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New Challenges in the Study of Liver Diseases: From Molecular...
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New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 58386

Special Issue Editor

Dr. Marica Meroni

E-Mail Website
Guest Editor
General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
Interests: liver diseases; genetics; metabolism; molecular biology; NAFLD; NASH; insulin resistance; genetics; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The liver plays an essential role in all metabolic processes, acting as a hub that integrates hormone and nutrient stimuli, and catabolic responses. It has a peculiar structure and anatomical localization that preserve the networking with the entire digestive system. Alterations in hepatic homeostasis are particularly harmful; hence, the increasing number of patients affected represents a global concern.

The term liver diseases embraces an umbrella of hepatic disorders, including viral and toxic hepatitis, inherited and acquired cholestatic injuries, nonalcoholic fatty liver disease (NAFLD), fibrosis, cirrhosis and hepatocellular carcinoma (HCC). These disorders are usually complex in their molecular pathogenesis, and multiple risk factors may intervene in these processes. Among them, genetics and epigenetic factors have a primary impact in their development. Likewise, liver disorders are usually related to extrahepatic comorbidities, such as cardiovascular and intestinal complications. Since the gold standard for their diagnosis is still invasive and no therapeutic consensus exists for their management, this Special Issue aims to focus on new horizons in the discovery of noninvasive biomarkers and novel perspectives in the definition of the precise molecular mechanisms that precipitate liver damage towards end-stage conditions.

Dr. Marica Meroni
Guest Editor

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Keywords

  • liver diseases and related pathologies
  • nonalcoholic fatty liver diseases (NAFLD)
  • obesity
  • type 2 diabetes
  • cardiovascular diseases
  • gut–liver axis
  • viral hepatitis
  • alcoholic liver diseases (ALD)
  • cholestatic disorders
  • personalized medicine

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Published Papers (18 papers)

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20 pages, 2512 KiB  
Article
The Role of Neuregulin-1 in Steatotic and Non-Steatotic Liver Transplantation from Brain-Dead Donors
by Marc Micó-Carnero, Araní Casillas-Ramírez, Alfredo Sánchez-González, Carlos Rojano-Alfonso and Carmen Peralta
Biomedicines 2022, 10(5), 978; https://doi.org/10.3390/biomedicines10050978 - 23 Apr 2022
Cited by 2 | Viewed by 1878
Abstract
Background. Brain death (BD) and steatosis are key risk factors to predict adverse post-transplant outcomes. We investigated the role of Neuregulin-1 (NRG1) in rat steatotic and non-steatotic liver transplantation (LT) from brain death donors (DBD). Methods: NRG1 pathways were characterized after surgery. Results: [...] Read more.
Background. Brain death (BD) and steatosis are key risk factors to predict adverse post-transplant outcomes. We investigated the role of Neuregulin-1 (NRG1) in rat steatotic and non-steatotic liver transplantation (LT) from brain death donors (DBD). Methods: NRG1 pathways were characterized after surgery. Results: NRG1 and p21-activated kinase 1 (PAK1) levels increased in steatotic and non-steatotic grafts from DBDs. The abolishment of NRG1 effects reduced PAK1. When the effect of either NRG1 nor PAK1 was inhibited, injury and regenerative failure were exacerbated. The benefits of the NRG-1-PAK1 axis in liver grafts from DBDs were associated with increased vascular endothelial growth factor-A (VEGFA) and insulin growth factor-1 (IGF1) levels, respectively. Indeed, VEGFA administration in non-steatotic livers and IGF1 treatment in steatotic grafts prevented damage and regenerative failure resulting from the inhibition of either NRG1 or PAK-1 activity in each type of liver. Exogenous NRG1 induced greater injury than BD induction. Conclusions: This study indicates the benefits of endogenous NRG1 in liver grafts from DBDs and underscores the specificity of the NRG1 signaling pathway depending on the type of liver: NRG1-PAK1-VEGFA in non-steatotic livers and NRG1-PAK1-IGF1 in steatotic livers. Exogenous NRG1 is not an appropriate strategy to apply to liver grafts from DBD. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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19 pages, 3214 KiB  
Article
Quantitative Metabolomics of Tissue, Perfusate, and Bile from Rat Livers Subjected to Normothermic Machine Perfusion
by Caterina Lonati, Daniele Dondossola, Laimdota Zizmare, Michele Battistin, Leonie Wüst, Luigi Vivona, Margherita Carbonaro, Alberto Zanella, Stefano Gatti, Andrea Schlegel and Christoph Trautwein
Biomedicines 2022, 10(3), 538; https://doi.org/10.3390/biomedicines10030538 - 24 Feb 2022
Cited by 7 | Viewed by 2803
Abstract
Machine perfusion (MP) allows the maintenance of liver cells in a metabolically active state ex vivo and can potentially revert metabolic perturbations caused by donor warm ischemia, procurement, and static cold storage (SCS). The present preclinical research investigated the metabolic outcome of the [...] Read more.
