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Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of nuclear receptors that could serve as lipid sensors. PPARγ is the target of a group of insulin sensitizers called thiazolidinediones (TZDs) which regulate the expression of genes involved in glucose and lipid metabolism as well as adipokines that regulate metabolic function in other tissues. Non-alcoholic fatty liver disease (NAFLD) has a high prevalence worldwide and is even higher in patients with obesity and insulin resistance. TZD-mediated activation of PPARγ could serve as a good treatment for NAFLD because TZDs have shown antifibrogenic and anti-inflammatory effects in vitro and increase insulin sensitivity in peripheral tissues which improves liver pathology. However, mechanistic studies in mouse models suggest that the activation of PPARγ in hepatocytes might reduce or limit the therapeutic potential of TZD against NAFLD. In this review, we briefly describe the short history of PPAR isoforms, the relevance of their expression in different tissues, as well as the pathogenesis and potential therapeutics for NAFLD. We also discuss some evidence derived from mouse models that could be useful for endocrinologists to assess tissue-specific roles of PPARs, complement reverse endocrinology approaches, and understand the direct role that PPARγ has in hepatocytes and non-parenchymal cells. [ABSTRACT FROM AUTHOR]

Primary liver cancers (PLC), including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are among the leading causes of cancer-related mortality worldwide. Bi-dimensional in vitro models are unable to recapitulate the key features of PLC; consequently, recent advancements in three-dimensional in vitro systems, such as organoids, opened up new avenues for the development of innovative models for studying tumour's pathological mechanisms. Liver organoids show self-assembly and self-renewal capabilities, retaining essential aspects of their respective in vivo tissue and allowing modelling diseases and personalized treatment development. In this review, we will discuss the current advances in the field of liver organoids focusing on existing development protocols and possible applications in regenerative medicine and drug discovery. [ABSTRACT FROM AUTHOR]

While epidemiological data have greatly contributed to the estimation of the dose and dose-rate effectiveness factor (DDREF) for human populations, studies using animal models have made significant contributions to provide quantitative data with mechanistic insights. The current article aims at compiling the animal studies, specific to rodents, with reference to the dose-rate effects of cancer development. This review focuses specifically on the results that explain the biological mechanisms underlying dose-rate effects and their potential involvement in radiation-induced carcinogenic processes. Since the adverse outcome pathway (AOP) concept together with the key events holds promise for improving the estimation of radiation risk at low doses and low dose-rates, the review intends to scrutinize dose-rate dependency of the key events in animal models and to consider novel key events involved in the dose-rate effects, which enables identification of important underlying mechanisms for linking animal experimental and human epidemiological studies in a unified manner. [ABSTRACT FROM AUTHOR]

Fibrosis describes a dysregulated tissue remodelling response to persistent cellular injury and is the final pathological consequence of many chronic diseases that affect the liver, kidney and lung. Nicotinamide adenine dinucleotide phosphate (NADPH)‐oxidase (NOX) enzymes produce reactive oxygen species (ROS) as their primary function. ROS derived from NOX1 and NOX4 are key mediators of liver, kidney and lung fibrosis. Setanaxib (GKT137831) is a first‐in‐class, dual inhibitor of NOX1/4 and is the first NOX inhibitor to progress to clinical trial investigation. The anti‐fibrotic effects of setanaxib in liver, kidney and lung fibrosis are supported by multiple lines of pre‐clinical evidence. However, despite advances in our understanding, the precise roles of NOX1/4 in fibrosis require further investigation. Additionally, there is a translational gap between the pre‐clinical observations of setanaxib to date and the applicability of these to human patients within a clinical setting. This narrative review critically examines the role of NOX1/4 in liver, kidney and lung fibrosis, alongside the available evidence investigating setanaxib as a therapeutic agent in pre‐clinical models of disease. We discuss the potential clinical translatability of this pre‐clinical evidence, which provides rationale to explore NOX1/4 inhibition by setanaxib across various fibrotic pathologies in clinical trials involving human patients. [ABSTRACT FROM AUTHOR]

The liver is the central metabolic organ of the body. The plethora of anabolic and catabolic pathways in the liver is tightly regulated by physiological signaling but may become imbalanced as a consequence of malnutrition or exposure to certain chemicals, so-called metabolic endocrine disrupters, or metabolism-disrupting chemicals (MDCs). Among different metabolism-related diseases, obesity and non-alcoholic fatty liver disease (NAFLD) constitute a growing health problem, which has been associated with a western lifestyle combining excessive caloric intake and reduced physical activity. In the past years, awareness of chemical exposure as an underlying cause of metabolic endocrine effects has continuously increased. Within this review, we have collected and summarized evidence that certain environmental MDCs are capable of contributing to metabolic diseases such as liver steatosis and cholestasis by different molecular mechanisms, thereby contributing to the metabolic syndrome. Despite the high relevance of metabolism-related diseases, standardized mechanistic assays for the identification and characterization of MDCs are missing. Therefore, the current state of candidate test systems to identify MDCs is presented, and their possible implementation into a testing strategy for MDCs is discussed. [ABSTRACT FROM AUTHOR]

The liver is a secondary and often collateral target of COVID-19 disease but can lead to important consequences. COVID-19 might directly cause a high number of complications in patients with pre-existing chronic liver disease, increasing their risk of hepatic decompensation. Moreover, it also determines indirect consequences in the management of patients with liver disease, especially in those suffering from decompensated cirrhosis and HCC, as well as in the execution of their follow-up and the availability of all therapeutic possibilities. Liver imaging in COVID-19 patients proved to be highly nonspecific, but it can still be useful for identifying the complications that derive from the infection. Moreover, the recent implementation of telemedicine constitutes a possible solution to both the physical distancing and the re-organizational difficulties arising from the pandemic. The present review aims to encompass the currently hypothesized pathophysiological mechanisms of liver injury in patients with COVID-19 mediated by both the direct invasion of the virus and its indirect effects and analyze the consequence of the pandemic in patients with chronic liver disease and liver tumors, with particular regard to the management strategies that have been implemented to face this worldwide emergency and that can be further improved. [ABSTRACT FROM AUTHOR]

