The janus face of serotonin: Regenerative promoter and chronic liver disease aggravator.

The progression of liver diseases, from viral hepatitis and fatty liver disease to cirrhosis and hepatocellular carcinoma (HCC), is the most representative series of pathological events in liver diseases. While serotonin (5-HT) primarily regulates brain functions such as psychology, mood, and appetite in the central nervous system (CNS), peripheral 5-HT plays a crucial role in regulating tumor development, glucose and lipid metabolism, immune function and inflammatory response related to liver diseases. These peripheral physiological processes involving 5-HT are the key mechanisms driving the development of these liver diseases. This study presents an overview of the existing literature, focusing on the role of 5-HT in HCC, cirrhosis, fatty liver disease, viral hepatitis, and liver injury. In summary, while 5-HT promotes liver regeneration, it can also contribute to the progression of chronic liver disease. These findings indicate the potential for the development and use of 5-HT-related drugs for the treatment of liver diseases, including HCC and cirrhosis.

Role of high-volume plasmapheresis in the management of paediatric acute liver failure.

OBJECTIVES: Paediatric acute liver failure (PALF) is a life-threatening disease. Management aims to support hepatic regeneration or to bridge to liver transplantation. High-volume plasmapheresis (HVP) removes protein-bound substances, alleviates inflammation, and improves survival in adult acute liver failure. However, experience with HVP in PALF is limited. Aim of this study is to report on feasibility, safety, efficacy and outcomes of HVP in PALF. METHODS: Retrospective observational study in children with PALF. HVP was performed upon identification of negative prognostic indicators, in toxic aetiology or multiorgan failure (MOF). Exchanged volume with fresh-frozen plasma corresponded to 1.5-2.0 times the patient's estimated plasma volume. One daily cycle was performed until the patient met criteria for discontinuation, that is, liver regeneration, liver transplantation, or death. RESULTS: Twenty-two children with PALF (body weight 2.5-106 kg) received 1-7 HVP cycles. No bleeding or procedure-related mortality occurred. Alkalosis, hypothermia and reduction in platelets were observed. Haemolysis led to HVP termination in one infant. Seven children (32%) survived with their native livers, 13 patients (59%) underwent liver transplantation. Two infants died due to MOF. Overall survival was 86%. International normalization ratio (INR), alanine aminotransaminases (ALT), bilirubin and inotropic support were reduced significantly (p < 0.05) after the first HVP-cycle (median): INR 2.85 versus 1.5; ALT 1280 versus 434 U/L; bilirubin 12.7 versus 6.7 mg/dL; norepinephrine dosage 0.083 versus 0.009 µg/kg/min. Median soluble-interleukin-2-receptor dropped significantly following HVP (n = 7): 2407 versus 950 U/mL (p < 0.02). CONCLUSIONS: HVP in PALF is feasible, safe, improves markers of liver failure and inflammation and is associated with lowering inotropic support. Prospective and controlled studies are required to confirm efficacy of HVP in PALF.

The Hepatic Nerves Regulated Inflammatory Effect in the Process of Liver Injury: Is Nerve the Key Treating Target for Liver Inflammation?

Liver injury is a common pathological basis for various liver diseases. Chronic liver injury is often an important initiating factor in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Currently, hepatitis A and E infections are the most common causes of acute liver injury worldwide, whereas drug toxicity (paracetamol overdose) in the USA and part of Western Europe. In recent years, chronic liver injury has become a common disease that harms human health. Meanwhile, the main causes of chronic liver injury are viral hepatitis (B, C) and long-term alcohol consumption worldwide. During the process of liver injury, massive inflammatory cytokines are stimulated by these hazardous factors, leading to a systemic inflammatory response syndrome, followed by a compensatory anti-inflammatory response, which causes immune cell dysfunction and sepsis, subsequent multi-organ failure. Cytokine release and immune cell infiltration-mediated aseptic inflammation are the most important features of the pathobiology of liver failure. From this perspective, diminishing the onset and progression of liver inflammation is of clinical importance in the treatment of liver injury. Although many studies have hinted at the critical role of nerves in regulating inflammation, there largely remains undetermined how hepatic nerves mediate immune inflammation and how the inflammatory factors released by these nerves are involved in the process of liver injury. Therefore, the purpose of this article is to summarize previous studies in the field related to hepatic nerve and inflammation as well as future perspectives on the aforementioned questions. Our findings were presented in three aspects: types of nerve distribution in the liver, how these nerves regulate immunity, and the role of liver nerves in hepatitis and liver failure.

