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9 pages, 537 KiB

Open AccessArticle

Liraglutide-Induced Hepatotoxicity

by Yaakov Maor, David Ergaz, Stephen D. H. Malnick, Ehud Melzer and Manuela G. Neuman

Biomedicines 2021, 9(2), 106; https://doi.org/10.3390/biomedicines9020106 - 22 Jan 2021

Cited by 9 | Viewed by 2959

Abstract

A 52-year-old woman with a BMI of 31.2 kg/m² was treated with the glucagon-like peptide 1 (GLP-1) agonist liraglutide as part of her weight-reduction program. Following this, she developed an idiosyncratic drug-related liver injury (IDILI). Advances in noninvasive techniques enabled this diagnosis [...] Read more.

A 52-year-old woman with a BMI of 31.2 kg/m² was treated with the glucagon-like peptide 1 (GLP-1) agonist liraglutide as part of her weight-reduction program. Following this, she developed an idiosyncratic drug-related liver injury (IDILI). Advances in noninvasive techniques enabled this diagnosis to be established. By employing easily quantifiable methods based on serum biomarkers, we could explore a wide variety of endpoints in assessing personalized DILI. In addition, we can test endpoints that are associated with the drug’s mechanism of action. Personalized medicine and therapeutic pharmacovigilance of incretin-based hypoglycemic agents are needed to ensure the safety of patients. Full article

(This article belongs to the Special Issue Experimental and Translational Research on Liver Disease)

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11 pages, 2103 KiB

Open AccessEditor’s ChoiceArticle

The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model

by Philipp Schwabl, Eva Hambruch, Grant R. Budas, Paul Supper, Michael Burnet, John T. Liles, Manfred Birkel, Ksenia Brusilovskaya, Philipp Königshofer, Markus Peck-Radosavljevic, William J. Watkins, Michael Trauner, David G. Breckenridge, Claus Kremoser and Thomas Reiberger

Biomedicines 2021, 9(1), 60; https://doi.org/10.3390/biomedicines9010060 - 09 Jan 2021

Cited by 38 | Viewed by 5570

Abstract

Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was [...] Read more.

Background: The farnesoid X receptor (FXR) influences hepatic metabolism, inflammation and liver fibrosis as key components of non-alcoholic steatohepatitis (NASH). We studied the effects of the non-steroidal FXR agonist cilofexor (formerly GS-9674) on portal pressure and fibrosis in experimental NASH. Methods: NASH was induced in Wistar rats using a choline-deficient high-fat diet plus intraperitoneal sodium nitrite injections. First, a dose-finding study was performed with 10 mg/kg and 30 mg/kg of cilofexor, focusing on histological readouts. Liver fibrosis was assessed by Picro-Sirius-Red, desmin staining and hepatic hydroxyproline content. Gene expression was determined by RT-PCR. In a subsequent hemodynamic study, rats received 30 mg/kg cilofexor with or without propranolol (25 mg/kg). Portal pressure, systemic hemodynamics and splanchnic blood flow were measured. Results: Cilofexor dose-dependently induced FXR target genes shp, cyp7a1 and fgf15 in hepatic and ileal tissues, paralleled by a dose-dependent reduction in liver fibrosis area (Picro-Sirius-Red) of −41% (10 mg/kg) and −69% (30 mg/kg), respectively. The 30 mg/kg cilofexor dose significantly reduced hepatic hydroxyproline content (−41%), expression of col1a1 (−37%) and pdgfr-β (−36%), as well as desmin area (−42%) in NASH rats. Importantly, cilofexor decreased portal pressure (11.9 ± 2.1 vs. 8.9 ± 2.2 mmHg; p = 0.020) without affecting splanchnic blood-flow or systemic hemodynamics. The addition of propranolol to cilofexor additionally reduced splanchnic inflow (−28%) but also mean arterial pressure (−25%) and heart rate (−37%). Conclusion: The non-steroidal FXR agonist cilofexor decreased portal hypertension and reduced liver fibrosis in NASH rats. While cilofexor seems to primarily decrease sinusoidal resistance in cirrhotic portal hypertension, the combination with propranolol additionally reduced mesenteric hyperperfusion. Full article

(This article belongs to the Special Issue Experimental and Translational Research on Liver Disease)