Machine perfusion (MP) allows the maintenance of liver cells in a metabolically active state ex vivo and can potentially revert metabolic perturbations caused by donor warm ischemia, procurement, and static cold storage (SCS). The present preclinical research investigated the metabolic outcome of the MP procedure by analyzing rat liver tissue, bile, and perfusate samples by means of high-field (600 MHz) nuclear magnetic resonance (NMR) spectroscopy. An established rat model of normothermic MP (NMP) was used. Experiments were carried out with the addition of an oxygen carrier (OxC) to the perfusion fluid (OxC-NMP, n = 5) or without (h-NMP, n = 5). Bile and perfusate samples were collected throughout the procedure, while biopsies were only taken at the end of NMP. Two additional groups were: (1) Native, in which tissue or bile specimens were collected from rats in resting conditions; and (2) SCS, in which biopsies were taken from cold-stored livers. Generally, NMP groups showed a distinctive metabolomic signature in all the analyzed biological matrices. In particular, many of the differentially expressed metabolites were involved in mitochondrial biochemical pathways. Succinate, acetate, 3-hydroxybutyrate, creatine, and O-phosphocholine were deeply modulated in ex vivo perfused livers compared to both the Native and SCS groups. These novel results demonstrate a broad modulation of mitochondrial metabolism during NMP that exceeds energy production and redox balance maintenance. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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9 pages, 2100 KiB  
Article
Transient Elastography in Community Alcohol Services: Can It Detect Significant Liver Disease and Impact Drinking Behaviour?
by Mohsan Subhani, David J. Harman, Robert A. Scott, Lucy Bennett, Emilie A. Wilkes, Martin W. James, Guruprasad P. Aithal, Stephen D. Ryder and Indra Neil Guha
Biomedicines 2022, 10(2), 477; https://doi.org/10.3390/biomedicines10020477 - 17 Feb 2022
Cited by 4 | Viewed by 2154
Abstract
Introduction: Alcohol is the leading cause of cirrhosis in Western populations. The early identification of high-risk drinkers followed by intervention is an effective way to reduce harm. We aim to assess the feasibility of integrating transient elastography (TE) into community alcohol services, [...] Read more.
Introduction: Alcohol is the leading cause of cirrhosis in Western populations. The early identification of high-risk drinkers followed by intervention is an effective way to reduce harm. We aim to assess the feasibility of integrating transient elastography (TE) into community alcohol services, and to determine its impact on modifying drinking behaviours. Method: A prospective cohort study was conducted at a community alcohol clinic in Nottingham, UK (April 2012 to March 2014). Patients (>18 years) with a primary alcohol problem were recruited. Those known to liver services or those known to have chronic liver disease were excluded. Significant liver fibrosis was defined by a liver stiffness of >8 kilopascal (kPa). Follow-up was for a minimum of six months. Data were descriptively analysed for significant differences between patients with a normal liver stiffness versus raised liver stiffness. Results: 156 patients were invited; n = 87 attended and n = 86 underwent successful TE. The majority were male (n = 53, 70.0%), and the mean age was 46.3 years (SD ± 9.8). Median liver stiffness was 6.9 kPa (range 3.1–75.0kPa). Clinically significant liver fibrosis was identified in n = 33 (38.4%), of which n = 6 were in the cirrhotic range (≥15 kPa). The baseline median self-reported alcohol intake for normal stiffness was 126 units per week (range 24–378) and in raised stiffness was 149.0 units per week (range 39.0–420.0); this difference was nonsignificant (p = 0.338). The median reduction in self-reported alcohol intake in the whole cohort was 65.0 units per week (range 27.0–88.0, p < 0.001); in the normal liver stiffness group it was 25.0 units per week (range 18.0–75.0, p = 0.154), and in the raised liver stiffness group it was 78.5 units per week (range 36.0–126.0, p < 0.001). Conclusion: The study demonstrated that transient elastography is a feasible tool to stratify clinically significant liver disease in community alcohol services. It can stimulate a change in high-risk drinking behaviour and a normal liver stiffness result does not provide false reassurance to participants. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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15 pages, 1719 KiB  
Article
Reducing the Pill Burden: Immunosuppressant Adherence and Safety after Conversion from a Twice-Daily (IR-Tac) to a Novel Once-Daily (LCP-Tac) Tacrolimus Formulation in 161 Liver Transplant Patients
by Max M. Maurer, Marius Ibach, Julius Plewe, Axel Winter, Paul Ritschl, Brigitta Globke, Robert Öllinger, Georg Lurje, Wenzel Schöning, Johann Pratschke and Dennis Eurich
Biomedicines 2022, 10(2), 272; https://doi.org/10.3390/biomedicines10020272 - 26 Jan 2022
Cited by 5 | Viewed by 2027
Abstract
Non-adherence to immunosuppressant therapy reduces long-term graft and patient survival after solid organ transplantation. The objective of this 24-month prospective study was to determine adherence, efficacy and safety after conversion of stable liver transplant (LT) recipients from a standard twice-daily immediate release Tacrolimus [...] Read more.