Administration of Secretome Derived from Human Mesenchymal Stem Cells Induces Hepatoprotective Effects in Models of Idiosyncratic Drug-Induced Liver Injury Caused by Amiodarone or Tamoxifen.

Drug-induced liver injury (DILI) is one of the leading causes of acute liver injury. While many factors may contribute to the susceptibility to DILI, obese patients with hepatic steatosis are particularly prone to suffer DILI. The secretome derived from mesenchymal stem cell has been shown to have hepatoprotective effects in diverse in vitro and in vivo models. In this study, we evaluate whether MSC secretome could improve DILI mediated by amiodarone (AMI) or tamoxifen (TMX). Hepatic HepG2 and HepaRG cells were incubated with AMI or TMX, alone or with the secretome of MSCs obtained from human adipose tissue. These studies demonstrate that coincubation of AMI or TMX with MSC secretome increases cell viability, prevents the activation of apoptosis pathways, and stimulates the expression of priming phase genes, leading to higher proliferation rates. As proof of concept, in a C57BL/6 mouse model of hepatic steatosis and chronic exposure to AMI, the MSC secretome was administered endovenously. In this study, liver injury was significantly attenuated, with a decrease in cell infiltration and stimulation of the regenerative response. The present results indicate that MSC secretome administration has the potential to be an adjunctive cell-free therapy to prevent liver failure derived from DILI caused by TMX or AMI.

RNA-Sequencing Analysis Identifies Etiology Specific Transcriptional Signatures in Neonatal Acute Liver Failure.

OBJECTIVE: To assess hepatic transcriptional signatures in infants with gestational alloimmune liver disease (GALD) compared with other etiologies of neonatal acute liver failure (ALF) and older pediatric patients with ALF. STUDY DESIGN: Neonates with ALF (international normalized ratio ≥2 within 30 days of life) and deceased neonates without liver disease (<30 days of age) with available liver tissue between 2010 and 2021 were identified at Ann & Robert H. Lurie Children's Hospital of Chicago. Clinical information, liver histology, and data from RNA-sequencing analysis was compared between neonates with GALD, non-GALD etiologies of neonatal ALF, and nondiseased neonatal liver. RESULTS: Quantification of trichrome staining showed an increase in fibrosis in patients with GALD vs those with non-GALD neonatal ALF (P = .012); however, quantification of α-cytokeratin 19-positive ductules did not differ between groups (P = .244). Gene set enrichment analysis of RNA-sequencing data identified the pathways of complement activation, fibrosis, and organogenesis to be upregulated in patients with GALD with ALF. In contrast, patients with non-GALD causes of neonatal ALF had increased gene expression for interferon-driven immune pathways. Individual genes upregulated in GALD included matrix metallopeptidase 7, hepatocyte growth factor, and chemokine ligand 14. CONCLUSIONS: We have identified distinct pathways that are significantly upregulated in patients with GALD and potential disease-specific diagnostic biomarkers. Future studies will aim to validate these findings and help identify GALD-specific diagnostic biomarkers to improve diagnostic accuracy and reduce GALD-associated patient mortality.

Alleviation of cisplatin-induced hepatotoxicity and nephrotoxicity by L-carnitine.