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7 pages, 737 KiB

Open AccessCommunication

Splenectomy Prior to Experimental Induction of Autoimmune Hepatitis Promotes More Severe Hepatic Inflammation, Production of IL-17 and Apoptosis

by Laura Elisa Buitrago-Molina, Janine Dywicki, Fatih Noyan, Martin Trippler, Julia Pietrek, Jerome Schlue, Michael P. Manns, Heiner Wedemeyer, Elmar Jaeckel and Matthias Hardtke-Wolenski

Biomedicines 2021, 9(1), 58; https://doi.org/10.3390/biomedicines9010058 - 09 Jan 2021

Cited by 6 | Viewed by 2860

Abstract

Autoimmune hepatitis (AIH) is detected at a late stage in the course of the disease. Therefore, induction and etiology are largely unclear. It is controversial if the induction of autoimmunity occurs in the liver or in the spleen. In our experimental murine AIH [...] Read more.

Autoimmune hepatitis (AIH) is detected at a late stage in the course of the disease. Therefore, induction and etiology are largely unclear. It is controversial if the induction of autoimmunity occurs in the liver or in the spleen. In our experimental murine AIH model, the induction of autoimmunity did not occur in the spleen. Instead, a protective role of the spleen could be more likely. Therefore, we splenectomized mice followed by induction of experimental murine AIH. Splenectomized mice presented more severe portal inflammation. Furthermore, these mice had more IL-17, IL-23 receptor (IL-23R) and caspase 3 (casp3) and a decreased amount of erythropoietin in serum, while intrahepatic T cell compartments were unaffected. These results indicate that the spleen is not necessary for induction of AIH, and splenectomy disrupts the ability to immune regulate the intensity of hepatic inflammation, production of IL-17 and apoptosis. Full article

(This article belongs to the Special Issue Experimental and Translational Research on Liver Disease)

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13 pages, 1603 KiB

Open AccessArticle

Characterization of Early-Stage Alcoholic Liver Disease with Hyperhomocysteinemia and Gut Dysfunction and Associated Immune Response in Alcohol Use Disorder Patients

by Vatsalya Vatsalya, Khushboo S. Gala, Ammar Z. Hassan, Jane Frimodig, Maiying Kong, Nachiketa Sinha and Melanie L. Schwandt

Biomedicines 2021, 9(1), 7; https://doi.org/10.3390/biomedicines9010007 - 24 Dec 2020

Cited by 7 | Viewed by 2646

Abstract

Heavy alcohol consumption can cause hyperhomocysteinemia, which could be consequential in the proinflammatory response and worsening of the neurobehavioral domains of alcohol use disorder (AUD), such as alcohol withdrawal. We examined the role of heavy drinking, hyperhomocysteinemia, gut dysfunction and inflammation in early-stage [...] Read more.

Heavy alcohol consumption can cause hyperhomocysteinemia, which could be consequential in the proinflammatory response and worsening of the neurobehavioral domains of alcohol use disorder (AUD), such as alcohol withdrawal. We examined the role of heavy drinking, hyperhomocysteinemia, gut dysfunction and inflammation in early-stage alcoholic liver disease (ALD) in AUD patients. A total of 110 AUD patients without clinical manifestations of liver injury were grouped by the serum homocysteine levels (SHL): normal ≤ 13 µmol/L (Group 1 (Gr.1); n = 80), and elevated > 13 µmol/L (Group 2 (Gr.2), n = 30). A comprehensive metabolic panel, SHL, a nutritional assessment, and drinking history assessed by the timeline followback questionnaire were evaluated. A subset analysis was performed on 47 subjects (Gr.1 n = 27; Gr.2 n = 20) for additional measures: Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score, plasma cytokines (interleukin-1β (IL-1β)), gut dysfunction markers (lipopolysaccharide (LPS), and LPS-binding protein (LBP)); 27% of the AUD patients exhibited hyperhomocysteinemia. SHL was significantly associated (p = 0.034) with heavy drinking days (HDD90). Subset analyses showed that the withdrawal ratings were both clinically and statistically (p = 0.033) elevated and significantly associated with hyperhomocysteinemia (p = 0.016) in Gr.2. LBP, IL1-β, SHL, and HDD90 showed significant cumulative effects (adjusted R² = 0.627) on withdrawal ratings in Gr.2 subset. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher in all Gr.2 patients; AUROC showed a fair level of true positivity for ALT (0.676), and AST (0.686). Il1-β, LBP, SHL, and HDD90 showed significant cumulative effects (adjusted R² = 0.554) on the elevated ALT in Gr.2 subset as well. The gut-brain derived proinflammatory response, patterns of heavy drinking, and hyperhomocysteinemia were closely associated with clinically elevated alcohol withdrawal and elevated liver injury. Hyperhomocysteinemia could have a potential phenotypic marker response indicative of early-stage ALD along with AUD. Full article