Obesogenic endocrine-disrupting chemicals (EDCs) belong to the group of environmental contaminants, which can adversely affect human health. A growing body of evidence supports that chronic exposure to EDCs can contribute to a rapid increase in obesity among adults and children, especially in wealthy industrialized countries with a high production of widely used industrial chemicals such as plasticizers (bisphenols and phthalates), parabens, flame retardants, and pesticides. The main source of human exposure to obesogenic EDCs is through diet, particularly with the consumption of contaminated food such as meat, fish, fruit, vegetables, milk, and dairy products. EDCs can promote obesity by stimulating adipo- and lipogenesis of target cells such as adipocytes and hepatocytes, disrupting glucose metabolism and insulin secretion, and impacting hormonal appetite/satiety regulation. In vitro models still play an essential role in investigating potential environmental obesogens. The review aimed to provide information on currently available two-dimensional (2D) in vitro animal and human cell models applied for studying the mechanisms of obesogenic action of various industrial chemicals such as food contaminants. The advantages and limitations of in vitro models representing the crucial endocrine tissue (adipose tissue) and organs (liver and pancreas) involved in the etiology of obesity and metabolic diseases, which are applied to evaluate the effects of obesogenic EDCs and their disruption activity, were thoroughly and critically discussed. [ABSTRACT FROM AUTHOR]

In this paper, we present a literature review of the role of CXC motif chemokine ligand 1 (CXCL1) in physiology, and in selected major non-cancer diseases of the cardiovascular system, respiratory system and skin. CXCL1, a cytokine belonging to the CXC sub-family of chemokines with CXC motif chemokine receptor 2 (CXCR2) as its main receptor, causes the migration and infiltration of neutrophils to the sites of high expression. This implicates CXCL1 in many adverse conditions associated with inflammation and the accumulation of neutrophils. The aim of this study was to describe the significance of CXCL1 in selected diseases of the cardiovascular system (atherosclerosis, atrial fibrillation, chronic ischemic heart disease, hypertension, sepsis including sepsis-associated encephalopathy and sepsis-associated acute kidney injury), the respiratory system (asthma, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis, coronavirus disease 2019 (COVID-19), influenza, lung transplantation and ischemic-reperfusion injury and tuberculosis) and the skin (wound healing, psoriasis, sunburn and xeroderma pigmentosum). Additionally, the significance of CXCL1 is described in vascular physiology, such as the effects of CXCL1 on angiogenesis and arteriogenesis. [ABSTRACT FROM AUTHOR]

Background: Several treatments induce liver hypertrophy for patients with liver malignancies but insufficient future liver remnant (FLR). Herein, the aim of this study is to compare the efficacy and safety of existing surgical techniques using network meta-analysis (NMA). Methods: We searched PubMed, Web of Science, and Cochrane Library from databases for abstracts and full-text articles published from database inception through Feb 2022. The primary outcome was the efficacy of different procedures, including standardized FLR (sFLR) increase, time to hepatectomy, resection rate, and R0 resection margin. The secondary outcome was the safety of different treatments, including the rate of Clavien-Dindo≥3a and 90-day mortality. Results: Twenty-seven studies, including three randomized controlled trials (RCTs), three prospective trials (PTs), and twenty-one retrospective trials (RTs), and a total number of 2075 patients were recruited in this study. NMA demonstrated that the Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) had much higher sFLR increase when compared to portal vein embolization (PVE) (55.25%, 95% CI 45.27–65.24%), or liver venous deprivation(LVD) (43.26%, 95% CI 22.05–64.47%), or two-stage hepatectomy (TSH) (30.53%, 95% CI 16.84–44.21%), or portal vein ligation (PVL) (58.42%, 95% CI 37.62–79.23%). ALPPS showed significantly shorter time to hepatectomy when compared to PVE (−32.79d, 95% CI −42.92–22.66), or LVD (−34.02d, 95% CI −47.85–20.20), or TSH (−22.85d, 95% CI −30.97–14.72), or PVL (−43.37d, 95% CI −64.11–22.62); ALPPS was considered as the highest resection rate when compared to TSH (OR=6.09; 95% CI 2.76–13.41), or PVL (OR =3.52; 95% CI 1.16–10.72), or PVE (OR =4.12; 95% CI 2.19–7.77). ALPPS had comparable resection rate with LVD (OR =2.20; 95% CI 0.83–5.86). There was no significant difference between them when considering the R0 marge rate. ALPPS had a higher Clavien-Dindo≥3a complication rate and 90-day mortality compared to other treatments, although there were no significant differences between different procedures. Conclusions: ALPPS demonstrated a higher regeneration rate, shorter time to hepatectomy, and higher resection rate than PVL, PVE, or TSH. There was no significant difference between them when considering the R0 marge rate. However, ALPPS developed the trend of higher Clavien-Dindo≥3a complication rate and 90-day mortality compared to other treatments. [ABSTRACT FROM AUTHOR]

Transplantation is currently the treatment of choice for end-stage liver diseases but is burdened by the shortage of donor organs. Livers from so-called extended-criteria donors represent a valid option to overcome organ shortage, but they are at risk for severe post-operative complications, especially when preserved with conventional static cold storage. Machine perfusion technology reduces ischemia-reperfusion injury and allows viability assessment of these organs, limiting their discard rate and improving short- and long-term outcomes after transplantation. Moreover, by keeping the graft metabolically active, the normothermic preservation technique guarantees a unique platform to administer regenerative therapies ex vivo. With their anti-inflammatory and immunomodulatory properties, mesenchymal stem cells are among the most promising sources of therapies for acute and chronic liver failure, but their routine clinical application is limited by several biosafety concerns. It is emerging that dynamic preservation and stem cell therapy may supplement each other if combined, as machine perfusion can be used to deliver stem cells to highly injured grafts, avoiding potential systemic side effects. The aim of this narrative review is to provide a comprehensive overview on liver preservation techniques and mesenchymal stem cell-based therapies, focusing on their application in liver graft reconditioning. [ABSTRACT FROM AUTHOR]