Objectives: To assess the protective effect of L-carnitine in reducing cisplatin toxicity via estimating biochemical tests, histomorphometric, and immunohistochemistry (IHC) of ß-catenin and cyclin D. Materials and Methods: Fifteen adult male rabbits were used in this study and allocated into 3 groups; Group 1 (Control negative), rabbits of this group were not given any treatment. In group 2, the animals were injected with cisplatin single-dose/per week. Group 3 rabbits were treated with Cisplatin+L-carnitine orally by gavage tube for 29 days. At the end of the experiments, blood samples from all rabbits were taken from the earlobe, and then the biochemical test was done, the kidney and tissue sections were prepared for both H& E and IHC for both ß-catenin and cyclin D genes. Results: Treatment with L-carnitine reduced the injury effect of cisplatin via a decline in serum creatinine, urea, bilirubin, GPT, GOP, and ALP significantly (P<0.05). Also, administration of LC attenuates the histopathologic abnormality in the kidney (15.71% vs 85.18%) and liver (score 3 vs 15 ) induced by cisplatin. L-carnitine elevates the expression of ß-catenin and cyclin D in renal and hepatic parenchyma by diffuse, moderate-strong positivity vs cisplatin that showed local-weak staining. Conclusion: These findings imply that L-carnitine, by its pleiotropic actions in activating Wnt signaling, alleviates cisplatin-induced renal and hepatic destruction. It might be a method of preventing cisplatin-related nephrotoxicity and hepatotoxicity.

The Effects of Growth Factors and Cytokines on Hepatic Regeneration: A Systematic Review.

The incidence of liver disease increases throughout the years due to many lifestyle factors; thus, the only definite treatment available for chronic liver disease is a liver transplant. However, the liver has a natural ability to repair itself and regenerate its hepatic tissue from stem cells. It is hypothesized that by inducing the liver with specific growth factors and cytokines such as interleukin 6 (IL-6) compared to general growth factors like growth differentiation factor 15 (GDF-15), it can regenerate, decreasing the need for liver transplant procedures. MEDLINE, the Journal of Hepatology, and Google Scholar were used to find articles. Various studies, including epidemiological studies dated from the year 2000 and greater, were used for the introduction. The results used only randomized control trials, experimental studies, and primary articles published since 2000. This compared the results of manipulating variables to determine the effects of hepatic regeneration by either specific hepatocyte growth factors or general growth factors like GDF-15. A total of 10 collected studies showed increased levels of gene expression and function, improved gross morphology, and histological appearance of the liver when induced by cytokines and specific growth factors versus general growth factors. Overall, the hypothesis was proven. The effects of GDF-15 were not significant compared to the effects of hepatocyte-specific growth factors and cytokines like IL-6 because they have two different effects on the liver after liver injury. Future studies should investigate this topic on the human hepatic regenerative ability, plus compare the effects of general growth factors like GDF-15 and specific hepatocyte growth factors and cytokines such as IL-6 in human liver tissue.

Review on Multicomponent Hydrogel Bioinks Based on Natural Biomaterials for Bioprinting 3D Liver Tissues.

Three-dimensional (3D)-printed in vitro tissue models have been used in various biomedical fields owing to numerous advantages such as enhancements in cell response and functionality. In liver tissue engineering, several studies have been reported using 3D-printed liver tissue models with improved cellular responses and functions in drug screening, liver disease, and liver regenerative medicine. However, the application of conventional single-component bioinks for the printing of 3D in vitro liver constructs remains problematic because of the complex structural and physiological characteristics of the liver. The use of multicomponent bioinks has become an attractive strategy for bioprinting 3D functional in vitro liver tissue models because of the various advantages of multicomponent bioinks, such as improved mechanical properties of the printed tissue construct and cell functionality. Therefore, it is essential to review various 3D bioprinting techniques and multicomponent hydrogel bioinks proposed for liver tissue engineering to suggest future directions for liver tissue engineering. Accordingly, we herein review multicomponent bioinks for 3D-bioprinted liver tissues. We first describe the fabrication methods capable of printing multicomponent bioinks and introduce considerations for bioprinting. We subsequently categorize and evaluate the materials typically utilized for multicomponent bioinks based on their characteristics. In addition, we also review recent studies for the application of multicomponent bioinks to fabricate in vitro liver tissue models. Finally, we discuss the limitations of current studies and emphasize aspects that must be resolved to enhance the future applicability of such bioinks.