Non-adherence to immunosuppressant therapy reduces long-term graft and patient survival after solid organ transplantation. The objective of this 24-month prospective study was to determine adherence, efficacy and safety after conversion of stable liver transplant (LT) recipients from a standard twice-daily immediate release Tacrolimus (IR-Tac) to a novel once-daily life cycle pharma Tacrolimus (LCP-Tac) formulation. We converted a total of 161 LT patients at baseline, collecting Tacrolimus trough levels, laboratories, physical examination data and the BAASIS© questionnaire for self-reported adherence to immunosuppression at regular intervals. With 134 participants completing the study period (17% dropouts), the overall adherence to the BAASIS© increased by 57% until month 24 compared to baseline (51% vs. 80%). Patients who required only a morning dose of their concomitant medications reported the largest improvement in adherence after conversion. The intra-patient variability (IPV) of consecutive Tacrolimus trough levels after conversion did not change significantly compared to pre-conversion levels. Despite reducing the daily dose by 30% at baseline as recommended by the manufacturer, Tac-trough levels remained stable, reflected by an increase in the concentration-dose (C/D) ratio. No episodes of graft rejection or loss occurred. Our data suggest that the use of LCP-Tac in liver transplant patients is safe and can increase adherence to immunosuppression compared to conventional IR-Tac. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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12 pages, 2003 KiB  
Article
Metabolically Improved Stem Cell Derived Hepatocyte-Like Cells Support HBV Life Cycle and Are a Promising Tool for HBV Studies and Antiviral Drug Screenings
by Tine Tricot, Hendrik Jan Thibaut, Kayvan Abbasi, Ruben Boon, Nicky Helsen, Manoj Kumar, Johan Neyts and Catherine Verfaillie
Biomedicines 2022, 10(2), 268; https://doi.org/10.3390/biomedicines10020268 - 26 Jan 2022
Cited by 3 | Viewed by 2541
Abstract
More than 300 million people worldwide are diagnosed with a chronic hepatitis B virus (HBV) infection. Nucleos(t)ide viral polymerase inhibitors are available on the market and can efficiently treat patients with chronic HBV. However, life-long treatment is needed as covalently closed circular DNA [...] Read more.
More than 300 million people worldwide are diagnosed with a chronic hepatitis B virus (HBV) infection. Nucleos(t)ide viral polymerase inhibitors are available on the market and can efficiently treat patients with chronic HBV. However, life-long treatment is needed as covalently closed circular DNA (cccDNA) persists in the hepatocyte nucleus. Hence, there is a high demand for novel therapeutics that can eliminate cccDNA from the hepatocyte nucleus and cure chronically infected HBV patients. The gold standard for in vitro HBV studies is primary human hepatocytes (PHHs). However, alternatives are needed due to donor organ shortage and high batch-to-batch variability. Therefore, human pluripotent stem cell (hPSC)-derived hepatocyte-like cells (HLCs) are being explored as an in vitro HBV infection model. We recently generated hPSC lines that overexpress three transcription factors (HC3x) and that, upon differentiation in a high amino-acid supplemented maturation medium, generate a more mature hepatocyte progeny (HC3x-AA-HLCs). Here, we demonstrate that HBV can efficiently infect these HC3x-AA-HLCs, as was shown by the presence of HBV core (HBc) and surface antigens. A clear increasing release of HBV surface and e antigens was detected, indicating the formation of functional cccDNA. Moreover, back-titration of culture supernatant of HBV-infected HC3x-AA-HLCs on HepG2-NTCP cells revealed the production of novel infectious HBV particles. Additionally, an increasing number of HBc-positive HC3x-AA-HLCs over time suggests viral spreading is occurring. Finally, the HC3x-AA-HLC model was validated for use in antiviral drug studies using the nucleoside reverse-transcriptase inhibitor, lamivudine, and the HBV entry inhibitor, Myrcludex B. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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17 pages, 1653 KiB  
Article
Butyrate Protects against Diet-Induced NASH and Liver Fibrosis and Suppresses Specific Non-Canonical TGF-β Signaling Pathways in Human Hepatic Stellate Cells
by Eveline Gart, Wim van Duyvenvoorde, Karin Toet, Martien P. M. Caspers, Lars Verschuren, Mette Juul Nielsen, Diana Julie Leeming, Everton Souto Lima, Aswin Menke, Roeland Hanemaaijer, Jaap Keijer, Kanita Salic, Robert Kleemann and Martine C. Morrison
Biomedicines 2021, 9(12), 1954; https://doi.org/10.3390/biomedicines9121954 - 20 Dec 2021
Cited by 23 | Viewed by 3623
Abstract
In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, which is the main determinant of NASH-associated mortality. The short-chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver [...] Read more.