The nuclear receptor farnesoid X receptor (FXR, NR1H4) is a bile acid (BA) sensor that links the enterohepatic circuit that regulates BA metabolism and elimination to systemic lipid homeostasis. Furthermore, FXR represents a real guardian of the hepatic function, preserving, in a multifactorial fashion, the integrity and function of hepatocytes from chronic and acute insults. This review summarizes how FXR modulates the expression of pathway-specific as well as polyspecific transporters and enzymes, thereby acting at the interface of BA, lipid and drug metabolism, and influencing the onset and progression of hepatotoxicity of varying etiopathogeneses. Furthermore, this review article provides an overview of the advances and the clinical development of FXR agonists in the treatment of liver diseases. [ABSTRACT FROM AUTHOR]

Hepatic ischemia-reperfusion injury (IRI) represents a major challenge during liver surgery, liver preservation for transplantation, and can cause hemorrhagic shock with severe hypoxemia and trauma. The reduction of blood supply with a concomitant deficit in oxygen delivery initiates various molecular mechanisms involving the innate and adaptive immune response, alterations in gene transcription, induction of cell death programs, and changes in metabolic state and vascular function. Hepatic IRI is a major cause of morbidity and mortality, and is associated with an increased risk for tumor growth and recurrence after oncologic surgery for primary and secondary hepatobiliary malignancies. Therapeutic strategies to prevent or treat hepatic IRI have been investigated in animal models but, for the most part, have failed to provide a protective effect in a clinical setting. This review focuses on the molecular mechanisms underlying hepatic IRI and regeneration, as well as its clinical implications. A better understanding of this complex and highly dynamic process may allow for the development of innovative therapeutic approaches and optimize patient outcomes. [ABSTRACT FROM AUTHOR]

The sympathetic nervous system maintains metabolic homeostasis by orchestrating the activity of organs such as the pancreas, liver, and white and brown adipose tissues. From the first renderings by Thomas Willis to contemporary techniques for visualization, tracing, and functional probing of axonal arborizations within organs, our understanding of the sympathetic nervous system has started to grow beyond classical models. In the present review, we outline the evolution of these findings and provide updated neuroanatomical maps of sympathetic innervation. We offer an autonomic framework for the neuroendocrine loop of leptin action, and we discuss the role of immune cells in regulating sympathetic terminals and metabolism. We highlight potential anti-obesity therapeutic approaches that emerge from the modern appreciation of SNS as a neural network vis a vis the historical fear of sympathomimetic pharmacology, while shifting focus from post- to pre-synaptic targeting. Finally, we critically appraise the field and where it needs to go. In this review, we update the neuroanatomical maps of sympathetic innervation of the pancreas, liver, and adipose tissues. We discuss the role of the immune cells in regulating sympathetic terminals and metabolism. We conjecture on novel anti-obesity therapies that could emerge from the modern appreciation of SNS as a neural network modulated by immune cells. [ABSTRACT FROM AUTHOR]

Background: Liver diseases post-COVID-19 vaccination is extremely rare but can occur. A growing body of evidence has indicated that portal vein thrombosis, autoimmune hepatitis, raised liver enzymes and liver injuries, etc., may be potential consequence of COVID-19 vaccines.Objectives: To describe the results of a systematic review for new-onset and relapsed liver disease following COVID-19 vaccination.Methods: For this systematic review, we searched Proquest, Medline, Embase, PubMed, CINAHL, Wiley online library, Scopus and Nature through the Preferred Reporting Items for Systematic Reviews and Meta Analyses PRISMA guideline for studies on the incidence of new onset or relapsed liver diseases post-COVID-19 vaccination, published from December 1, 2020 to July 31, 2022, with English language restriction.Results: Two hundred seventy-five cases from one hundred and eighteen articles were included in the qualitative synthesis of this systematic review. Autoimmune hepatitis (138 cases) was the most frequent pathology observed post-COVID-19 vaccination, followed by portal vein thrombosis (52 cases), raised liver enzymes (26 cases) and liver injury (21 cases). Other cases include splanchnic vein thrombosis, acute cellular rejection of the liver, jaundice, hepatomegaly, acute hepatic failure and hepatic porphyria. Mortality was reported in any of the included cases for acute hepatic failure (n = 4, 50%), portal vein thrombosis (n = 25, 48.1%), splanchnic vein thrombosis (n = 6, 42.8%), jaundice (n = 1, 12.5%), raised liver enzymes (n = 2, 7.7%), and autoimmune hepatitis (n = 3, 2.2%). Most patients were easily treated without any serious complications, recovered and did not require long-term hepatic therapy.Conclusion: Reported evidence of liver diseases post-COIVD-19 vaccination should not discourage vaccination against this worldwide pandemic. The number of reported cases is relatively very small in relation to the hundreds of millions of vaccinations that have occurred and the protective benefits offered by COVID-19 vaccination far outweigh the risks. [ABSTRACT FROM AUTHOR]