[Role of CXCL12-CXCR4/CXCR7 signal axis in liver regeneration and liver fibrosis].

Chemokine CXC ligand 12 (CXCL12)-chemokine receptor 4 (CXCR4) signal axis is involved in the regulation of liver injury repair and the occurrence and development of liver fibrosis. In case of acute and chronic liver injury, the expression of CXCL12 is up-regulated to collect CXCR4-positive immune cells to migrate to the liver. The CXCL12-CXCR4 pathway participates in the occurrence of liver fibrosis by promoting the activation and proliferation of hepatic stellate cells. The emergence of small molecule inhibitors of CXCR4 makes this receptor an attractive target for anti-fibrosis therapy. At present, CXCR4 has been tried as an anti-fibrosis treatment targets for fibrosis of various organs, including pulmonary fibrosis and chronic pancreatitis. However, some studies have shown that simply blocking the CXCL12/CXCR4 axis cannot improve liver fibrosis and even aggravate liver injury. In recent years, with the discovery and understanding of CXCR7, another receptor of CXCR12, the counteracting role of CXCR4-promoting fibrosis pathway and CXCR7-promoting regeneration pathway in liver regeneration and liver fibrosis has been interpreted. Therefore, a full understanding of the regulatory mechanism of CXCL12-CXCR4/CXCR7 pathway, the development of corresponding targeted therapy research for liver disease, and the rebalancing of CXCR4 and CXCR7 are expected to become a new strategy for the liver fibrosis therapy.

The adipose-derived mesenchymal stem cell secretome promotes hepatic regeneration in miniature pigs after liver ischaemia-reperfusion combined with partial resection.

BACKGROUND: Hepatic ischaemia-reperfusion injury (HIRI) is inevitable in complicated liver surgery and is a major factor leading to postoperative complications and liver dysfunction. Studies have shown that the paracrine mechanisms of stem cell may be essential to tissue repair and functional improvement after transplantation. However, the role of the adipose-derived mesenchymal stem cell secretome (ASC-secretome) in liver regeneration in large animals remains to be determined. METHODS: Twenty-four miniature pigs were subjected to laparoscopic liver ischaemia-reperfusion combined with partial hepatectomy and divided into the following four groups: the saline group, the DMEM group, the ASC group and the ASC-secretome group. Serum and liver tissue samples were collected before the operation and at 1, 3 and 7 days after the operation, and changes in tissue pathology, serum inflammation, liver function, angiogenesis-related factors and liver tissue regeneration-related genes and proteins were evaluated. RESULTS: Detailed histological analysis showed that ASCs and the ASC-secretome changed pathological damage to liver tissue after liver ischaemia-reperfusion combined with partial hepatectomy (1 and 3 days: p < 0.01). Compared with the saline and DMEM control groups, the ASC-secretome group had significantly reduced expression levels of ALP (1 and 3 days: p < 0.05), ALT (1 day: p < 0.01; 3 days: p < 0.05) and AST (1 and 3 days: p < 0.01), which promoted the recovery of liver function. Moreover, detection of the expression levels of TNF-α and IL-1ß (1 day: p < 0.01; 3 days: p < 0.05), IL-6 (1 and 3 days: p < 0.05) and IL-10 (1 and 3 days: p < 0.01) in serum confirmed that the ASC-secretome had obvious anti-inflammatory effects. In addition, the ASC-secretome increased the expression levels of ANG-1 (3 days: p < 0.01), ANG-2 (3 and 7 days: p < 0.01) and VEGF (1 and 7 days: p < 0.05; 3 days: p < 0.01) and promoted angiogenesis during liver regeneration. Moreover, it promoted the mRNA expression of HGF and Cyclin D1 (1 and 3 days: p < 0.01); increased the levels of p-STAT3 (1 and 3 days: p < 0.01), PCNA and Ki67 (1 and 3 days: p < 0.01; 7 days: p < 0.05); inhibited the negative feedback of SOCS3 (1 and 3 days: p < 0.01); and decreased the mRNA expression of TGF-ß (3 days: p < 0.01). The cytokines and growth factors detected in the ASC-secretome included TNF-α, IL-6, IL-1ß, ANG-1, ANG-2, VEGF and b-FGF. CONCLUSION: The ASC-secretome alleviates the inflammatory response induced by ischaemia-reperfusion combined with partial hepatectomy in miniature pigs and promotes liver regeneration.

