Role of FGF15 in Hepatic Surgery in the Presence of Tumorigenesis: Dr. Jekyll or Mr. Hyde?

The pro-tumorigenic activity of fibroblast growth factor (FGF) 19 (FGF15 in its rodent orthologue) in hepatocellular carcinoma (HCC), as well as the unsolved problem that ischemia-reperfusion (IR) injury supposes in liver surgeries, are well known. However, it has been shown that FGF15 administration protects against liver damage and regenerative failure in liver transplantation (LT) from brain-dead donors without tumor signals, providing a benefit in avoiding IR injury. The protection provided by FGF15/19 is due to its anti-apoptotic and pro-regenerative properties, which make this molecule a potentially beneficial or harmful factor, depending on the disease. In the present review, we describe the preclinical models currently available to understand the signaling pathways responsible for the apparent controversial effects of FGF15/19 in the liver (to repair a damaged liver or to promote tumorigenesis). As well, we study the potential pharmacological use that has the activation or inhibition of FGF15/19 pathways depending on the disease to be treated. We also discuss whether FGF15/19 non-pro-tumorigenic variants, which have been developed for the treatment of liver diseases, might be promising approaches in the surgery of hepatic resections and LT using healthy livers and livers from extended-criteria donors.

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The Role of Endoglin in Hepatocellular Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22063208 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3208

Author(s):

Kuo-Shyang Jeng ◽

I-Shyan Sheen ◽

Shu-Sheng Lin ◽

Chuen-Miin Leu ◽

Chiung-Fang Chang

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Diseases ◽

Transforming Growth Factor ◽

Antiangiogenic Therapy ◽

Transforming Growth Factor Β ◽

Postoperative Recurrence ◽

Transmembrane Glycoprotein ◽

Early Progression

Endoglin (CD105) is a type-1 integral transmembrane glycoprotein and coreceptor for transforming growth factor-β (TGF-β) ligands. The endoglin/TGF-β signaling pathway regulates hemostasis, cell proliferation/migration, extracellular matrix (ECM) synthesis and angiogenesis. Angiogenesis contributes to early progression, invasion, postoperative recurrence, and metastasis in hepatocellular carcinoma (HCC), one of the most widespread malignancies globally. Endoglin is overexpressed in newly formed HCC microvessels. It increases microvessel density in cirrhotic and regenerative HCC nodules. In addition, circulating endoglin is present in HCC patients, suggesting potential for use as a diagnostic or prognostic factor. HCC angiogenesis is dynamic and endoglin expression varies by stage. TRC105 (carotuximab) is an antibody against endoglin, and three of its clinical trials were related to liver diseases. A partial response was achieved when combining TRC105 with sorafenib. Although antiangiogenic therapy still carries some risks, combination therapy with endoglin inhibitors or other targeted therapies holds promise.

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The cGAS-STING Pathway: Novel Perspectives in Liver Diseases

Frontiers in Immunology ◽

10.3389/fimmu.2021.682736 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dongwei Xu ◽

Yizhu Tian ◽

Qiang Xia ◽

Bibo Ke

Keyword(s):

Liver Disease ◽

Cyclic Gmp ◽

Liver Diseases ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Innate Immune ◽

Microbial Pathogens ◽

Hepatic Ischemia ◽

Sting Pathway

Liver diseases represent a major global health burden accounting for approximately 2 million deaths per year worldwide. The liver functions as a primary immune organ that is largely enriched with various innate immune cells, including macrophages, dendritic cells, neutrophils, NK cells, and NKT cells. Activation of these cells orchestrates the innate immune response and initiates liver inflammation in response to the danger signal from pathogens or injured cells and tissues. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial signaling cascade of the innate immune system activated by cytosol DNA. Recognizing DNA as an immune-stimulatory molecule is an evolutionarily preserved mechanism in initiating rapid innate immune responses against microbial pathogens. The cGAS is a cytosolic DNA sensor eliciting robust immunity via the production of cyclic GMP-AMPs that bind and activate STING. Although the cGAS-STING pathway has been previously considered to have essential roles in innate immunity and host defense, recent advances have extended the role of the cGAS-STING pathway to liver diseases. Emerging evidence indicates that overactivation of cGAS-STING may contribute to the development of liver disorders, implying that the cGAS-STING pathway is a promising therapeutic target. Here, we review and discuss the role of the cGAS-STING DNA-sensing signaling pathway in a variety of liver diseases, including viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary hepatocellular cancer (HCC), and hepatic ischemia-reperfusion injury (IRI), with highlights on currently available therapeutic options.