Warm ischaemia is usually induced by the Pringle manoeuver (PM) during hepatectomy. Currently, there is no widely accepted standard protocol to minimise ischaemia-related injury, so reducing ischaemia-reperfusion damage is an active area of research. This systematic review and meta-analysis focused on inducible nitric oxide synthase (iNOS) as an early inflammatory response to hepatic ischaemia reperfusion injury (HIRI) in mouse- and rat-liver models. A systematic search of studies was performed within three databases. Studies meeting the inclusion criteria were subjected to qualitative and quantitative synthesis of results. We performed a meta-analysis of studies grouped by different HIRI models and ischaemia times. Additionally, we investigated a possible correlation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) regulation with iNOS expression. Of 124 included studies, 49 were eligible for the meta-analysis, revealing that iNOS was upregulated in almost all HIRIs. We were able to show an increase of iNOS regardless of ischemia or reperfusion time. Additionally, we found no direct associations of eNOS or NO with iNOS. A sex gap of primarily male experimental animals used was observed, leading to a higher risk of outcomes not being translatable to humans of all sexes. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease is a huge cause of chronic liver failure around the world. This condition has become more prevalent as rates of metabolic syndrome, type 2 diabetes, and obesity have also escalated. The unfortunate outcome for many people is liver cirrhosis that warrants transplantation or being unable to receive a transplant since many livers are discarded due to high levels of steatosis. Over the past several years, however, a great deal of work has gone into understanding the pathophysiology of this disease as well as possible treatment options. This review summarizes various defatting strategies including in vitro use of pharmacologic agents, machine perfusion of extracted livers, and genomic approaches targeting specific proteins. The goal of the field is to reduce the number of necessary transplants and expand the pool of organs available for use. [ABSTRACT FROM AUTHOR]

With the increased use of extended-criteria donors, machine perfusion became a beneficial alternative to cold storage in preservation strategy for donor livers with the intent to expand donor pool. Both normothermic and hypothermic approach achieved good results in terms of mid- and long-term outcome in liver transplantation. Many markers and molecules have been proposed for the assessment of liver, but no definitive criteria for graft viability have been validated in large clinical trials and key parameters during perfusion still require optimization.In this review, we address the current literature of viability criteria during normothermic and hypothermic machine perfusion and discuss about future steps and evolution of these technologies. [ABSTRACT FROM AUTHOR]

Macrophages are key participants in the maintenance of tissue homeostasis under normal and pathological conditions, and implement a rich diversity of functions. The largest population of resident tissue macrophages is found in the liver. Hepatic macrophages, termed Kupffer cells, are involved in the regulation of multiple liver functionalities. Specific differentiation profiles and functional activities of tissue macrophages have been attributed to the shaping role of the so-called tissue niche microenvironments. The fundamental macrophage niche concept was lately shaken by a flood of new data, leading to a revision and substantial update of the concept, which constitutes the main focus of this review. The macrophage community discusses contemporary evidence on the developmental origins of resident macrophages, notably Kupffer cells and the issues of heterogeneity of the hepatic macrophage populations, as well as the roles of proliferation, cell death and migration processes in the maintenance of macrophage populations of the liver. Special consideration is given to interactions of Kupffer cells with other local cell lineages, including Ito cells, sinusoidal endothelium and hepatocytes, which participate in the maintenance of their phenotypical and functional identity. [ABSTRACT FROM AUTHOR]

Sepsis is a critical condition characterized by increased levels of pro-inflammatory cytokines and proliferating cells such as neutrophils and macrophages in response to microbial pathogens. Such processes lead to an abnormal inflammatory response and multi-organ failure. MicroRNAs (miRNA) are single-stranded non-coding RNAs with the function of gene regulation. This means that miRNAs are involved in multiple intracellular pathways and thus contribute to or inhibit inflammation. As a result, their variable expression in different tissues and organs may play a key role in regulating the pathophysiological events of sepsis. Thanks to this property, miRNAs may serve as potential diagnostic and prognostic biomarkers in such life-threatening events. In this narrative review, we collect the results of recent studies on the expression of miRNAs in heart, blood, lung, liver, brain, and kidney during sepsis and the molecular processes in which they are involved. In reviewing the literature, we find at least 122 miRNAs and signaling pathways involved in sepsis-related organ dysfunction. This may help clinicians to detect, prevent, and treat sepsis-related organ failures early, although further studies are needed to deepen the knowledge of their potential contribution. [ABSTRACT FROM AUTHOR]

Clinical imaging (e.g., magnetic resonance imaging and computed tomography) is a crucial adjunct for clinicians, aiding in the diagnosis of diseases and planning of appropriate interventions. This is especially true in malignant conditions such as hepatocellular carcinoma (HCC), where image segmentation (such as accurate delineation of liver and tumor) is the preliminary step taken by the clinicians to optimize diagnosis, staging, and treatment planning and intervention (e.g., transplantation, surgical resection, radiotherapy, PVE, embolization, etc). Thus, segmentation methods could potentially impact the diagnosis and treatment outcomes. This paper comprehensively reviews the literature (during the year 2012–2021) for relevant segmentation methods and proposes a broad categorization based on their clinical utility (i.e., surgical and radiological interventions) in HCC. The categorization is based on the parameters such as precision, accuracy, and automation. [ABSTRACT FROM AUTHOR]

Biliary atresia (BA) is a progressive fibro-obliterative process with a variable degree of inflammation involving the hepatobiliary system. Its consequences are incalculable for the patients, the affected families, relatives, and the healthcare system. Scientific communities have identified a rate of about 1 case per 10,000–20,000 live births, but the percentage may be higher, considering the late diagnoses. The etiology is heterogeneous. BA, which is considered in half of the causes leading to orthotopic liver transplantation, occurs in primates and non-primates. To consolidate any model, (1) more transport and cell membrane studies are needed to identify the exact mechanism of noxa-related hepatotoxicity; (2) an online platform may be key to share data from pilot projects and new techniques; and (3) the introduction of differentially expressed genes may be useful in investigating the liver metabolism to target the most intricate bilio-toxic effects of pharmaceutical drugs and toxins. As a challenge, such methodologies are still limited to very few centers, making the identification of highly functional animal models like finding a "needle in a haystack". This review compiles models from the haystack and hopes that a combinatorial search will eventually be the root for a successful pathway. [ABSTRACT FROM AUTHOR]

Autophagy is a complex process of degradation of senescent or dysfunctional organelles in cells. Dysfunctional autophagy is associated with many diseases such as cancers, immune dysfunction, and aging. Hydrogen sulfide (H2S) is considered to be the third gas signal molecule after nitrous oxide and carbon monoxide. In recent years, H2S has been found to have a variety of important biological functions, and plays an important role in a variety of physiological and pathological processes. In this review, we review the recent role and mechanism of H2S in regulating autophagy in liver disorders, in order to provide a basis for further research in the future. [ABSTRACT FROM AUTHOR]