(This article belongs to the Special Issue Experimental and Translational Research on Liver Disease)

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15 pages, 3079 KiB

Open AccessArticle

Dietary-Induced Low-Grade Inflammation in the Liver

by Nicole Power Guerra, Luisa Müller, Kristin Pilz, Annika Glatzel, Daniel Jenderny, Deborah Janowitz, Brigitte Vollmar and Angela Kuhla

Biomedicines 2020, 8(12), 587; https://doi.org/10.3390/biomedicines8120587 - 09 Dec 2020

Cited by 12 | Viewed by 2911

Abstract

The literature describes a close correlation between metabolic disorders and abnormal immune responses, like low-grade inflammation (LGI), which may be one mechanistic link between obesity and various comorbidities, including non-alcoholic fatty liver disease (NAFLD). In our study, we investigated the influence of dietary [...] Read more.

The literature describes a close correlation between metabolic disorders and abnormal immune responses, like low-grade inflammation (LGI), which may be one mechanistic link between obesity and various comorbidities, including non-alcoholic fatty liver disease (NAFLD). In our study, we investigated the influence of dietary composition on obesity-derived LGI in the liver. We used a dietary induced obesity mouse model of C57BL/6J mice fed with high fat diet (HFD, 60% fat, 20% protein, 20% carbohydrates) and two different controls. One was rich in carbohydrates (10% fat, 20% protein, 70% carbohydrates), further referred to as the control diet (CD), and the other one is referred to as the standard diet (SD), with a more balanced macronutrient content (9% fat, 33% protein, 58% carbohydrates). Our results showed a significant increased NAFLD activity score in HFD compared to both controls, but livers of the CD group also differed in their macroscopic appearance from healthy livers. Hepatic fat content showed significantly elevated cholesterol concentrations in the CD group. Histologic analysis of the cellular immune response in the liver showed no difference between HFD and CD and expression analysis of immunologic mediators like interleukin (IL)-1β, IL-6, IL-10 and tumor necrosis factor alpha also point towards a pro-inflammatory response to CD, comparable to LGI in HFD. Therefore, when studying diet-induced obesity with a focus on inflammatory processes, we encourage researchers to carefully select controls and not use a control diet disproportionally rich in carbohydrates. Full article

(This article belongs to the Special Issue Experimental and Translational Research on Liver Disease)

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Review

Jump to: Research, Other

11 pages, 1146 KiB

Open AccessReview

HuR Protein in Hepatocellular Carcinoma: Implications in Development, Prognosis and Treatment

by Vasiliki Papatheofani, Georgia Levidou, Panagiotis Sarantis, Evangelos Koustas, Michalis V. Karamouzis, Alexandros Pergaris, Gregorios Kouraklis and Stamatios Theocharis

Biomedicines 2021, 9(2), 119; https://doi.org/10.3390/biomedicines9020119 - 27 Jan 2021

Cited by 17 | Viewed by 2620

Abstract

Hu-antigen R (HuR) is a post-transcriptional regulator that belongs to the embryonic lethal abnormal vision Drosophila-like family (ELAV). HuR regulates the stability, translation, subcellular localization, and degradation of several target mRNAs, which are implicated in carcinogenesis and could affect therapeutic options. HuR protein [...] Read more.

Hu-antigen R (HuR) is a post-transcriptional regulator that belongs to the embryonic lethal abnormal vision Drosophila-like family (ELAV). HuR regulates the stability, translation, subcellular localization, and degradation of several target mRNAs, which are implicated in carcinogenesis and could affect therapeutic options. HuR protein is consistently highly expressed in hepatocellular carcinoma (HCC) compared to the adjacent normal liver tissue and is involved in the post-transcriptional regulation of various genes implicated in liver malignant transformation. Additionally, HuR protein seems to be a putative prognosticator in HCC, predicting worse survival. This review summarizes the recent evidence regarding the role of HuR in primary liver tumors, as presented in clinical studies, in vitro experiments and in vivo animal models. In conclusion, our review supports the consistent role of HuR protein in the development, prognosis, and treatment of HCC. Additional studies are expected to expand current information and exploit its putative employment as a future candidate for more personalized treatment in these tumors. Full article