Does taurolidine have any effect on liver regeneration and oxidation in the experimental hepatectomy model?

Objectives: Taurolidine is a bicyclic molecule produced by the natural amino acid taurine. Antibacterial, antiendotoxic and cytoprotective effects of taurolidine have been shown experimentally. Data on the effects of taurolidine on oxidative stress and hepatic regeneration are limited. The aim of the study was to evaluate the effect of taurolidine on hepatic regeneration and oxidative stress in rats undergoing partial hepatectomy. Material and Methods: Forty adult, male Wistar Albino rats were randomly divided into four equal groups: sham (S) group (n= 10), post-sham opera- tion taurolidine administered (ST) group (n= 10), partial hepatectomy (H) group (n= 10) and post-partial hepatectomy taurolidine administered (HT) group (n= 10). 100 mg/kg/day taurolidine was administered for seven days. Blood and liver tissue samples were collected on postoperative day seven. Liver tissue malondialdehyde, glutathione and Cu-Zn superoxide dismutase activity (SOD) were measured to assess oxidative stress. Binuclear hepato- cyte and Ki-67 antigen levels were measured to evaluate hepatic regeneration. Results: There was no difference between the groups for malondialdehyde, Cu-Zn superoxide dismutase and glutathione levels (p> 0.05). Binuclear nuclei levels were comparable between the H and HT groups (p= 0.06), while taurolidine decreased binuclear hepatocyte levels in the sham operated groups (p= 0.02). Taurolidine application decreased Ki-67 levels after partial hepatectomy (p= 0.001). Conclusion: Taurolidine may cause anti-regenerative effects after partial hepatectomy without causing oxidative damage.

Preparing for liver surgery with "Alphabet Soup": PVE, ALPPS, TAE-PVE, LVD and RL.

Future liver remnant (FLR) size and function is a critical limiting factor for treatment eligibility and postoperative prognosis when considering surgical hepatectomy. Pre-operative portal vein embolization (PVE) has been proven effective in modulating FLR and now widely accepted as a standard of care. However, PVE is not always effective due to potentially inadequate augmentation of the FLR as well as tumor progression while awaiting liver growth. These concerns have prompted exploration of alternative techniques: associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), transarterial embolization-portal vein embolization (TAE-PVE), liver venous deprivation (LVD), and radiation lobectomy (RL). The article aims to review the principles and applications of PVE and these newer hepatic regenerative techniques.

Improving the Safety of Major Resection for Hepatobiliary Malignancy: Portal Vein Embolization and Recent Innovations in Liver Regeneration Strategies.

PURPOSE OF REVIEW: For three decades, portal vein embolization (PVE) has been the "gold-standard" strategy to hypertrophy the anticipated future liver remnant (FLR) in advance of major hepatectomy. During this time, CT volumetry was the most common method to preoperatively assess FLR quality and function and used to determine which patients are appropriate surgical candidates. This review provides the most up-to-date methods for preoperatively assessing the anticipated FLR and summarizes data from the currently available strategies used to induce FLR hypertrophy before surgery for hepatobiliary malignancy. RECENT FINDINGS: Functional and physiological imaging is increasingly replacing standard CT volumetry as the method of choice for preoperative FLR assessment. PVE, associating liver partition and portal vein ligation, radiation lobectomy, and liver venous deprivation are all currently available techniques to hypertrophy the FLR. Each strategy has pros and cons based on tumor type, extent of resection, presence or absence of underlying liver disease, age, performance status, complication rates, and other factors. Numerous strategies can lead to FLR hypertrophy and improve the safety of major hepatectomy. Which is best has yet to be determined.

