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Selecting Cells for Bioartificial Liver Devices and the Importance of a 3D Culture Environment: A Functional Comparison between the HepaRG and C3A Cell Lines

Selecting Cells for Bioartificial Liver Devices and the Importance of a 3D Culture Environment: A Functional Comparison between the HepaRG and C3A Cell Lines

AAA: aromatic amino acids; ADP: adenosine diphosphate; AFP: alpha fetoprotein; ALB: albumin; ALF: Acute liver failure; AMC: Academic medical center; ARG1: Arginase 1; AST: aspartate aminotransferase; BAL: bioartificial liver; BCAA: branched chain amino acids; CAR: constitutive androstane receptor; CEBPA: CCAAT/enhancer- binding protein alpha; CPS1: carbamoyl phosphate synthetase 1; CYP2B6: cytochrome P450 2B6; CYP3A4: cytochrome P450 3A4; CYP3A7: cytochrome P450 3A7; FVII: blood coagulation factor VII; GLS1: Glutaminase1; GLS2: Glutaminase2; GLUL: glutamine synthetase; HNF4A: hepatic nuclear factor four-alpha; HPLC: High-performance liquid chromatography; LDH: lactate dehydrogenase; NTCP: Sodium/bile acid cotransporter; OTC: Ornithine transcarbamylase; PPH: primary porcine hepatocyte; PXR: Pregnane X receptor; qRT-PCR: quantitative reverse transcription- polymerase chain reaction; SLCO1B1: solute carrier organic anion transporter family member 1B1; TF: transferrin; UC: urea cycle.
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Nanostructured self-assembling peptides as a defined extracellular matrix for long-term functional maintenance of primary hepatocytes in a bioartificial liver modular device

Nanostructured self-assembling peptides as a defined extracellular matrix for long-term functional maintenance of primary hepatocytes in a bioartificial liver modular device

the liver, from minimal dose to maximum dose tolerance. Drug screening data obtained from unnatural conventional 2D systems is often confusing and matrigel, collagen based systems are often associated with unphysiological substances, while animal models are expensive, time consuming, and present ethical dilemmas. Herein, we reported a challeng- ing, alternative, novel, non-animal approach in a bioartificial liver modular platform to replace animal testing for assessing the chronic toxic effects of drug candidates to find out the observed primary toxic effects before further trials to the later clinical stage. The 3D defined hepatocyte culture system pres- ents the great challenge of maintaining hepatocyte cells for the extended period of time of up to 90 days that is required to assess the chronic toxic drug screening effects. The pres- ent proof of concept experiment generated great challenges with a new strategy (self-assembling peptides, growth factors, cytokines, enhanced oxygenation, and 3D signaling) for the long-term maintenance of primary hepatocytes in a bioar- tificial liver module using a defined microenvironment. We hope that this 3D interaction of growth factors and cytokines in nanostructured self-assembling peptides in a bioartificial liver modular device might add significant value to other existing toxicology screening devices as well as to the phar- maceutical industrial methodology, enabling more accurate toxicological assays and increasing the predictive accuracy during drug candidate screening. This 3D signaling can be useful in other existing micropatterned co-culture modules, 2
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A preliminary study for constructing a bioartificial liver device with induced pluripotent stem cell-derived hepatocytes

A preliminary study for constructing a bioartificial liver device with induced pluripotent stem cell-derived hepatocytes

A bioartificial liver (BAL) system is composed of bioreactors and embedded hepato- cytes that provide protein synthesis, ureogenesis, ureagenesis and glucogenesis, and de- toxification through P450 activity [8,10,11]. Various cell types, such as primary human hepatocytes, immortalized cell lines of C3A human hepatoblastoma cells, and cryopre- served porcine hepatocytes have been studied for BAL applications. Several studies of BAL use have been reported as clinical trials [12-15], although none of these BAL sys- tems has yet been approved by the FDA. Major problems of BAL systems include insuf- ficient supply of functional hepatocytes, premature death of hepatocytes by immune mechanisms, and the inadequate performance of devices for mass transfer [16].
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Novel spheroid reservoir bioartificial liver improves survival of nonhuman primates in a toxin-induced model of acute liver failure