The liver is one of the richest organs in mitochondria, serving as a hub for key metabolic pathways such as β-oxidation, the tricarboxylic acid (TCA) cycle, ketogenesis, respiratory activity, and adenosine triphosphate (ATP) synthesis, all of which provide metabolic energy for the entire body. Mitochondrial dysfunction has been linked to subcellular organelle dysfunction in liver diseases, particularly fatty liver disease. Acute fatty liver of pregnancy (AFLP) is a life-threatening liver disorder unique to pregnancy, which can result in serious maternal and fetal complications, including death. Pregnant mothers with this disease require early detection, prompt delivery, and supportive maternal care. AFLP was considered a mysterious illness and though its pathogenesis has not been fully elucidated, molecular research over the past two decades has linked AFLP to mitochondrial dysfunction and defects in fetal fatty-acid oxidation (FAO). Due to deficient placental and fetal FAO, harmful 3-hydroxy fatty acid metabolites accumulate in the maternal circulation, causing oxidative stress and microvesicular fatty infiltration of the liver, resulting in AFLP. In this review, we provide an overview of AFLP and mitochondrial FAO followed by discussion of how altered mitochondrial function plays an important role in the pathogenesis of AFLP. [ABSTRACT FROM AUTHOR]

Background: Biliary adenofibroma (BAF) is a rare primary hepatic tumor with the potential risk of malignant transformation. Given the extreme rarity of the disease, the imaging features of BAF are unclear. We presented a case of malignant BAF and conducted a systematic literature review. We highlighted the key imaging features in the diagnosis and aggressiveness assessment of BAF, as well as the role of various imaging modalities in evaluating BAF. Case presentation: We reported a 64-year-old woman with a 5-months history of pain in the right upper quadrant abdomen. US of the liver showed a hypoechoic subcapsular nodule. CT scan revealed a subcapsular solid-cystic mass in segment V of the liver. The mass showed a marked enhancement in the arterial phase followed by wash-out in the venous phase. The patient underwent partial resection of liver's right lobe. The mass was diagnosed as BAF with malignant transformation by postoperative pathology. Conclusions: CT and MRI are helpful in recognizing and characterizing BAF. The imaging features of BAF include a solitary, large solid-cystic mass with a well-defined margin, lobulated shape, and internal septa; subcapsular location; no intrahepatic bile duct communication; the presence of von Meyenberg complexes in background liver. The enhancement patterns may have the potential to assess the aggressiveness of BAF, and that marked enhancement in the arterial phase followed by wash-out in the venous phase is suggestive of malignant BAF. [ABSTRACT FROM AUTHOR]

Background: The timely and effective treatments are vital to the prognosis of patients with hepatocellular carcinoma, and the role of Apatinib combined with TACE in the treatment of hepatocellular carcinoma remains unclear. Therefore, we aimed to conduct a systematic review and meta-analysis to evaluate the efficacy and safety of Apatinib combined with transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma. Methods: We searched for randomized controlled trials (RCTs) on Apatinib and TACE use in the treatment of hepatocellular carcinoma. Cochrane Central Register of Controlled Trials, Embase, PubMed, China Biomedical Literature Database, China Knowledge Network, Wanfang Database, and Weipu Chinese Science and Technology Journal Database were searched up to 16 April 2021. Two researchers independently screened the literature and extracted data according to the inclusion and exclusion criteria. RevMan 5.3 software was used for Meta-analysis. This meta-analysis protocol had been registered online (available at: https://inplasy.com/inplasy-2021-6-0047/). Results: A total of 14 RCTs involving 936 hepatocellular carcinoma patients were included. The objective remission rate (OR = 2.93, 95% CI 2.17–3.95), 1-year survival (OR = 2.47, 95% CI 1.65–3.68), 2-year survival (OR = 2.67, 95% CI 1.41–5.04), the incidence of hand-foot syndrome (OR = 32.09, 95% CI 10.87–94.74) and the incidence of proteinuria (OR = 14.79, 95% CI 6.07–36.06) of the Apatinib + TACE group was significantly higher than that of the TACE group (all P < 0.05). There were no significant differences in the incidence of myelosuppression (OR = 1.01, 95% CI 0.61–1.67), the incidence of hypertension (OR = 7.56, 95% CI 0.95–1.67, P = 60.17) between Apatinib + TACE and TACE group (all P > 0.05). Conclusions: Apatinib combined with TACE is more effective than TACE alone in the treatment of hepatocellular carcinoma, but it has certain adverse reactions. [ABSTRACT FROM AUTHOR]

Phosphatases of regenerating liver (PRLs) are protein phosphatases involved in the control of cell growth and migration. They are known to promote cancer metastasis but, despite over 20 years of study, there is still no consensus about their mechanism of action. Recent work has revealed that PRLs lead double lives, acting both as catalytically active enzymes and as pseudophosphatases. The three known PRLs belong to the large family of cysteine phosphatases that form a phosphocysteine intermediate during catalysis. Uniquely to PRLs, this intermediate is stable, with a lifetime measured in hours. As a consequence, PRLs have very little phosphatase activity. Independently, PRLs also act as pseudophosphatases by binding CNNM membrane proteins to regulate magnesium homeostasis. In this function, an aspartic acid from CNNM inserts into the phosphatase catalytic site of PRLs, mimicking a substrate-enzyme interaction. The delineation of PRL pseudophosphatase and phosphatase activities in vivo was impossible until the recent identification of PRL mutants defective in one activity or the other. These mutants showed that CNNM binding was sufficient for PRL oncogenicity in one model of metastasis, but left unresolved its role in other contexts. As the presence of phosphocysteine prevents CNNM binding and CNNM-binding blocks catalytic activity, these two activities are inherently linked. Additional studies are needed to untangle the intertwined catalytic and noncatalytic functions of PRLs. Here, we review the current understanding of the structure and biophysical properties of PRL phosphatases. [ABSTRACT FROM AUTHOR]