In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, which is the main determinant of NASH-associated mortality. The short-chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH-associated liver fibrosis remain unclear. Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared with a HFD-control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). HFD-fed mice developed obesity, insulin resistance, increased plasma leptin levels, adipose tissue inflammation, gut permeability, dysbiosis, and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels, and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 levels and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways Rho-like GTPases and PI3K/AKT and other important pro-fibrotic regulators (e.g., YAP/TAZ, MYC) by butyrate, providing a potential rationale for its antifibrotic effects. In conclusion, butyrate protects against obesity development, insulin resistance-associated NASH, and liver fibrosis. These antifibrotic effects are at least partly attributable to a direct effect of butyrate on collagen production in hepatic stellate cells, involving inhibition of non-canonical TGF-β signaling pathways. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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11 pages, 447 KiB  
Article
Hospital Frailty Risk Score Is Independently Associated with Mortality and Encephalopathy in Hospitalized Patients with Hepatocellular Carcinoma
by Daryl Ramai, Khoi P. Dang-Ho, Anjali Kewalramani, Praneeth Bandaru, Rodolfo Sacco, Luca Giacomelli, Aashni Shah, Simonetta Papa, Francesca Cappellini, Fabio Perversi, Sara di Nunzio and Antonio Facciorusso
Biomedicines 2021, 9(11), 1693; https://doi.org/10.3390/biomedicines9111693 - 15 Nov 2021
Cited by 7 | Viewed by 1730
Abstract
Frailty represents a state of vulnerability to multiple internal physiologic factors, as well as external pressures, and has been associated with clinical outcomes. We aim to understand the impact of frailty on patients admitted with hepatocellular carcinoma (HCC) by using the validated Hospital [...] Read more.
Frailty represents a state of vulnerability to multiple internal physiologic factors, as well as external pressures, and has been associated with clinical outcomes. We aim to understand the impact of frailty on patients admitted with hepatocellular carcinoma (HCC) by using the validated Hospital Frailty Risk Score, which is implemented in several hospitals worldwide. We conducted a nation-wide retrospective cohort study to determine the effect of frailty on the risk of in-patient mortality, hepatic encephalopathy, length of stay and cost. Frailty was associated with a 4.5-fold increased risk of mortality and a 2.3-fold increased risk of hepatic encephalopathy. Adjusted Cox regression showed that frailty was correlated with increased risk of in-patient mortality (hazard ratio: 2.3, 95% CI 1.9–2.8, p < 0.001). Frail HCC patients had longer hospital stay (median 5 days) vs. non-frail HCC patients (median 3 days). Additionally, frail patients had higher total costs of hospitalization ($40,875) compared with non-frail patients ($31,667). Frailty is an independent predictor of hepatic encephalopathy and in-patient mortality. Frailty is a surrogate marker of hospital length of stay and cost. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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13 pages, 3959 KiB  
Article
Liver Fibrosis and 8-Year All-Cause Mortality Trajectories in the Aging Cohort of the Salus in Apulia Study
by Roberta Zupo, Fabio Castellana, Sara De Nucci, Giovanni De Pergola, Madia Lozupone, Ilaria Bortone, Marco Castellana, Giancarlo Sborgia, Luisa Lampignano, Gianluigi Giannelli, Francesco Panza and Rodolfo Sardone
Biomedicines 2021, 9(11), 1617; https://doi.org/10.3390/biomedicines9111617 - 04 Nov 2021
Cited by 3 | Viewed by 2003
Abstract
Age is a major contributor to the liver fibrosis rate and its adverse health-related outcomes, including mortality, but older populations are still under-explored. We investigated multimorbidity and inflammatory biomarkers in relation to the increasing liver fibrosis risk to delineate 8-year all-cause mortality trajectories [...] Read more.