Novel spheroid reservoir bioartificial liver improves survival of nonhuman primates in a toxin-induced model of acute liver failure

encephalopathy; H & E: hematoxylin and eosin; HGB: hemoglobin; HGF: hepatocyte growth factor; HR: heart rate; HSCs: hepatic stellate cells; HUVECs: human umbilical vein endothelial cells; ICP: intracranial pressure; IFN: interferon; IL: interleukin; IL-1RA: IL-1 receptor antagonist; KCs: Kupffer cells; LPS: lipopolysaccharide; MAP: mean artery pressure; MARS: molecular adsorbents recirculating system; M-CSF: macrophage colony-stimulating factor; MIF: macrophage migration inhibitory factor; MST: median survival time; PBMCs: peripheral blood mononuclear cells; PERV: porcine endogenous retrovirus; PLT: platelet; PT: prothrombin time; RBC: red blood cell; RR: respiratory rate; SRBAL: spheroid reservoir bioartificial liver; TB: total bilirubin; TLR-4: toll-like receptor-4; TNF: tumor necrosis factor; VEGF: vascular endothelial growth factor.
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In vitro Testing of a Novel Fibre-In-Fibre Bioartificial Liver (FIF-BAL) With Bovine Plasma

In vitro Testing of a Novel Fibre-In-Fibre Bioartificial Liver (FIF-BAL) With Bovine Plasma

Numerous groups worldwide are currently developing and evaluating BAL devices. Some designs have already reached clinical trials [1-3] whilst others are still under laboratory evaluation [4]. Some devices are perfused with whole blood [5] and others with plasma obtained by upstream plasmapheresis [6]. Many bioartificial liver support systems incorporate a means of oxygenating the perfusate in order to maintain cell function and viability. The oxygenation element may be integral within the reactor [7-9] or situated in series with the bioreactor in the circuit [10-11]. The latter is a more complicated alternative and costs more.
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Development of optimised cryopreservation protocol for encapsulated liver cell spheroids: towards delivery of a bioartificial liver

Development of optimised cryopreservation protocol for encapsulated liver cell spheroids: towards delivery of a bioartificial liver

Trolox, vitamin E, is lipophilic and closely associated with plasma membranes. Trolox is preferentially oxidised over poly-unsaturated fats in the plasma membrane and this provides its protective mechanism. Again, no literature could be found regarding the use of Trolox in liver cell cryopreservation protocols. However, Trolox has been shown to improve recovery of sperm cells as assessed using parameters including motility and mitochondrial membrane potential (Pena et al. 2004; Thuwanut et al. 2008). Unlike catalase, Trolox appears to be cytotoxic (as indicated by reduced viable cell numbers compared to the control when 5mM Trolox was used). It may be that due to Trolox’s association with the plasma membrane, prolonged exposure may lead to irreversible damaging alterations to ELS. These observations also raise an interesting point for cryopreservation strategies that interventions with antioxidants can have both positive and negative effects depending on dose and exposure time. Thus “blanket” application of antioxidants, without suitable dose range studies or consideration of the stage of cryopreservation at which they are administered, may not result in improvements (Dai & Meng 2011).
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NFkappaB prevents apoptosis and liver dysfunction during liver regeneration

NFkappaB prevents apoptosis and liver dysfunction during liver regeneration

Ad5I k B-infected animals was indicated by the increased am- monia level compared with the uninfected and Ad5LacZ- infected animals, which were indistinguishable after PH (Fig. 5 C). Thus, the pathophysiological sequelae of expression of the I k B superrepressor resulted in jaundice, as documented by in- creased total bilirubin, and liver dysfunction as documented by ammonia, both possibly the result of massive cell loss from apop- tosis, although more subtle metabolic changes in surviving cells cannot be ruled out. The lack of an increase in ALT re- flects the predominant mechanism of cell death, i.e., apoptosis, and not necrosis.
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A TIME TO ACT: IMPROVING LIVER HEALTH AND OUTCOMES IN LIVER DISEASE