[Display omitted] Liver fibrosis is the excessive accumulation of extracellular matrix due to chronic injuries, such as viral infection, alcohol abuse, high-fat diet, and toxins. Liver fibrosis is reversible before it progresses to cirrhosis and hepatocellular carcinoma. Type 2 diabetes significantly increases the risk of developing various complications including liver diseases. Abundant evidence suggests that type 2 diabetes and liver diseases are bidirectionally associated. Patients with type 2 diabetes experience more severe symptoms and accelerated progression of live diseases. Obesity and insulin resistance resulting from hyperlipidemia and hyperglycemia are regarded as the two major risk factors that link type 2 diabetes and liver fibrosis. This review summarizes possible mechanisms of the association between type 2 diabetes and liver fibrosis. The cellular protein markers that can be used for diagnosis and therapy of type 2 diabetes-associated liver fibrosis are discussed. We also highlight the potential therapeutic agents and their delivery systems that have been investigated for type 2 diabetes-associated liver fibrosis. [ABSTRACT FROM AUTHOR]

The widespread use of nanomaterials (NMs) has raised concerns that exposure to them may introduce potential risks to the human body and environment. The liver is the main target organ for NMs. Hepatotoxic effects caused by NMs have been observed in recent studies but have not been linked to liver disease, and the intrinsic mechanisms are poorly elucidated. Additionally, NMs exhibit varied toxicokinetics and induce enhanced toxic effects in susceptible livers; however, thus far, this issue has not been thoroughly reviewed. This review provides an overview of the toxicokinetics of NMs. We highlight the possibility that NMs induce hepatic diseases, including nonalcoholic steatohepatitis (NASH), fibrosis, liver cancer, and metabolic disorders, and explore the underlying intrinsic mechanisms. Additionally, NM toxicokinetics and the potential induced risks in the livers of susceptible individuals, including subjects with liver disease, obese individuals, aging individuals and individuals of both sexes, are summarized. To understand how NM type affect their toxicity, the influences of the physicochemical and morphological (PCM) properties of NMs on their toxicokinetics and toxicity are also explored. This review provides guidance for further toxicological studies on NMs and will be important for the further development of NMs for applications in various fields. [ABSTRACT FROM AUTHOR]

Normal function of the hypothalamic-pituitary-adrenal (HPA) axis is critical for survival, and its development is choreographed for age-, sex- and context-specific actions. The liver influences HPA ontogeny, integrating diverse endocrine signals that inhibit or activate its development. This review examines how developmental changes in the expression of genes in the liver coordinate postnatal changes in multiple endocrine systems that facilitate the maturation and sexual dimorphism of the rat HPA axis. Specifically, it examines how the ontogeny of testicular androgen production, somatostatin-growth hormone activities, and hypothalamic-pituitary-thyroid axis activity intersect to influence the hepatic gene expression of insulin-like growth factor 1, corticosteroid-binding globulin, thyroxine-binding globulin, 11β-hydroxysteroid dehydrogenase type 1 and 5α-reductase type 1. The timing of such molecular changes vary between mammalian species, but they are evolutionarily conserved and are poised to control homeostasis broadly, especially during adversity. Importantly, with the liver as their nexus, these diverse endocrine systems establish the fundamental organization of the HPA axis throughout postnatal development, and thereby ultimately determine the actions of glucocorticoids during adulthood. [ABSTRACT FROM AUTHOR]

Excessive sugar consumption is a contributor to the worldwide epidemic of cardiometabolic disease. Understanding mechanisms by which sugar is sensed and regulates metabolic processes may provide new opportunities to prevent and treat these epidemics. Carbohydrate Responsive-Element Binding Protein (ChREBP) is a sugar-sensing transcription factor that mediates genomic responses to changes in carbohydrate abundance in key metabolic tissues. Carbohydrate metabolites activate the canonical form of ChREBP, ChREBP-alpha, which stimulates production of a potent, constitutively active ChREBP isoform called ChREBP-beta. Carbohydrate metabolites and other metabolic signals may also regulate ChREBP activity via posttranslational modifications including phosphorylation, acetylation, and O-GlcNAcylation that can affect ChREBP's cellular localization, stability, binding to cofactors, and transcriptional activity. In this review, we discuss mechanisms regulating ChREBP activity and highlight phenotypes and controversies in ChREBP gain- and loss-of-function genetic rodent models focused on the liver and pancreatic islets. [ABSTRACT FROM AUTHOR]

An energy-restricted diet is often prescribed before bariatric surgery to reduce weight and liver volume. While very-low-calorie diets (VLCDs, 450–800 kcal per day) have shown to be effective, the effectiveness of low-calorie diets (LCDs, 800–1500 kcal per day) is less obvious. The objective of this systematic review was to elucidate the effectiveness of LCD on liver volume reduction in patients awaiting bariatric surgery. Eight studies (n = 251) were included describing nine different diets (800–1200 kcal, 2–8 weeks). An LCD was effective in liver volume reduction (12–27%) and weight loss (4–17%), particularly during the first weeks. The LCD showed an acceptable patients' compliance. Based on these findings, an LCD (800–1200 kcal), instead of a VLCD, for 2 to 4 weeks should be preferred. [ABSTRACT FROM AUTHOR]

Exosomes are extracellular vesicles with diameters ranging from 30 to 150 nm, which contain several donor cell‐associated proteins as well as mRNA, miRNA, and lipids and coordinate multiple physiological and pathological functions through horizontal communication between cells. Almost all types of liver cells, such as hepatocytes and Kupffer cells, are exosome‐releasing and/or exosome‐targeted cells. Exosomes secreted by liver cells play an important role in regulating general physiological functions and also participate in the onset and development of liver diseases, including liver cancer, liver injury, liver fibrosis and viral hepatitis. Liver cell‐derived exosomes carry liver cell‐specific proteins and miRNAs, which can be used as diagnostic biomarkers and treatment targets of liver disease. This review discusses the functions of exosomes derived from different liver cells and provides novel insights based on the latest developments regarding the roles of exosomes in the diagnosis and treatment of liver diseases. [ABSTRACT FROM AUTHOR]