(This article belongs to the Special Issue Experimental and Translational Research on Liver Disease)

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18 pages, 1073 KiB

Open AccessReview

Checkpoint Inhibitors and Hepatotoxicity

by Stephen D. H. Malnick, Ali Abdullah and Manuela G. Neuman

Biomedicines 2021, 9(2), 101; https://doi.org/10.3390/biomedicines9020101 - 21 Jan 2021

Cited by 18 | Viewed by 3395

Abstract

Uncontrolled immune response to a pathogen or any protein can lead to tissue damage and autoimmune diseases, that represent aberrant immune responses of the individual to its own cells and/or proteins. The immune checkpoint system is the regulatory mechanism that controls immune responses. [...] Read more.

Uncontrolled immune response to a pathogen or any protein can lead to tissue damage and autoimmune diseases, that represent aberrant immune responses of the individual to its own cells and/or proteins. The immune checkpoint system is the regulatory mechanism that controls immune responses. Tumor cells escape the immune surveillance mechanism, avoiding immune detection and elimination by activating these checkpoints and suppressing the anti-tumor response, thus allowing formation of tumors. Antigenic modulation facilitates masking and contributes to the escape of tumor cells. In addition, there are growing cell promoters, like transforming growth factor β (TGF-β), contributing to escape mechanisms. Targeting the immunological escape of malignant cells is the basis of immune oncology. Checkpoint inhibitors, cytokines and their antibodies may enhance the immune system’s response to tumors. Currently, immunomodulatory agents have been designed, evaluated in clinical trials and have been approved by both European and United States Drug Agencies. The present review is a reflection of the increasingly important role of the checkpoint inhibitors. Our aim is to review the side effects with the emphasis on hepatic adverse reactions of these novel biological drug interventions. Full article

(This article belongs to the Special Issue Experimental and Translational Research on Liver Disease)

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21 pages, 1008 KiB

Open AccessReview

Circulating Long and Circular Noncoding RNA as Non-Invasive Diagnostic Tools of Hepatocellular Carcinoma

by Caecilia H. C. Sukowati, Loraine Kay D. Cabral, Claudio Tiribelli and Devis Pascut

Biomedicines 2021, 9(1), 90; https://doi.org/10.3390/biomedicines9010090 - 19 Jan 2021

Cited by 27 | Viewed by 3768

Abstract

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide, partially due to late diagnosis of the disease. Growing evidence in the field of biomarker discovery has shown the promising use of nucleic acid in the early detection of [...] Read more.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide, partially due to late diagnosis of the disease. Growing evidence in the field of biomarker discovery has shown the promising use of nucleic acid in the early detection of many cancers, including HCC. Here, we review data on how various long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) could be used as a diagnostic tool for HCC being differentially expressed in HCC compared to non-HCC patients. These non-coding RNAs (ncRNAs) showed high stability in the blood being present as free-circulating molecules or encapsulated into exosomes. This review reports some recent evidence on the use of lncRNAs and circRNAs as possible diagnostic biomarkers for HCC. Further, their pathophysiological mechanism in liver carcinogenesis was also described, elucidating the complex regulatory networks making these ncRNAs of particular relevance for the study of liver malignancy cancer. Full article

(This article belongs to the Special Issue Experimental and Translational Research on Liver Disease)

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17 pages, 516 KiB

Open AccessReview

Biomarkers in Hepatocellular Carcinoma: Current Status and Future Perspectives

by Yasi Pan, Huarong Chen and Jun Yu

Biomedicines 2020, 8(12), 576; https://doi.org/10.3390/biomedicines8120576 - 07 Dec 2020

Cited by 35 | Viewed by 5953

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and one of the leading causes of cancer-related death worldwide. HCC is highly heterogeneous, both within the tumor and among individuals, which is closely related to the HCC surveillance, diagnosis, prognosis, and treatment [...] Read more.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and one of the leading causes of cancer-related death worldwide. HCC is highly heterogeneous, both within the tumor and among individuals, which is closely related to the HCC surveillance, diagnosis, prognosis, and treatment response. With the advances of next-generation sequencing, the genomic landscape of HCC has been identified which vastly improves our understanding of genetic and epigenetic changes and their interaction during HCC development. In particular, gene mutations, epigenetic modifications, aberrant expression of coding and non-coding RNAs have been extensively explored and many of them are considered as biomarkers for HCC. Most recently, the gut microbiome has been proposed as potential non-invasive biomarkers for HCC diagnosis. In this review, we summarize the current development of HCC biomarkers studies and provide insights on further steps towards precision medicine of HCC. Full article