A TIME TO ACT: IMPROVING LIVER HEALTH AND OUTCOMES IN LIVER DISEASE

The basis for all liver disease, or indeed the majority of chronic disease is identical and involves chronic inflammation. In order to explain to patients the effect of excess fat on their liver there is a simple analogy that many patients can understand as the basis of their disease, and it is as follows. “If you prick your hand with a needle just once, every day for a week, your hand will be a bit sore, maybe a bit red in places, but so what? If you prick it everyday for a year, your hand will be red and sore, with some areas that are quite inflamed. If you prick your hand everyday for 20 years it will look a mess, with scar tissue, areas of redness, and areas where your skin is trying to re-grow and recover.“ This is what we do to our livers everyday when we drink to excess, or if we are obese, or if we have chronic viral hepatitis. The pathology is basically the same. Insult (alcohol, virus or fat) causes mild degrees of inflammation and repair. In the liver, t is only when it is sustained that we get the end result of excessive scarring and areas of
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The association of liver function and quality of life of patients with liver cancer

The association of liver function and quality of life of patients with liver cancer

Liver cancer ranked the fifth most common cancer in the world, with 782,451 new cases per year in 2012. It was also the second leading cause of cancer death world- wide, responsible for 745,533 deaths in 2012. The ratio of mortality to incidence was 0.95, signifying its very aggressive nature and poor prognosis [1]. Screening population at risk for HCC by regular ultrasonography and alpha fetoprotein (AFP) level has been proven in one study to improve rate of early detection and increase the chances of curative treatment and survival [2]. How- ever, for most parts of the world, only opportunistic screening is offered to patients with chronic liver dis- eases [3]. Various management guidelines for HCC are available, these include the Barcelona Clinic Liver Can- cer staging classification and treatment approach for HCC (BCLC) [4, 5], Asia-Pacific Association for the Study of the Liver guidelines on the management of HCC (APASL) [6], European Association For The Study Of The Liver-European Organization For Research And Treatment Of Cancer clinical practice guidelines on management of HCC (EASL) [7], and the American As- sociation for the Study of Liver Diseases guidelines for the treatment of HCC (AASLD) [8]. These guidelines unanimously recommend that preserved liver function is an important pre-requisite to deliver effective treatment to HCC patients.
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Non-alcoholic fatty liver disease: an emerging liver disease

Non-alcoholic fatty liver disease: an emerging liver disease

The liver normally contains less than 5% of fat but under certain conditions excess fat may accumulate in the liver. Fatty liver can occur for many different reasons, the most known of which is excessive alcohol consumption. Other causes are the metabolic syndrome, obesity, protein- calorie malnutrition, starvation or rapid weight loss, total parenteral nutrition, various drugs such as Amiodarone, Tamoxifen, Glucocorticoids, Tetracycline, Oestrogens, Methotrexate and Thallium. Also certain types of metabolic disorders can cause fatty liver such as Wilson disease and Glycogen storage disorders. However, today, the most common cause is non-alcoholic fatty liver disease (NAFLD) which is a disorder closely related to the metabolic syndrome and obesity. NAFLD is increasing immensely in the western world and a similar trend is seen in Asian countries. Over the last 10 years, the prevalence of obesity has doubled among the adult population and tripled in children, and according to American national institutes of health (NIH), two thirds or up to as many as 85% of the American population is now overweight or obese. It is estimated that 75 % of the overweight population or those with type 2 diabetes have NAFLD. About 20% of those with NAFLD have an inflammation in the liver so called non-alcoholic steatohepatitis (NASH). Some studies show that among patients with non-NASH (simple steatosis and steatosis with inflammation), about 40% progress to fibrosis and over half developed NASH during 4-13 years follow-up [1, 2].
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Liver fibrosis