[Exploring the mechanism of liver enzyme abnormalities in patients with novel coronavirus-infected pneumonia].

Objective: To explore and analyze the possible mechanism of liver injury in patients with coronavirus disease 2019 (novel coronavirus pneumonia, NCP). Methods: The correlation between ALT, AST and other liver enzyme changes condition and NCP patients' disease status reported in the literature was comprehensively analyzed. ACE2 expression in liver tissue for novel coronavirus was analyzed based on single cell sequencing (GSE115469) data. RNA-Seq method was used to analyze Ace2 expression and transcription factors related to its expression in liver tissues at various time-points after hepatectomy in mouse model of acute liver injury with partial hepatectomy. t-test or Spearman rank correlation analysis was used for statistical analysis. Results: ALT and AST were abnormally elevated in some patients with novel coronavirus infection, and the rate and extent of ALT and AST elevation in severe NCP patients were higher than those in non-severe patients. Liver tissue results of single cell sequencing and immunohistochemistry showed that ACE2 was only expressed in bile duct epithelial cells of normal liver tissues, and very low in hepatocytes. In a mouse model of acute liver injury with partial hepatectomy, Ace2 expression was down-regulated on the first day, but it was elevated up to twice of the normal level on the third day, and returned to normal level on seventh day when the liver recovered and hepatocyte proliferation stopped. Whether this phenomenon suggests that the bile duct epithelial cells with positive expression of Ace2 participate in the process of liver regeneration after partial hepatectomy deserves further study. In RNA-Seq data, 77 transcription factors were positively correlated with the expression of Ace2 (r > 0.2, FDR < 0.05), which were mainly enriched in the development, differentiation, morphogenesis and cell proliferation of glandular epithelial cells. Conclusion: We assumed that in addition to the over activated inflammatory response in patients with NCP, the up-regulation of ACE2 expression in liver tissue caused by compensatory proliferation of hepatocytes derived from bile duct epithelial cells may also be the possible mechanism of liver tissue injury caused by 2019 novel coronavirus infection.

Protective Effects of Cydonia oblonga Mill. Fruit on Carbon Tetrachloride-induced Hepatotoxicity Mediated through Mitochondria and Restoration of Cellular Energy Content.

Quince (Cydonia oblonga Mill.) is one of the medicinal plant with a broad range of pharmacological activities such as hepatoprotective effect. The present study was conducted to evaluate the effect of aqueous extract of Cydonia oblonga Mill. fruit (ACOF) against carbon tetrachloride (CCl4)-induced liver damage in rats. Hepatotoxicity was induced by CCl4 and all tested group animals were treated with the plant extract at a dose of 75, 150, and 300 mg/kg orally for 5 days. Blood was collected for the assessment of serum marker enzymes (alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH)). Adenosine triphosphate (ATP) of liver mitochondria was also measured using a validated high performance liquid chromatography (HPLC) method. The antioxidant capacity of the extract resulted in the reduction of MDA and the restoration of GSH in the liver (P < 0.05). Free radical scavenging activity of the extract was evaluated by DPPH method and the IC50 value was found to be 568 µg/mL. Our results indicated that bioenergetic depletion occurred in the intoxicated rats as a consequence of mitochondrial dysfunction and ATP production collapse. ACOF markedly restored ATP contents that is a key step in liver regeneration. It can be concluded that the role of ACOF to improve liver function on CCl4-hepatoxicity could be attributed, at least partially, to its action at mitochondira by preventing the loss of ATP content.

Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells.

