive conventional markers, serum WFA
+
-M2BP had the greatest AUROC for diagnosing severe fibrosis and cirrhosis.
Conclusions
Serum WFA
+
-M2BP values are useful for assessing the stage of liver fibrosis in patients with NAFLD.
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•Calcium phosphate-loaded carboxymethyl cellulose non-woven sheets (CMC/CaP sheet) were fabricated.•The combined effect of CMC and CaP promoted osteoblast differentiation of human ...mesenchymal stromal cells in vitro.•In vivo bone regeneration by the CMC/CaP sheet was demonstrated in a mouse calvarial defect model.
Calcium phosphate-loaded carboxymethyl cellulose non-woven sheets (CMC/CaP sheet) were fabricated and their potential to induce in vitro osteoblast differentiation and in vivo bone regeneration were investigated. The CMC/CaP sheets were prepared by alternately soaking protonated-CMC non-woven sheets in CaCl2 and Na2HPO4 aqueous solutions. Because of its slow water uptake rate, the protonated-CMC was successfully loaded with a mixed phase of brushite and hydroxyapatite. In vitro, the CMC/CaP sheet induced osteoblast differentiation of human mesenchymal stromal cells (hMSCs), as shown by calcification and the upregulation of osteoblast marker genes. In absence of CaP, hMSCs on the CMC sheet had enhanced expression of alkaline phosphatase (ALP) only, indicative of early osteoblast differentiation. Finally, bone regeneration by the CMC/CaP sheet was demonstrated in a mouse calvarial defect model, based on micro-computed tomography (micro-CT), Masson’s trichrome staining, and immunostaining for osteoblast markers. Cells expressing the transcription factor Sp7/Osterix, which is essential for osteoblast differentiation, were detected around the new bone. The combined effect of CMC and CaP enhanced osteoblast differentiation and the CMC/CaP non-woven sheet was found to be an easy-to-handle and flexible scaffold for bone regeneration.
Hepatitis C virus (HCV) infection has been known to use autophagy for its replication. However, the mechanisms by which HCV modulates autophagy remain controversial. We used HCV-Japanese fulminant ...hepatitis-1-infected Huh7 cells. HCV infection induced the accumulation of autophagosomes. Morphological analyses of monomeric red fluorescent protein (mRFP)-green fluorescent protein (GFP) tandem fluorescent-tagged LC3 transfection showed HCV infection impaired autophagic flux. Autophagosome-lysosome fusion assessed by transfection of mRFP- or GFP-LC3 and immunostaining of lysosomal-associated membrane protein 1 was inhibited by HCV infection. Decrease of HCV-induced endoplasmic reticulum (ER) stress by 4-phenylbutyric acid, a chemical chaperone, improved the HCV-mediated autophagic flux impairment. HCV infection-induced oxidative stress and subsequently DNA damage, but not apoptosis. Furthermore, HCV induced cytoprotective effects against the cellular stress by facilitating the formation of cytoplasmic inclusion bodies as shown by p62 expression and by modulating keratin protein expression and activated nuclear factor erythroid 2-related factor 2. HCV eradication by direct-acting antivirals improved autophagic flux, but DNA damage persisted. In conclusion, HCV-induced ER stress correlates with autophagic flux impairment. Decrease of ER stress is considered to be a promising therapeutic strategy for HCV-related chronic liver diseases. However, we should be aware that the risk of hepatocarcinogenesis remains even after HCV eradication.
The liver is the major iron storage organ in the body, and therefore, iron metabolic disorder is sometimes involved in chronic liver diseases. Chronic hepatitis C is one of the liver diseases that ...show hepatic iron accumulation, even though its level should be recognized to be basically mild to moderate and sometimes within the normal range. The mechanisms underlying hepatic iron accumulation in chronic hepatitis C have not been fully elucidated. Reduction of the hepcidin transcription activity by hepatitis C virus (HCV)‐induced reactive oxygen species may in part account for it, but the regulation of hepcidin is very complex and may depend on many variables, including the particular stage of the systemic and/or hepatic inflammatory conditions and the circulating transferrin‐bound iron and intracellular iron stores. This might explain the variations in hepatic iron concentrations reported among patients with HCV‐related chronic liver disease. However, even mild‐to‐moderate iron overload in the liver contributes to disease progression and hepatocarcinogenesis in chronic hepatitis C probably by reinforcing the HCV‐induced oxidative stress through Fenton reaction. The present review highlights the current concept of hepatic iron overload status in chronic hepatitis C and discusses how iron metabolic disorder develops in this disease and the impact of hepatic iron overload on disease progression and its relevance to hepatocarcinogenesis.
Human adult dental pulp stem cells (DPSCs) are a type of mesenchymal stem cells (MSCs). Recently, DPSCs have been proposed as a new MSC source for treating immune-mediated, inflammatory, and ...degenerative diseases via cell-based therapy. Hence, large-scale industrial production of the required cell number will be necessary. In this study, to investigate the cationic surface charge effect on DPSC proliferation, we fabricated two types of 2-diethylaminoethyl -modified cellulose porous beads (CPB-DEAE) with different ion exchange capacities. The cationic surface charge effect increased with increase in DPSC proliferation rate for the ion exchange capacity of 0.55–1.82 meq/g. However, the DPSC proliferation rate decreased at 2.50 meq/g. Thus, the optimal ion exchange capacity was determined to be 1.82 meq/g for DPSC proliferation. Additionally, the total amount of protein produced from the DPSCs on the CPB-DEAE microcarriers was higher than that produced under the conventional monolayer culture conditions. Furthermore, the hepatocyte growth factor, which is one of the anti-inflammatory growth factors, was produced from the DPSCs on the CPB-DEAE microcarriers. Finally, the DPSCs were confirmed to maintain their proliferative and multidifferentiation ability after culture on the CPB-DEAE microcarriers. CPB-DEAE microcarriers have the potential to be used for large-scale MSC expansion and protein production.