Liver fibrosis

angiotensin II) have opposite effects (67, 89). Endothelin-1, a pow- erful vasoconstrictor, stimulates fibrogenesis through its type A receptor (90). Among vasoactive cytokines, angiotensin II seems to play a major role in liver fibrogenesis. Angiotensin II is the effector peptide of the renin-angiotensin system, which is a major regulator of arterial pressure homeostasis in humans. Key components of this system are locally expressed in chronically injured livers, and acti- vated HSCs de novo generate angiotensin II (91, 92). Importantly, pharmacological and/or genetic ablation of the renin-angiotensin system markedly attenuates experimental liver fibrosis (70, 93–98). Angiotensin II induces hepatic inflammation and stimulates an array of fibrogenic actions in activated HSCs, including cell prolif- eration, cell migration, secretion of proinflammatory cytokines, and collagen synthesis (66, 99, 100). These actions are largely mediated by ROS generated by a nonphagocytic form of NADPH oxidase. Unlike the phagocytic type, NADPH oxidases present in fibrogenic cell types are constitutively active, producing relatively low levels of ROS under basal conditions and generating higher levels of oxidants in response to cytokines, stimulating redox-sensitive intracellular pathways. NADPH oxidase also plays a key role in the inflamma- tory actions of Kupffer cells (101). Disruption of an active NADPH oxidase protects mice from developing severe liver injury following prolonged alcohol intake and/or bile duct ligation (66, 102).
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Liver transplantation

Liver transplantation

Azathioprine used as 1 mg/kg/day is preferred in some institutions for patients transplanted with hepatitis C because of a slower fibrosis progression and reduced risk of decompensation of severe recur- rent disease, as recently shown in a randomized controlled trial with a median follow-up of 8 years and with protocol biopsies [58]. The prolonged use of azathioprine has been associated with an increased risk of nonmelanoma skin cancer, which may be explained by a dual mechanism, including an increased DNA damage powered by the inter- action between ultraviolet-A radiation and 6-thio- guanine, and an impaired DNA repair system [59,60]. The actual implication of nonmelanoma skin cancer, which usually is diagnosed at early stages, on prognosis is a matter of debate [61,62]. In inflammatory bowel disease patients treated with azathioprine, there is a four- to five-fold increased risk of lymphoproliferative disorders, especially in elderly patients, but still lymphoma is a very uncom- mon malignancy [63]. However, these data are hardly transferred to the liver transplant popu- lation, as doses of azathioprine are at least twice in patients with inflammatory bowel disease. The risk of Burkitt lymphoma is increased in liver trans- plantation patients compared with renal recipients according to a large registry from the USA, and azathioprine appeared as an independent risk factor in this cohort [20]. In liver transplantation patients, Benlloch et al. [64] retrospectively analyzed a single- institution experience (n ¼ 772) on the develop- ment of non-skin malignancy and the risk factors involved. They found azathioprine as an independ- ent predictor of any tumour development after liver transplantation (OR ¼ 3.8; 95% CI 1.7–8.6; P ¼ 0.004).
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Abnormal liver enzyme levels may signal liver damage

Abnormal liver enzyme levels may signal liver damage

travel to areas endemic for viral hepatitis or parenteral ex- posure may help identify the cause and should drive the subsequent investigation. Patients with suspected acute vi- ral hepatitis should be tested for IgM antibodies to hepati- tis A and hepatitus B core virus, hepatitis B surface anti- gens and hepatitis C virus (HCV) antibodies. Testing for hepatitis D infection should be limited to patients with ev- idence of hepatitis B surface antigens. If test results for HCV antibodies are negative and there is no evidence of acute hepatitis A or B infection, testing for HCV RNA may be a useful strategy since a recent study has demon- strated that, although these patients are rarely at risk of acute liver failure, they may benefit from early antiviral treatment. 34
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The effects of quercetin on liver regeneration after liver resection in rats