Fibrosis results from a disordered wound healing response within the liver with activated hepatic stellate cells laying down dense, collagen-rich extracellularmatrix that eventually restricts liver hepatic synthetic function and causes increased sinusoidal resistance. The end result of progressive fibrosis, cirrhosis, is associated with significant morbidity and mortality as well as tremendous economic burden. Fibrosis can be conceptualized as an aberrant wound healing response analogous to a chronic ankle sprain that is driven by chronic liver injury commonly over decades. Two unique aspects of hepatic fibrosis - the chronic nature of insult required and the liver's unique ability to regenerate - give an opportunity for pharmacologic intervention to stop or slow the pace of fibrosis in patients early in the course of their liver disease. Two potential biologic mechanisms link together hemostasis and fibrosis: focal parenchymal extinction and direct stellate cell activation by thrombin and Factor Xa. Available translational research further supports the role of thrombosis in fibrosis. In this review, we will summarize what is known about the convergence of hemostatic changes and hepatic fibrosis in chronic liver disease and present current preclinical and clinical data exploring the relationship between the two. We will also present clinical trial data that underscores the potential use of anticoagulant therapy as an antifibrotic factor in liver disease. [ABSTRACT FROM AUTHOR]

Currently, there are at least 70 pure domestic pig breeds, but only certain breeds are used in biomedical research. The domestic pig liver is suitable for preclinical research because its size, physiology, and anatomy are similar to that of the human liver; in addition, there is a high degree of genetic similarity between the two species. For planning experiments and identifying improvements in both invasive and noninvasive methods of liver disease management, the morphological similarities and dissimilarities of the pig liver to its human counterpart must be taken into consideration along with sexual dimorphism and interindividual and interspecific variability. Recent histological evaluations based on stereological methods enable precise quantitative morphological estimates and guarantee their unbiased accuracy. The results thereof are crucial for revealing and assessing histological changes and can contribute to the optimization of study designs. New trends in computed tomography data processing have also been introduced. This review article summarizes the newest trends and findings in the field of porcine liver anatomy and histology as applicable to preclinical research. [ABSTRACT FROM AUTHOR]

Hepatocarcinogens are agents that increase the incidence of liver cancer in exposed animals or humans. It is now established that carcinogenic exposures have a widespread impact on the transcriptome, inducing both adaptive and adverse changes in the activities of genes and pathways. Chemical hepatocarcinogens have also been shown to affect expression of microRNA (miRNA), the evolutionarily conserved noncoding RNA that regulates gene expression posttranscriptionally. Considerable effort has been invested into examining the involvement of mRNA in chemical hepatocarcinogenesis and their potential usage for the classification and prediction of new chemical entities. For miRNA, there has been an increasing number of studies reported over the past decade, although not to the same degree as for transcriptomic studies. Current data suggest that it is unlikely that any gene or miRNA signature associated with short-term carcinogen exposure can replace the rodent bioassay. In this review, we discuss the application of transcriptomic and miRNA profiles to increase mechanistic understanding of chemical carcinogens and to aid in their classification. [ABSTRACT FROM AUTHOR]

Inflammatory pseudotumors of the liver are rare entities, only few cases being reported so far, pathogenesis of these lesions being scarcely understood. However since now multiple mechanisms have been proposed in order to explain the development of these lesions, the knowledge of their pathogenesis being mandatory in order to further orientate the therapeutic strategy. The current paper is a literature review of the largest studies which aimed to discuss the etiopathogenesis of the inflammatory pseudotumors of the liver. [ABSTRACT FROM AUTHOR]

Pancreatic cancer remains one of the most aggressive neoplasms affecting people worldwide, with lower than one year rates of survival, especially if metastatic disease is encountered. In such cases palliative chemotherapy has been proposed, but the overall prognostic remains extremely poor. Meanwhile, in certain cases, spectacular response to chemotherapy has been observed, with significant reduction and even disappearance of the liver lesions. In this respect, attention was focused on establishing whether surgery might improve the outcomes in such cases. This is a literature review of the largest studies conducted on this issue. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is, by far, the most common liver malignancy. The risk factors for the development of HCC are numerous with liver cirrhosis, chronic hepatitis B and C viral infections and alcohol abuse on top of the list. Several studies were devoted to evaluate the complex radiological appearance of HCC and its correlation with histopathologic grade/stage as well as possible mimickers of HCC, all of which have a significant impact on diagnosis and management of patients with HCC. Objectives: Evaluation of the radiological findings of HCC and its correlation with histopathologic grade/stage as well as mimickers of HCC. Methods: This is a review article of some of the existing literature regarding radiological findings and histopathologic diagnosis of progressed hepatocellular carcinoma. Conclusion: Imaging findings of progressed HCCs are complex and different from the standard findings of welldifferentiated HCCs. Evaluation of enhancement and washout patterns, as well as the possibility of the presence of microvascular invasion, should be undertaken by the reporting radiologist and delivered comprehensively to the treating multidisciplinary team for proper management. [ABSTRACT FROM AUTHOR]

Serotonin is a biogenic amine synthesized from the essential amino acid tryptophan. Because serotonin cannot cross the blood-brain barrier, it func tions differently in neuronal and non-neuronal tissues. In the CNS, serotonin regulates mood, behavior, appetite, and energy expenditure. Although most serotonin in the body is synthesized at the periphery, its biological roles have not been well elucidated. Older studies using chemical agonists and antagonists yielded conflicting results, b ecause the complexity of serotonin receptors and the low selectivity of agonists and antagonists were not known. Several recent studies using specific knock-out of seroto nin receptors have been performed to assess the role of peripheral serotonin in regulating energy metabolism. This review discusses (1) the tissue-specific roles of periphera l serotonin in regulating energy metabolism, (2) the mechanism by which dysfunctional peripheral serotonin signaling can progress to metabolic diseases, and (3) how peripheral serotonin signaling could be a therapeutic target for metabolic diseases. [ABSTRACT FROM AUTHOR]