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•Two types of DEAE modified microcarriers were prepared for DPSC culture.•DPSCs adhered and proliferated on DEAE modified microcarriers.•The optimal surface charge of microcarriers for DPSC proliferation was 1.82 meq/g.•DPSCs secreted hepatocyte growth factor on DEAE modified microcarriers.•DPSCs retained their multipotency after culture on DEAE modified microcarriers.
The aim of this study was to demonstrate the safety and efficacy of H2-saline infusion for treatment of rheumatoid arthritis (RA). We conducted a randomized, double-blind, placebo-controlled ...investigation of the infusion of 1ppm H2-dissolved saline (H2-saline) in 24 RA patients. Patients were randomized 1:1 to receive 500ml of either H2-saline or placebo-saline, which was drop infused intravenously (DIV) daily for 5days. The disease activity score in 28 joints (DAS28) was measured at baseline, immediately post infusion, and after 4weeks. Therapeutic effects of H2-saline on joint inflammation were estimated by measuring serum biomarkers for RA, tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), and urinary 8-hydroxydeoxyguanosine (8-OHdG). In the H2-infused group, average DAS28 decreased from 5.18±1.16 to 4.02±1.25 immediately post infusion and reached 3.74±1.22 after 4weeks. No significant decrease in DAS28 was observed in the placebo group throughout the study. IL-6 levels in the H2 group significantly decreased in 4 weeks by 37.3±62.0% compared to baseline, whereas it increased by 33.6±34.4% in the placebo group. TNFα levels did not change remarkably in the H2 or placebo groups in 4 weeks post-infusion compared to baseline. The relative ratio of 8-OHdG in the H2 group also significantly decreased by 4.7%. After 4weeks, MMP3 was significantly reduced by 19.2%±24.6% in the H2 group, and increased by 16.9%±50.2% in the placebo group. Drop infusion of H2 safely and effectively reduced RA disease activity.
•Intravenous infusion of H2-saline reduced the disease activities of RA.•Serum IL-6, serum MMP-3 and urinary 8-OHdG decreased due to infusion of H2-saline.•5days infusion of H2-saline was effective after 3weeks washout period.
There are several lines of evidence suggesting that oxidative stress is present in hepatitis C to a greater degree than in other inflammatory liver diseases and is closely related to disease ...progression. The main production site of reactive oxygen species (ROS) is assumed to be mitochondria, which concept is supported by evidence that hepatitis C virus (HCV) core protein is directly associated with them. The detoxification of ROS also is an important function of the cellular redox homeostasis system. These results draw our attention to how HCV‐induced mitochondrial ROS production is beyond redox regulation and affects the disease progression and development of hepatocellular carcinoma (HCC) in chronic hepatitis C. On the other hand, HCV‐related chronic liver diseases are characterized by metabolic alterations such as insulin resistance, hepatic steatosis and/or iron accumulation in the liver. These metabolic disorders also are relevant to the development of HCC in HCV‐related chronic liver diseases. Here, we review the mechanisms by which HCV increases mitochondrial ROS production and offer new insights as to how mitochondrial ROS are linked to metabolic disorders such as insulin resistance, hepatic steatosis and hepatic iron accumulation that are observed in HCV‐related chronic liver diseases.
Immune checkpoint inhibitors have shed light on the importance of antitumor immunity as a therapeutic strategy for hepatocellular carcinoma (HCC). The altered glucose metabolism known as the Warburg ...effect recently has gained attention as a cancer immune-resistance mechanism. Considering glycolysis inhibitors as therapeutic agents, their specific delivery to cancer cells is critical not to induce adverse effects. Thus, we investigated antitumor effects of a glycolysis inhibitor, consisting of 2-deoxy-D-glucose (2DG)-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (2DG-PLGA-NPs), against hepatocellular carcinoma in mice.
The antitumor effects of 2DG-PLGA-NPs were examined using hepatoma cell lines, xenograft tumors, and hepatocarcinogenic and syngeneic mouse models.
The 2DG-PLGA-NPs induced cytotoxic effects and antitumor immunity through enhanced T-cell trafficking. In addition, 2DG-PLGA-NPs induced decreased lactate production and increased interferon-γ–positive T cells in liver tumors. Human CD8+ T cells cocultured with 2DG-PLGA-NP–treated Huh7 cells showed their increased interferon-γ production and glucose uptake compared with the CD8+ T cells co-cultured with PLGA-NP–treated Huh7 cells. Chemotaxis of CD8+ T cells was suppressed by lactate and enhanced by glucose. Interferon-γ enhanced CD8+ T-cell chemotaxis in both an autocrine and paracrine manner. Notably, the 2DG-PLGA-NPs augmented chemokine (CXCL9/CXCL10) production in liver tumors via interferon-γ–Janus kinase–signal transducers and activator of transcription pathway and 5' adenosine monophosphate-activated protein kinase–mediated suppression of histone H3 lysine 27 trimethylation. These 2DG-PLGA-NPs not only amplified antitumor effects induced by sorafenib or an anti–programmed death-1 antibody, but also suppressed anti–programmed death-1–resistant tumors.
The newly developed 2DG-PLGA-NPs showed antitumor immunity and cytotoxicity in liver tumors in mice, suggesting the potential of 2DG-PLGA-NPs for future clinical applications.
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Non-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the ...14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker.
Eighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control. One patient was excluded due to low RT-PCR signal.
Compared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, low-density-lipoprotein cholesterol and non-high-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism-related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379.
Serum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.
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