Age is a major contributor to the liver fibrosis rate and its adverse health-related outcomes, including mortality, but older populations are still under-explored. We investigated multimorbidity and inflammatory biomarkers in relation to the increasing liver fibrosis risk to delineate 8-year all-cause mortality trajectories in 1929 older adults from the population-based Salus in Apulia Study. Liver fibrosis risk was assumed using the fibrosis-4 (FIB-4) score, assigned to three liver fibrosis risk groups (low, intermediate, high). In the secondary analyses, the APRI score was also calculated to allow for comparisons. Male subjects (prevalence difference: −13.49, 95% confidence interval (CI): −18.96 to −8.03), a higher multimorbidity burden (effect size, ES: −0.14, 95% CI: −0.26 to −0.02), a higher prevalence of physical frailty (ES: 6.77, 95% CI: 0.07 to 13.47), and a more pronounced inflammatory pattern as indicated by tumor growth factor-α circulating levels (ES: −0.12, 95% CI: −0.23 to −0.01) were significantly more common in the highest-risk FIB-4 score group. Liver function characterized by lipid profile and platelet levels worsened with increasing FIB-4 risk score. The 8-year risk of death was nearly double in subjects in the highest-risk FIB-4 score group, even after controlling for possible confounders. Furthermore, a steeper mortality curve was clearly observed for FIB-4 scores as compared with the APRI scoring system with respect to liver fibrosis risk. In conclusion, using a scoring tool based on simple routine biomarkers to detect liver fibrosis risk may enhance biological knowledge of age-related outcomes of chronic liver disease and be helpful in the clinical setting to identify subjects at risk for adverse health-related outcomes, including mortality. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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18 pages, 1618 KiB  
Article
Effluent Molecular Analysis Guides Liver Graft Allocation to Clinical Hypothermic Oxygenated Machine Perfusion
by Caterina Lonati, Andrea Schlegel, Michele Battistin, Riccardo Merighi, Margherita Carbonaro, Paola Dongiovanni, Patrizia Leonardi, Alberto Zanella and Daniele Dondossola
Biomedicines 2021, 9(10), 1444; https://doi.org/10.3390/biomedicines9101444 - 11 Oct 2021
Cited by 8 | Viewed by 1796
Abstract
Hypothermic-oxygenated-machine-perfusion (HOPE) allows assessment/reconditioning of livers procured from high-risk donors before transplantation. Graft referral to HOPE mostly depends on surgeons’ subjective judgment, as objective criteria are still insufficient. We investigated whether analysis of effluent fluids collected upon organ flush during static-cold-storage can improve [...] Read more.
Hypothermic-oxygenated-machine-perfusion (HOPE) allows assessment/reconditioning of livers procured from high-risk donors before transplantation. Graft referral to HOPE mostly depends on surgeons’ subjective judgment, as objective criteria are still insufficient. We investigated whether analysis of effluent fluids collected upon organ flush during static-cold-storage can improve selection criteria for HOPE utilization. Effluents were analyzed to determine cytolysis enzymes, metabolites, inflammation-related mediators, and damage-associated-molecular-patterns. Molecular profiles were assessed by unsupervised cluster analysis. Differences between “machine perfusion (MP)-yes” vs. “MP-no”; “brain-death (DBD) vs. donation-after-circulatory-death (DCD)”; “early-allograft-dysfunction (EAD)-yes” vs. “EAD-no” groups, as well as correlation between effluent variables and transplantation outcome, were investigated. Livers assigned to HOPE (n = 18) showed a different molecular profile relative to grafts transplanted without this procedure (n = 21, p = 0.021). Increases in the inflammatory mediators PTX3 (p = 0.048), CXCL8/IL-8 (p = 0.017), TNF-α (p = 0.038), and ANGPTL4 (p = 0.010) were observed, whereas the anti-inflammatory cytokine IL-10 was reduced (p = 0.007). Peculiar inflammation, cell death, and coagulation signatures were observed in fluids collected from DCD livers compared to those from DBD grafts. AST (p = 0.034), ALT (p = 0.047), and LDH (p = 0.047) were higher in the “EAD-yes” compared to the “EAD-no” group. Cytolysis markers and hyaluronan correlated with recipient creatinine, AST, and ICU stay. The study demonstrates that effluent molecular analysis can provide directions about the use of HOPE. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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22 pages, 5413 KiB  
Article
Combined Metabolic Activators Decrease Liver Steatosis by Activating Mitochondrial Metabolism in Hamsters Fed with a High-Fat Diet
by Hong Yang, Jordi Mayneris-Perxachs, Noemí Boqué, Josep M. del Bas, Lluís Arola, Meng Yuan, Hasan Türkez, Mathias Uhlén, Jan Borén, Cheng Zhang, Adil Mardinoglu and Antoni Caimari
Biomedicines 2021, 9(10), 1440; https://doi.org/10.3390/biomedicines9101440 - 11 Oct 2021
Cited by 8 | Viewed by 3308
Abstract
Although the prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase, there is no effective treatment approved for this condition. We previously showed, in high-fat diet (HFD)-fed mice, that the supplementation of combined metabolic activators (CMA), including nicotinamide riboside (NAD+ precursor) [...] Read more.