The effects of quercetin on liver regeneration after liver resection in rats

There are a number of studies in accordance with our results that indicate considerable decrease in the number of myenteric neurons in the colon and small intestine, as well as in the[r]

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A Comparative Study of Serum Cholinesterase and Liver Function Tests in Liver Disease

A Comparative Study of Serum Cholinesterase and Liver Function Tests in Liver Disease

Liver being the largest vital organ, has wide range of functions. Liver disease are one of the major causes of mortality in India and also worldwide. Biochemical tests of assessing the liver function, includes measurements of serum bilirubin, serum protein, serum albumin, serum aspartate transaminase, alanine transaminase and alkaline phosphatase. These tests often show abnormal results in patient with clinical conditions other than liver dysfunction.

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Effects of flavonoids on sphingolipid turnover in the toxin-damaged liver and liver cells

Effects of flavonoids on sphingolipid turnover in the toxin-damaged liver and liver cells

The mechanism by which the flavonoids could affect the sphingolipid turnover has not been explored. It is known that the generation of ceramide can be regulated by numerous factors. From the present study, two factors are worthy of discussion. First, it is known, that AP7Glu, LU7Glu and quercitin prevented the glutathione deple- tion and lipid peroxidation induced by an acute intoxica- tion with the CCl 4 or ethanol in the liver [13,14]. The flavonoids of chamomile (chamiloflan) normalized the ceramide levels soon after flavonoids addition to the toxin-treated hepatocytes or injection to the rats. The glu- tathione has been found to be a powerful negative regula- tor of neutral SMase activity in the different cells [9,10]. Thus, the flavonoids of chamiloflan could reduce the neu- tral SMase activity via the elevation of glutathione in the liver of the CCl 4 - or ethanol-treated rats or the isolated liver cells. Second, it is well known that the CCl 4 - induced production of the reactive oxygen species coincides with the phospholipase A 2 (PLA 2 ) activation and arachidonic acid (AA) release in the damaged liver cells [29]. AA is a known activator of SMase [30] and inhibitor of the ceram- idase activities in the different cells [31]. It has been deter- mined that the flavonoids, especially the apeginine and gurcetine are the inhibitors of PLA 2 activity in the toxin- damaged cells [32-34]. To summarize, the flavonoid- dependent PLA 2 inhibition may be responsible for the decreased neutral SMase and the increased ceramidase activities in the CCl 4 -treated liver cells. Further investiga- tions are needed to elucidate these conclusions.
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Complete Plasmodium falciparum liver stage development in liver chimeric mice