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Role of high molecular weight isoforms of fibroblast growth factor-2 (FGF-2) in cardiac ischemia–reperfusion injury (I/R)

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2007.03.601 ◽

2007 ◽

Vol 42 (6) ◽

pp. S198 ◽

Cited By ~ 1

Author(s):

Siyun Liao ◽

Gilbert Newman ◽

Thomas Doetschman ◽

Jo El J. Schultz

Keyword(s):

Molecular Weight ◽

Growth Factor ◽

Reperfusion Injury ◽

Fibroblast Growth Factor ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Cardiac Ischemia ◽

Fibroblast Growth Factor 2 ◽

Fibroblast Growth

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Data on Adiponectin from 2010 to 2020: Therapeutic Target and Prognostic Factor for Liver Diseases?

International Journal of Molecular Sciences ◽

10.3390/ijms21155242 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5242 ◽

Cited By ~ 2

Author(s):

Misaq Heydari ◽

María Eugenia Cornide-Petronio ◽

Mónica B. Jiménez-Castro ◽

Carmen Peralta

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Liver Disease ◽

Therapeutic Target ◽

Liver Diseases ◽

Therapeutic Strategies ◽

Potential Therapeutic Target ◽

Surgical Interventions ◽

Scientific Controversies

The review describes the role of adiponectin in liver diseases in the presence and absence of surgery reported in the literature in the last ten years. The most updated therapeutic strategies based on the regulation of adiponectin including pharmacological and surgical interventions and adiponectin knockout rodents, as well as some of the scientific controversies in this field, are described. Whether adiponectin could be a potential therapeutic target for the treatment of liver diseases and patients submitted to hepatic resection or liver transplantation are discussed. Furthermore, preclinical and clinical data on the mechanism of action of adiponectin in different liver diseases (nonalcoholic fatty disease, alcoholic liver disease, nonalcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma) in the absence or presence of surgery are evaluated in order to establish potential targets that might be useful for the treatment of liver disease as well as in the practice of liver surgery associated with the hepatic resections of tumors and liver transplantation.

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The Role of IL-1 Family Members and Kupffer Cells in Liver Regeneration

BioMed Research International ◽

10.1155/2016/6495793 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 13

Author(s):

Quanhui Tan ◽

Jianjun Hu ◽

Xiaolan Yu ◽

Wen Guan ◽

Huili Lu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Regeneration ◽

Receptor Antagonist ◽

Kupffer Cells ◽

Liver Diseases ◽

Close Association ◽

Interleukin 1 ◽

Family Members ◽

Systemic Review

Interleukin-1 (IL-1) family and Kupffer cells are linked with liver regeneration, but their precise roles remain unclear. IL-1 family members are pleiotropic factors with a range of biological roles in liver diseases, inducing hepatitis, cirrhosis, and hepatocellular carcinoma, as well as liver regeneration. Kupffer cells are the main source of IL-1 and IL-1 receptor antagonist (IL-1Ra), the key members of IL-1 family. This systemic review highlights a close association of IL-1 family members and Kupffer cells with liver regeneration, although their specific roles are inconclusive. Moreover, IL-1 members are proposed to induce effects on liver regeneration through Kupffer cells.

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The Role of IL-35 in the Pathophysiological Processes of Liver Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2020.569575 ◽

2021 ◽

Vol 11 ◽

Author(s):