(This article belongs to the Special Issue Experimental and Translational Research on Liver Disease)

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15 pages, 1395 KiB

Open AccessReview

Potential Use of Anti-Inflammatory Synthetic Heparan Sulfate to Attenuate Liver Damage

by Katelyn Arnold, Yi-En Liao and Jian Liu

Biomedicines 2020, 8(11), 503; https://doi.org/10.3390/biomedicines8110503 - 16 Nov 2020

Cited by 6 | Viewed by 3607

Abstract

Heparan sulfate is a highly sulfated polysaccharide abundant on the surface of hepatocytes and surrounding extracellular matrix. Emerging evidence demonstrates that heparan sulfate plays an important role in neutralizing the activities of proinflammatory damage associate molecular patterns (DAMPs) that are released from hepatocytes [...] Read more.

Heparan sulfate is a highly sulfated polysaccharide abundant on the surface of hepatocytes and surrounding extracellular matrix. Emerging evidence demonstrates that heparan sulfate plays an important role in neutralizing the activities of proinflammatory damage associate molecular patterns (DAMPs) that are released from hepatocytes under pathological conditions. Unlike proteins and nucleic acids, isolation of homogenous heparan sulfate polysaccharides from biological sources is not possible, adding difficulty to study the functional role of heparan sulfate. Recent advancement in the development of a chemoenzymatic approach allows production of a large number of structurally defined oligosaccharides. These oligosaccharides are used to probe the physiological functions of heparan sulfate in liver damage under different pathological conditions. The findings provide a potential new therapeutic agent to treat liver diseases that are associated with excessive inflammation. Full article

(This article belongs to the Special Issue Experimental and Translational Research on Liver Disease)

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Other

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10 pages, 4447 KiB

Open AccessCase Report

Denosumab-Induced Immune Hepatitis

by Viviana Ostrovsky, Stephen Malnick, Shahar Ish-Shalom, Nadya Ziv Sokolowskaia, Ady Yosepovich and Manuela Neuman

Biomedicines 2021, 9(1), 76; https://doi.org/10.3390/biomedicines9010076 - 14 Jan 2021

Cited by 5 | Viewed by 3520

Abstract

Denosumab–Prolia®, Xgeva® (Amgen) is a fully human antibody to the receptor activator of the nuclear factor-K ligand (RANKL). Hepatotoxicity is extremely rare, with only one reported case of immune origin. We present a second case of hepatotoxicity resulting from an immune reaction to [...] Read more.

Denosumab–Prolia®, Xgeva® (Amgen) is a fully human antibody to the receptor activator of the nuclear factor-K ligand (RANKL). Hepatotoxicity is extremely rare, with only one reported case of immune origin. We present a second case of hepatotoxicity resulting from an immune reaction to denosumab. A 43-year-old female was referred to the Endocrinology, Diabetes & Metabolism Department for treatment of low bone mineral density (BMD) following endocrine therapy with letrozole and lucrin because of breast cancer. She developed premature menopause at the age of 36 years when she underwent a left lumpectomy due to an infiltrating duct carcinoma of the breast (T1 NO MO) and was subsequently started on endocrine therapy. Denosumab was started to prevent osteoporosis. On the third year after starting on denosumab and one month after she received the last injection, she became ill. The routine biochemical analysis showed that the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) rose appreciatively to 10 times the upper limit of normal (ULN). The gamma-glutamyl transferase (GGT) level was elevated slightly to 67 U/L (0–38 U/L). The serum gamma-globulin level was elevated to 1.72 g/dL (0.7–1.6 gr/dl), while the total bilirubin (TB) and serum albumin levels were normal. A liver biopsy revealed a moderate to severe chronic inflammatory infiltrate containing MUM-1 positive plasma cells. In addition, numerous CD-3 positive small T lymphocytes and few CD-20 positive B lymphocytes and eosinophils were seen in the portal tracts. Moderate to severe interface hepatitis, bile duct proliferation and mild portal fibrosis were also identified. The results could be consistent with the diagnosis of drug-induced liver injury (DILI). Full article

(This article belongs to the Special Issue Experimental and Translational Research on Liver Disease)

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