Complete Plasmodium falciparum liver stage development in liver chimeric mice

IFAs on infected liver sections demonstrated that P. falciparum LS developed in the FRG huHep mice. At day 3 after infection, spherical LS were detected using a circumsporozoite protein (CSP) antibody, which localizes to the parasite surface and, as expected, was expressed in a circumferential pattern (Figure 1A). Using an antibody specific for human FAH, it was evident that P. falciparum LS always grew within the huHeps (Figure 1A). DAPI staining showed between 4 and 8 nuclear centers on day 3 of LS, indicating that parasite DNA replication was progressing. At day 5 after infection, LS had further grown and maintained their near spherical shape. The parasites were specifically labeled with an antibody to exported protein-2 (EXP-2) (26) in a pattern indica- tive of PV localization (Figure 1B). EXP-2 was previously localized to the PV membrane (PVM) of blood stages (27). More recently, EXP-2 was shown to be part of the P. falciparum translocon of exported proteins (PTEX) (28), a translocon that is believed to be responsible for the trafficking of exported parasite proteins into the erythrocyte cytoplasm. A further protein component of the translocon is PTEX150, and interestingly, we also detected expres- sion of this protein at 5 days of LS development (Figure 1B). Its localization was similar to that seen for EXP-2 (Figure 1B). Thus, components of the translocon are present in LS and are local- ized to the PV. Day 5 LS still expressed CSP (Figure 1B), the tran- script of which was also detected at this time point in the SCID Alb-uPA huHep mouse LS infections (16). Day 5 LS also expressed PF10_0164 (ETRAMP10.3) (Figure 1B) in the PVM, the syntenic ortholog of the rodent malaria parasite gene coding for UIS4 (14). At day 7 after infection, we observed large multinucleated LS schizonts that had displaced the surrounding tissue. The LS were readily detected with EXP-2 and merozoite surface protein 1 (MSP1) antibodies (Figure 1, C and D). Codetection with the FAH antibody clearly showed the LS contained within a vastly expand- ed huHep with only remnant cytoplasm and a single nucleus pushed to the periphery of the infected cell (Figure 1C). The pattern of EXP-2 expression ceased to be circumferential, result- ing in a complex internal pattern of staining as seen in Figure 1C, likely due to EXP-2 expression being associated with the PV lumen at this developmental stage. The PVM markers EXP-1 and EXP-2 did not overlap in late LS parasites, indicating that EXP-1 remained in the PVM during late LS development, but EXP-2 did orthologs such as LS antigen 1 (LSA1) (13). Furthermore, studies
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Liver cirrhosis induces renal and liver phospholipase A2 activity in rats

Liver cirrhosis induces renal and liver phospholipase A2 activity in rats

While the role of prostanoids in the liver is ambiguous, at least exogeneous prostaglandins being protective but leukotri- enes, prostacyclin, and thromboxane being pathogenetically involved in cirrhogenesis and maintenance of portal hyperten- sion and hyperdynamic circulation, the situation appears much clearer in the kidney. Through their vasodilator effect, pros- taglandins modify intrarenal vascular resistance and thereby maintain glomerular filtration rate (74). Furthermore, they promote natriuresis and free water clearance (20, 22). This ex- plains the deleterious effect of cyclooxygenase inhibitors on renal function in cirrhosis (75).
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Echinocandins for management of invasive candidiasis in patients with liver disease and liver transplantation

Echinocandins for management of invasive candidiasis in patients with liver disease and liver transplantation

major differences between them largely related to the route of metabolism, half-life and safety. These are important in selecting appropriate agents in patients with LD. In this review, we have examined the epidemiology, risk factors and diagnosis of IC in patients with LD as well as in patients with liver transplantation. We have also studied the differ- ences between three available echinocandins for treating this group of patients.

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The effects of quercetin on liver regeneration after liver resection in rats

The effects of quercetin on liver regeneration after liver resection in rats

The aim of the present study was to assess the influence of quercetine (QE) on liver regeneration after partial hepatectomy (PH) in rats. A total of 24 male Wistar albino rats were divided into three groups: sham-operated (SH), PH and PH+QE; each group contain 8 animals. The rats in QE-treated groups were given QE (15 mg/kg body weight) once a day i.p., for 7 days starting 3 days prior to hepa- tectomy operation. At 7 days after resection, liver samples were collected. The malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were estimated in liver homogenates. Moreover, histopathological examination, mitotic index (MI), proliferating cell nuclear antigen labelling, proliferation index (PI), transferase-mediated dUTP nick end-labelling assay, apoptotic index (AI) were evaluated at 7 days after hepatectomy. As a result, QE significantly increased MI, PI, and significantly decreased AI in PH rats. Additionally, QE remarkably inhibited the elevation of MDA, restored impaired antioxidant SOD activity and GSH level, and also attenuated hepatic vacuolar degeneration and sinusoidal congestion. These results suggested that QE treatment had a beneficial effect on liver rege- nerative capacity of the remnant liver tissue after hepatectomy, probably due to its antioxidative, antiapoptotic and proliferative property. (Folia Morphol 2016; 75, 2: 179–187)
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