While alternative methods for toxicity testing using re-constructed human skin and cornea have been written into guidelines and adopted by regulatory authorities, three-dimensional (3D) liver models are currently applied in the industrial settings for hepatotoxicity screening and prediction. These 3D liver models can recapitulate the architecture, functionality and toxicity response of the native liver, demonstrated by a set of related hallmarks. In this comprehensive review, non-scaffold and scaffold-based methods available for 3D liver model formation are introduced, with an emphasis on their advantages and drawbacks. We then focus on the characteristics of primary human hepatocytes, stem cell derived hepatocyte like cells, and immortalized hepatic cell lines as cell resources for model reconstruction. Primary hepatocytes are generally regarded to be superior to other cell types due to their comparable metabolic profiles to the native liver. Additionally, the application of 3D liver models (mostly liver spheroids) on the evaluation of drug induced liver injury and chronic liver diseases (steatosis, cirrhosis, cholestasis), as well as the potential of nanomaterials to introduce hepatotoxicity are summarized. Finally, the global 3D cell market from 3D liver model manufacturing to the contract service of in vitro hepatotoxicity testing using the models is extensively explored. However, 3D liver models face cultural and regulatory barriers in different countries, and therefore the business development of 3D liver models is not easy. Toxicologists, material scientists, engineers should work together to develop, validate and apply 3D liver models for hepatotoxicity testing under the support from industrial organizations and governmental agencies. [ABSTRACT FROM AUTHOR]

Liver cancer is a common cancer worldwide. Although the etiological factors of liver carcinogenesis are well defined, the underlying molecular mechanisms remain largely elusive. Epigenetic deregulations, such as aberrant DNA methylation and histone modifications, play a critical role in liver carcinogenesis. Analogous to DNA and core histone proteins, reversible chemical modifications on mRNA have recently been recognized as important regulatory mechanisms to control gene expression. N6-methyladenosine (m6A) is the most prevalent internal mRNA modification in mammalian cells. m6A modification is important for controlling many cellular and biological processes. Deregulation of m6A modification has been recently implicated in human carcinogenesis, including liver cancer. In this review, we summarize the recent findings on m6A regulation and its biological impacts in normal and cancer cells. We will focus on the deregulation of m6A modification and m6A regulators in liver diseases and liver cancers. We will highlight the clinical relevance of m6A deregulation in liver cancer. We will also discuss the potential of exploiting m6A modification for cancer diagnosis and therapeutics. [ABSTRACT FROM AUTHOR]

Liver diseases such as hepatitis, cirrhosis, and hepatocellular carcinoma are global health problems accounting for approximately 800 million cases and over 2 million deaths per year worldwide. Major drawbacks of standard pharmacological therapies are the inability to deliver a sufficient concentration of a therapeutic agent to the diseased liver, and nonspecific drug delivery leading to undesirable systemic side effects. Additionally, depending on the specific liver disease, drug delivery to a subset of liver cells is required. In recent years, lipid nanoparticles have been developed to passively and actively target drugs to the liver. The success of this approach has been highlighted by the FDA-approval of the first liver-targeting lipid nanoparticle, ONPATTRO, in 2018 and many other promising candidate technologies are expected to follow. This review summarizes recent developments of various lipid-based liver-targeting technologies, namely solid-lipid nanoparticles, liposomes, niosomes and micelles, and discusses the challenges and future perspectives in this field. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

The rapid growth in organ transplantation has created an illicit trade in human organs. The kidney trade has flourished in the last few decades, but in the last few years this has been coupled with an emerging liver trade. This article examines the liver trade sourced from poor sellers in Bangladesh. Through ethnographic fieldwork, I investigate how a landless farmer and a village housewife both sell their liver lobes on the black market, and how the recipients undergo liver transplants in Bangladesh and India. I reveal that liver selling, like kidney selling, is primarily driven by the sellers' debt. What is surprising, though, in this anthropological analysis is that microcredit, a Nobel Prize‐winning economic operation, has negatively contributed to organ selling in Bangladesh. I discover that the liver trade leads to tragic outcomes for both sellers and recipients: the sellers could not repay their loans by selling a liver lobe, while one of the recipients died just over a month after the surgery. I therefore argue that liver trade is advancing through a series of disturbing ironies, resulting in bioviolence, exploitation, and suffering for the vulnerable victims. [ABSTRACT FROM AUTHOR]

Anatomical liver resection guided by segmental portal inflow compression proved to be an efficient tool in order to maximize the curative surgical treatment in hepatocellular carcinoma. In this respect, in the last decades, once the concept of indocyanine guided surgery gained more field, the method has been also implemented in hepatic surgery. Therefore it seems that intravenous injection followed by portal pedicle clamping and liver inspection in infrared light inspection might delimitate the segments of the liver and might successfully guide the gesture of anatomical liver resection. The current paper is a literature review of the studies which analyzed the efficacy and safety of indocyanine green guided liver surgery. [ABSTRACT FROM AUTHOR]

Evans HM, Sharif K, Brown RM, Platt C, Crisp WJ and Kelly DA. Fatal and life threatening rupture of splenic artery aneurysms in children with portal hypertension. Pediatr Transplantation 2004: 8: 192–195. © 2004 Blackwell Munksgaard Aneurysms of the splenic artery (SAAs) are a rare complication of portal hypertension in adults. Although the risk of rupture is small, associated mortality is high. Furthermore, circulatory changes that occur following liver transplantation (OLT) may increase the risk of SAA rupture. The incidence in children with portal hypertension is unknown and thus we present our experience with two children who had ruptured SAA, one of whom died. Although there are no accepted methods for routine screening, hepatic angiography should be considered in children with long-standing portal hypertension (more than 10 yr), in order to detect and consider resection of the aneurysms, either before or at the time of liver transplantation. [ABSTRACT FROM AUTHOR]