Although the prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase, there is no effective treatment approved for this condition. We previously showed, in high-fat diet (HFD)-fed mice, that the supplementation of combined metabolic activators (CMA), including nicotinamide riboside (NAD+ precursor) and the potent glutathione precursors serine and N-acetyl-l-cysteine (NAC), significantly decreased fatty liver by promoting fat oxidation in mitochondria. Afterwards, in a one-day proof-of-concept human supplementation study, we observed that this CMA, including also L-carnitine tartrate (LCT), resulted in increased fatty acid oxidation and de novo glutathione synthesis. However, the underlying molecular mechanisms associated with supplementation of CMA have not been fully elucidated. Here, we demonstrated in hamsters that the chronic supplementation of this CMA (changing serine for betaine) at two doses significantly decreased hepatic steatosis. We further generated liver transcriptomics data and integrated these data using a liver-specific genome-scale metabolic model of liver tissue. We systemically determined the molecular changes after the supplementation of CMA and found that it activates mitochondria in the liver tissue by modulating global lipid, amino acid, antioxidant and folate metabolism. Our findings provide extra evidence about the beneficial effects of a treatment based on this CMA against NAFLD. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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13 pages, 7155 KiB  
Article
Protective Effects of Bee Venom-Derived Phospholipase A2 against Cholestatic Liver Disease in Mice
by Jung-Yeon Kim, Hyo-Jeong Jang, Jaechan Leem and Gyun-Moo Kim
Biomedicines 2021, 9(8), 992; https://doi.org/10.3390/biomedicines9080992 - 11 Aug 2021
Cited by 13 | Viewed by 2601
Abstract
Hepatocyte apoptosis and inflammation play important roles in cholestatic liver diseases. Bee venom-derived secretory phospholipase A2 (bvPLA2) has been shown to ameliorate various inflammatory diseases. However, whether bvPLA2 has a therapeutic effect against cholestatic liver disease has not been evaluated. Therefore, we investigated [...] Read more.
Hepatocyte apoptosis and inflammation play important roles in cholestatic liver diseases. Bee venom-derived secretory phospholipase A2 (bvPLA2) has been shown to ameliorate various inflammatory diseases. However, whether bvPLA2 has a therapeutic effect against cholestatic liver disease has not been evaluated. Therefore, we investigated the effects of bvPLA2 on cholestatic liver injury and fibrosis in a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding. The administration of bvPLA2 ameliorated liver damage, cholestasis, and fibrosis in DDC diet-fed mice, as assessed by serum biochemical tests and histological examinations. In addition, bvPLA2 reduced myofibroblast accumulation, concomitant with suppression of transforming growth factor-β signaling cascade. The administration of bvPLA2 inhibited hepatocyte apoptosis in DDC diet-fed mice as represented by a reduction in the number of cells stained with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and suppression of caspase-3 activation. Moreover, bvPLA2 reduced cytokine production along with the inhibition of the nuclear factor kappa-B pathway. The number of regulatory T-cells was increased by bvPLA2, while the number of other immune cells, including neutrophils, macrophages, and CD8+ T-cells, was decreased. Our data indicate that the administration of bvPLA2 ameliorates cholestatic liver injury and fibrosis by inhibiting hepatocyte apoptosis and inflammation. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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13 pages, 1635 KiB  
Article
Circulating MicroRNA-21 and MicroRNA-122 as Prognostic Biomarkers in Hepatocellular Carcinoma Patients Treated with Transarterial Chemoembolization
by Filippo Pelizzaro, Romilda Cardin, Anna Sartori, Angela Imondi, Barbara Penzo, Camillo Aliberti, Alberto Ponzoni, Alessandro Vitale, Umberto Cillo and Fabio Farinati
Biomedicines 2021, 9(8), 890; https://doi.org/10.3390/biomedicines9080890 - 25 Jul 2021
Cited by 7 | Viewed by 1903
Abstract
Background: MicroRNAs (miRNAs) have been proposed as biomarkers in hepatocellular carcinoma (HCC). We aim at evaluating miR-21 and miR-122 in HCC patients treated with drug-eluting beads transarterial chemoembolization (DEB-TACE) as prognostic biomarkers and investigating their correlation with hypoxia inducible factor-1α (HIF-1α) serum levels. [...] Read more.
Background: MicroRNAs (miRNAs) have been proposed as biomarkers in hepatocellular carcinoma (HCC). We aim at evaluating miR-21 and miR-122 in HCC patients treated with drug-eluting beads transarterial chemoembolization (DEB-TACE) as prognostic biomarkers and investigating their correlation with hypoxia inducible factor-1α (HIF-1α) serum levels. Methods: In this retrospective study, 12 healthy subjects, 28 cirrhotics, and 54 HCC patients (tested before and four weeks after DEB-TACE) were included. Whole blood miR-21 and miR-122 levels were measured by quantitative real time (qRT)-PCR, while serum HIF-1α was assessed by an enzyme-linked immunosorbent assay (ELISA) test. Results: The highest level of miR-21 was found in cirrhotics, while HCC patients had the highest level of miR-122 (which was even higher in “viral” HCC, p = 0.006). miR-21 ratio (after/before DEB-TACE) and miR-122 below their respective cut-offs identified patients with longer progression-free survival (p = 0.0002 and p = 0.02, respectively). The combined assessment of alpha-fetoprotein and miR-21 ratio, both independent prognostic predictors, identified early progressors among patients with complete or partial radiological response. miR-21 levels positively correlated with HIF-1α before (p = 0.045) and after DEB-TACE (p = 0.035). Conclusions: miR-21 ratio and miR-122 are useful prognostic markers after DEB-TACE. miR-21 correlates with HIF-1α and probably has a role in modulating angiogenesis in HCC. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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Review

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21 pages, 1248 KiB  
Review
Cutting-Edge Therapies and Novel Strategies for Acute Intermittent Porphyria: Step-by-Step towards the Solution
by Miriam Longo, Erika Paolini, Marica Meroni and Paola Dongiovanni
Biomedicines 2022, 10(3), 648; https://doi.org/10.3390/biomedicines10030648 - 11 Mar 2022
Cited by 8 | Viewed by 3327
Abstract
Acute intermittent porphyria (AIP) is an autosomal dominant disease caused by the hepatic deficiency of porphobilinogen deaminase (PBGD) and the slowdown of heme biosynthesis. AIP symptomatology includes life-threatening, acute neurovisceral or neuropsychiatric attacks manifesting in response to precipitating factors. The latter promote the [...] Read more.