OBJECTIVE: Liver fibrosis constitutes a major health problem worldwide due to its rapidly increasing prevalence and the lack of specific and effective treatments. Growing evidence suggests that signalling through cytokine-activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways regulates liver fibrosis and regeneration. Rilpivirine (RPV) is a widely used anti-HIV drug not reported to produce hepatotoxicity. We aimed to describe the potential hepatoprotective effects of RPV in different models of chronic liver injury, focusing on JAK-STAT signalling regulation. DESIGN: The effects of RPV on hepatic steatosis, inflammation and fibrogenesis were studied in a nutritional mouse model of non-alcoholic fatty liver disease, carbon tetrachloride-induced fibrosis and bile duct ligation-induced fibrosis. Primary human hepatic stellate cells (hHSC) and human cell lines LX-2 and Hep3B were used to investigate the underlying molecular mechanisms. RESULTS: RPV exerted a clear anti-inflammatory and antifibrotic effect in all the in vivo models of liver injury employed, and enhanced STAT3-dependent proliferation in hepatocytes and apoptosis in HSC through selective STAT1 activation. These results were reproduced in vitro; RPV undermined STAT3 activation and triggered STAT1-mediated pathways and apoptosis in HSC. Interestingly, this selective pro-apoptotic effect completely disappeared when STAT1 was silenced. Conditioned medium experiments showed that HSC apoptosis activated STAT3 in hepatocytes in an interleukin-6-dependent mechanism. CONCLUSION: RPV ameliorates liver fibrosis through selective STAT1-dependent induction of apoptosis in HSC, which exert paracrinal effects in hepatocytes, thus promoting liver regeneration. RPV's actions may represent an effective strategy to treat chronic liver diseases of different aetiologies and help identify novel therapeutic targets.

Exploring the mechanism of liver enzyme abnormalities in patients with novel coronavirus-infected pneumonia / 中华肝脏病杂志

Objective@#To explore and analyze the possible mechanism of liver injury in patients with coronavirus disease 2019 (novel coronavirus pneumonia, NCP).@*Methods@#The correlation between ALT, AST and other liver enzyme changes condition and NCP patients’ disease status reported in the literature was comprehensively analyzed. ACE2 expression in liver tissue for novel coronavirus was analyzed based on single cell sequencing (GSE115469) data. RNA-Seq method was used to analyze Ace2 expression and transcription factors related to its expression in liver tissues at various time-points after hepatectomy in mouse model of acute liver injury with partial hepatectomy. t-test or Spearman rank correlation analysis was used for statistical analysis.@*Results@#ALT and AST were abnormally elevated in some patients with novel coronavirus infection, and the rate and extent of ALT and AST elevation in severe NCP patients were higher than those in non-severe patients. Liver tissue results of single cell sequencing and immunohistochemistry showed that ACE2 was only expressed in bile duct epithelial cells of normal liver tissues, and very low in hepatocytes. In a mouse model of acute liver injury with partial hepatectomy, Ace2 expression was down-regulated on the first day, but it was elevated up to twice of the normal level on the third day, and returned to normal level on seventh day when the liver recovered and hepatocyte proliferation stopped. Whether this phenomenon suggests that the bile duct epithelial cells with positive expression of Ace2 participate in the process of liver regeneration after partial hepatectomy deserves further study. In RNA-Seq data, 77 transcription factors were positively correlated with the expression of ACE2 (r > 0.2, FDR < 0.05), which were mainly enriched in the development, differentiation, morphogenesis and cell proliferation of glandular epithelial cells.@*Conclusion@#We assumed that in addition to the over activated inflammatory response in patients with NCP, the up-regulation of ACE2 expression in liver tissue caused by compensatory proliferation of hepatocytes derived from bile duct epithelial cells may also be the possible mechanism of liver tissue injury caused by 2019 novel coronavirus infection.

Exploring the mechanism of liver enzyme abnormalities in patients with novel coronavirus-infected pneumonia / 中华肝脏病杂志