Shuang Hu ◽

Pan-pan Lian ◽

Ying Hu ◽

Xing-yu Zhu ◽

Shao-wei Jiang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cirrhosis ◽

Liver Diseases ◽

T Regulatory Cells ◽

Liver Inflammation ◽

Regulatory Cells ◽

Anti Inflammatory ◽

Lipid Metabolic Disorder ◽

Environmental Attack

It is known that liver diseases have several characteristics of massive lipid accumulation and lipid metabolic disorder, and are divided into liver inflammation, liver fibrosis, liver cirrhosis (LC), and hepatocellular carcinoma (HCC) in patients. Interleukin (IL)-35, a new-discovered cytokine, can protect the liver from the environmental attack by increasing the ratio of Tregs (T regulatory cells) which can increase the anti-inflammatory cytokines and inhibit the proliferation of immune cellular. Interestingly, two opposite mechanisms (pro-inflammatory and anti-inflammatory) have connection with the ultimate formation of liver diseases, which suggest that IL-35 may play crucial function in the process of liver diseases through immunosuppressive regulation. Besides, some obvious advantages also imply that IL-35 can be considered as a new therapeutic target to control the progression of liver diseases, while its mechanism of function still needs further research.

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Emerging Role of Interleukins for the Assessment and Treatment of Liver Diseases

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530321666211124102837 ◽

2021 ◽

Vol 21 ◽

Author(s):

Aaliya L. Ali ◽

Namrata P. Nailwal ◽

Gaurav M. Doshi

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trial ◽

Liver Disease ◽

Alcoholic Liver Disease ◽

Liver Diseases ◽

Clinical Trial Data ◽

Trial Data ◽

Alcoholic Fatty Liver ◽

Assessment And Treatment

Background: The most common liver diseases are fibrosis, alcoholic liver disease, non-alcoholic fatty disease, viral hepatitis, and hepatocellular carcinoma. These liver diseases account for approximately 2 million deaths per year worldwide, with cirrhosis accounting for 2.1% of the worldwide burden. The most widely used liver function tests for diagnosis are alanine transaminase, aspartate transaminase, serum proteins, serum albumin, and serum globulins, whereas antivirals and corticosteroids have been proven to be useful for the treatment of liver diseases. A major disadvantage of these diagnostic measures is the lack of specificity to a particular tissue or cell type, as these enzymes are common to one or more tissues. The major adverse effect of current treatment methods is drug resistance. To overcome these issues, interleukins have been investigated. The balance of these interleukins determines the outcome of an immune response. Interleukins are considered interesting therapeutic targets for the treatment of liver diseases. In this review, we summarize the current state of knowledge regarding interleukins in the diagnosis, treatment, and pathogenesis of different acute and chronic liver diseases. Objective: To understand the role of interleukins in the assessment and treatment of different types of liver diseases. Methods: A literature search was conducted using PubMed, Science Direct, and NCBI with the following keywords: Interleukins, Acute Liver Failure, Alcoholic Liver Disease, Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, Hepatocellular Carcinoma, Inflammation, Liver injury, Hepatoprotective effect. Clinical trial data on these interleukins have been searched on Clinicaltrials.gov. Results: Existing literature and preclinical and clinical trial data demonstrate that interleukins play a crucial role in the pathogenesis of liver diseases. Conclusion: Our findings indicate that IL-1, IL-6, IL-10, IL-17, IL-22, IL-35, and IL-37 are involved in the progression and control of various liver conditions via the regulation of cell signaling pathways. However, further investigation on the involvement of these interleukins is necessary for their use as a targeted therapy in liver diseases.

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Endocannabinoids and Liver Disease. III. Endocannabinoid effects on immune cells: implications for inflammatory liver diseases

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00523.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. G850-G854 ◽

Cited By ~ 27

Author(s):

Pál Pacher ◽

Bin Gao

Keyword(s):

Immune Cells ◽

Liver Diseases ◽

Ischemia Reperfusion ◽

Endocannabinoid System ◽

Inflammatory Cells ◽

The Novel ◽

Liver Inflammation ◽

Cirrhotic Cardiomyopathy ◽

Therapeutic Benefits

Recent studies have implicated dysregulation of the endocannabinoid system in various liver diseases and their complications (e.g., hepatitis, fibrosis, cirrhosis, cirrhotic cardiomyopathy, and ischemia-reperfusion), and demonstrated that its modulation by either cannabinoid 2 (CB2) receptor agonists or CB1 antagonists may be of significant therapeutic benefits. This review is aimed to focus on the triggers and sources of endocannabinoids during liver inflammation and on the novel role of CB2 receptors in the interplay between the activated endothelium and various inflammatory cells (leukocytes, lymphocytes, etc.), which play pivotal role in the early development and progression of inflammatory and other liver diseases.

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