Acute intermittent porphyria (AIP) is an autosomal dominant disease caused by the hepatic deficiency of porphobilinogen deaminase (PBGD) and the slowdown of heme biosynthesis. AIP symptomatology includes life-threatening, acute neurovisceral or neuropsychiatric attacks manifesting in response to precipitating factors. The latter promote the upregulation of 5-aminolevulinic acid synthase-1 (ALAS1), the first enzyme of heme biosynthesis, which promotes the overload of neurotoxic porphyrin precursors. Hemin or glucose infusions are the first-line therapies for the reduction of ALAS1 levels in patients with mild to severe AIP, while liver transplantation is the only curative treatment for refractory patients. Recently, the RNA-interference against ALAS1 was approved as a treatment for adult and adolescent patients with AIP. These emerging therapies aim to substitute dysfunctional PBGD with adeno-associated vectors for genome editing, human PBGD mRNA encapsulated in lipid nanoparticles, or PBGD protein linked to apolipoprotein A1. Finally, the impairment of glucose metabolism linked to insulin resistance, and mitochondrial aberrations during AIP pathophysiology provided new therapeutic targets. Therefore, the use of liver-targeted insulin and insulin-mimetics such as α-lipoic acid may be useful for overcoming metabolic dysfunction in these subjects. Herein, the present review aims to provide an overview of AIP pathophysiology and management, focusing on conventional and recent therapeutical approaches. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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21 pages, 754 KiB  
Review
Impact of Sarcopenia and Myosteatosis in Non-Cirrhotic Stages of Liver Diseases: Similarities and Differences across Aetiologies and Possible Therapeutic Strategies
by Annalisa Cespiati, Marica Meroni, Rosa Lombardi, Giovanna Oberti, Paola Dongiovanni and Anna Ludovica Fracanzani
Biomedicines 2022, 10(1), 182; https://doi.org/10.3390/biomedicines10010182 - 16 Jan 2022
Cited by 13 | Viewed by 2695
Abstract
Sarcopenia is defined as a loss of muscle strength, mass and function and it is a predictor of mortality. Sarcopenia is not only a geriatric disease, but it is related to several chronic conditions, including liver diseases in both its early and advanced [...] Read more.
Sarcopenia is defined as a loss of muscle strength, mass and function and it is a predictor of mortality. Sarcopenia is not only a geriatric disease, but it is related to several chronic conditions, including liver diseases in both its early and advanced stages. Despite the increasing number of studies exploring the role of sarcopenia in the early stages of chronic liver disease (CLD), its prevalence and the relationship between these two clinical entities are still controversial. Myosteatosis is characterized by fat accumulation in the muscles and it is related to advanced liver disease, although its role in the early stages is still under researched. Therefore, in this narrative review, we firstly aimed to evaluate the prevalence and the pathogenetic mechanisms underlying sarcopenia and myosteatosis in the early stage of CLD across different aetiologies (mainly non-alcoholic fatty liver disease, alcohol-related liver disease and viral hepatitis). Secondly, due to the increasing prevalence of sarcopenia worldwide, we aimed to revise the current and the future therapeutic approaches for the management of sarcopenia in CLD. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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20 pages, 16862 KiB  
Review
Breath-Taking Perspectives and Preliminary Data toward Early Detection of Chronic Liver Diseases
by Antonio Murgia, Yusuf Ahmed, Kelly Sweeney, Louise Nicholson-Scott, Kayleigh Arthur, Max Allsworth, Billy Boyle, Olga Gandelman, Agnieszka Smolinska and Giuseppe Ferrandino
Biomedicines 2021, 9(11), 1563; https://doi.org/10.3390/biomedicines9111563 - 28 Oct 2021
Cited by 8 | Viewed by 3552
Abstract
The gold standard method for chronic liver diseases diagnosis and staging remains liver biopsy, despite the spread of less invasive surrogate modalities based on imaging and blood biomarkers. Still, more than 50% of chronic liver disease cases are detected at later stages when [...] Read more.