To explore and analyze the possible mechanism of liver injury in patients with coronavirus disease 2019 (novel coronavirus pneumonia, NCP). The correlation between ALT, AST and other liver enzyme changes condition and NCP patients' disease status reported in the literature was comprehensively analyzed. ACE2 expression in liver tissue for novel coronavirus was analyzed based on single cell sequencing (GSE115469) data. RNA-Seq method was used to analyze Ace2 expression and transcription factors related to its expression in liver tissues at various time-points after hepatectomy in mouse model of acute liver injury with partial hepatectomy. -test or Spearman rank correlation analysis was used for statistical analysis. ALT and AST were abnormally elevated in some patients with novel coronavirus infection, and the rate and extent of ALT and AST elevation in severe NCP patients were higher than those in non-severe patients. Liver tissue results of single cell sequencing and immunohistochemistry showed that ACE2 was only expressed in bile duct epithelial cells of normal liver tissues, and very low in hepatocytes. In a mouse model of acute liver injury with partial hepatectomy, Ace2 expression was down-regulated on the first day, but it was elevated up to twice of the normal level on the third day, and returned to normal level on seventh day when the liver recovered and hepatocyte proliferation stopped. Whether this phenomenon suggests that the bile duct epithelial cells with positive expression of Ace2 participate in the process of liver regeneration after partial hepatectomy deserves further study. In RNA-Seq data, 77 transcription factors were positively correlated with the expression of ACE2 (r > 0.2, FDR < 0.05), which were mainly enriched in the development, differentiation, morphogenesis and cell proliferation of glandular epithelial cells. We assumed that in addition to the over activated inflammatory response in patients with NCP, the up-regulation of ACE2 expression in liver tissue caused by compensatory proliferation of hepatocytes derived from bile duct epithelial cells may also be the possible mechanism of liver tissue injury caused by 2019 novel coronavirus infection.

Current progress in hepatic tissue regeneration by tissue engineering.

BACKGROUND: Liver, as a vital organ, is responsible for a wide range of biological functions to maintain homeostasis and any type of damages to hepatic tissue contributes to disease progression and death. Viral infection, trauma, carcinoma, alcohol misuse and inborn errors of metabolism are common causes of liver diseases are a severe known reason for leading to end-stage liver disease or liver failure. In either way, liver transplantation is the only treatment option which is, however, hampered by the increasing scarcity of organ donor. Over the past years, considerable efforts have been directed toward liver regeneration aiming at developing new approaches and methodologies to enhance the transplantation process. These approaches include producing decellularized scaffolds from the liver organ, 3D bio-printing system, and nano-based 3D scaffolds to simulate the native liver microenvironment. The application of small molecules and micro-RNAs and genetic manipulation in favor of hepatic differentiation of distinct stem cells could also be exploited. All of these strategies will help to facilitate the application of stem cells in human medicine. This article reviews the most recent strategies to generate a high amount of mature hepatocyte-like cells and updates current knowledge on liver regenerative medicine.

Chemotherapeutic doses of arsenic trioxide delays hepatic regeneration by oxidative stress and hepatocyte apoptosis in partial hepatectomy rat.

The extensive regeneration potential of the liver makes use of hepatic re-sectioning and split liver transplantation for treating advanced liver diseases. Heavy metals such as cisplatin, carboplatin, and arsenic trioxide (ATO) are being practiced as chemotherapeutic agents for different cancers. Further, research is progressed on using different heavy metal nano-particles as a drug, drug carrier and diseases detective agent. Since liver is the chief organ metabolize ingested materials, the current study focuses on the involvement of ATO on acute liver injury regeneration using a partially hepatectomised (PHx) rat model. Scrutiny of serum liver markers such as albumin, AST, ALT & ALP and hepatic antioxidants like reduced glutathione, glutathione peroxidase, glutathione S-transferase, catalase & superoxide dismutase reveled ATO mediated hepatocyte injury and oxidative stress. Further, oxidative stress is confirmed with elevated TBARS and 8-OHdG in the hepatocyte nucleus in ATO supplemented healthy and regenerating liver and are co-relating with the H&E histological observations. It is noticed that ATO supplementation reduced liver regeneration potential as evidenced by reduced proliferative markers (Ki-67 and PCNA) and meanwhile increases apoptotic protein PARP-1. ICP-MS analysis displayed several-fold hiked serum and liver arsenic in ATO administrated normal and liver regenerating animals. This study concludes that ATO at a chemotherapeutic concentration augments oxidative stress and hepatocytes apoptosis, thereby delays liver regeneration potential and could affect the outcome of liver transplantation.