The gold standard method for chronic liver diseases diagnosis and staging remains liver biopsy, despite the spread of less invasive surrogate modalities based on imaging and blood biomarkers. Still, more than 50% of chronic liver disease cases are detected at later stages when patients exhibit episodes of liver decompensation. Breath analysis represents an attractive means for the development of non-invasive tests for several pathologies, including chronic liver diseases. In this perspective review, we summarize the main findings of studies that compared the breath of patients with chronic liver diseases against that of control subjects and found candidate biomarkers for a potential breath test. Interestingly, identified compounds with best classification performance are of exogenous origin and used as flavoring agents in food. Therefore, random dietary exposure of the general population to these compounds prevents the establishment of threshold levels for the identification of disease subjects. To overcome this limitation, we propose the exogenous volatile organic compounds (EVOCs) probe approach, where one or multiple of these flavoring agent(s) are administered at a standard dose and liver dysfunction associated with chronic liver diseases is evaluated as a washout of ingested compound(s). We report preliminary results in healthy subjects in support of the potential of the EVOC Probe approach. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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32 pages, 951 KiB  
Review
Genetics Is of the Essence to Face NAFLD
by Marica Meroni, Miriam Longo, Giada Tria and Paola Dongiovanni
Biomedicines 2021, 9(10), 1359; https://doi.org/10.3390/biomedicines9101359 - 30 Sep 2021
Cited by 33 | Viewed by 4459
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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18 pages, 817 KiB  
Review
HCC and Molecular Targeting Therapies: Back to the Future
by Luca Rinaldi, Erica Vetrano, Barbara Rinaldi, Raffaele Galiero, Alfredo Caturano, Teresa Salvatore and Ferdinando Carlo Sasso
Biomedicines 2021, 9(10), 1345; https://doi.org/10.3390/biomedicines9101345 - 28 Sep 2021
Cited by 25 | Viewed by 3715
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of death from cancer in the world. Recently, the effectiveness of new antiviral therapies and the HBV vaccine have reduced HCC’s incidence, while non-alcoholic steato-hepatitis is an emerging risk factor. This review focuses on [...] Read more.
Hepatocellular carcinoma (HCC) is one of the leading causes of death from cancer in the world. Recently, the effectiveness of new antiviral therapies and the HBV vaccine have reduced HCC’s incidence, while non-alcoholic steato-hepatitis is an emerging risk factor. This review focuses on antiangiogenic molecules and immune checkpoint inhibitors approved for HCC treatment and possible future approaches. Sorafenib was the first drug approved for the treatment of advanced HCC (aHCC) and it has been shown to increase survival by a few months. Lenvatinib, a multikinase inhibitor, has shown non-inferiority in survival compared with sorafenib and an improvement in progression-free survival (PFS). The combination of atezolizumab (an anti-PDL1 antibody) and bevacizumab (an anti-VEGF antibody) was the first drug combination approved for HCC, demonstrating improved survival compared with sorafenib (19.2 vs. 13.4 months). As a second line of therapy, three regimens (regorafenib, cabozantinib, and ramucirumab) have been approved for the treatment of aHCC after progression on sorafenib according to guidelines. Furthermore, nivolumab, pembrolizumab, and nivolumab plus ipilimumab have been approved by the FDA (2017, 2018, and 2020, respectively). Finally, immune target therapy, cancer vaccines, and epigenetic drugs represent three new possible weapons for the treatment of HCC. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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24 pages, 3150 KiB  
Review
Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease
by Ana Sánchez-Monteagudo, Edna Ripollés, Marina Berenguer and Carmen Espinós
Biomedicines 2021, 9(9), 1100; https://doi.org/10.3390/biomedicines9091100 - 28 Aug 2021
Cited by 19 | Viewed by 9602
Abstract
Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, [...] Read more.
Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, and other disturbances. WD has a specific treatment, so that early diagnosis is crucial to avoid disease progression and its devastating consequences. The clinical diagnosis is based on the Leipzig score, which considers clinical, histological, biochemical, and genetic data. However, even patients with an initial WD diagnosis based on a high Leipzig score may harbor other conditions that mimic the WD’s phenotype (Wilson-like). Many patients are diagnosed using current available methods, but others remain in an uncertain area because of bordering ceruloplasmin levels, inconclusive genetic findings and unclear phenotypes. Currently, the available biomarkers for WD are ceruloplasmin and copper in the liver or in 24 h urine, but they are not solid enough. Therefore, the characterization of biomarkers that allow us to anticipate the evolution of the disease and the monitoring of new drugs is essential to improve its diagnosis and prognosis. Full article
(This article belongs to the Special Issue New Challenges in the Study of Liver Diseases: From Molecular Pathogenesis to Therapeutic Approaches)
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