Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) as a wound healing process. Activated hepatic stellate cells (HpSCs) are the major producer of the ECM and play a central role in liver fibrogenesis. It has been widely accepted that elimination of activated HpSCs or reversion to a quiescent state can be a feasible strategy for resolving the disease, further highlighting the urgent need for novel therapeutic targets. Calreticulin (CRT) is a molecular chaperone that normally resides in the endoplasmic reticulum (ER), important in protein folding and trafficking through the secretory pathway. CRT also plays a critical role in calcium (Ca2+) homeostasis, with its Ca2+ storage capacity. In the current study, we aimed to demonstrate its function in directing HpSC activation. In a mouse liver injury model, CRT was up-regulated in HpSCs. In cellular experiments, we further showed that this activation was through modulating the canonical TGF-ß signaling. As down-regulation of CRT in HpSCs elevated intracellular Ca2+ levels through a form of Ca2+ influx, named store-operated Ca2+ entry (SOCE), we examined whether moderating SOCE affected TGF-ß signaling. Interestingly, blocking SOCE had little effect on TGF-ß-induced gene expression. In contrast, inhibition of ER Ca2+ release using the inositol trisphosphate receptor inhibitor 2-APB increased TGF-ß signaling. Treatment with 2-APB did not alter SOCE but decreased intracellular Ca2+ at the basal level. Indeed, adjusting Ca2+ concentrations by EGTA or BAPTA-AM chelation further enhanced TGF-ß-induced signaling. Our results suggest a crucial role of CRT in the liver fibrogenic process through modulating Ca2+ concentrations and TGF-ß signaling in HpSCs, which may provide new information and help advance the current discoveries for liver fibrosis.
BACKGROUND AND AIMS: The impact of antibody responses following direct-acting antiviral (DAA) therapy in hepatitis C virus (HCV)-infected recipients before and after liver transplantation (LT) is still undetermined. METHODS: In this observational cohort study, we aimed to explore the association between changes in anti-HCV antibody titers following pre-LT DAA therapy and allograft injury, including biliary complications (BCs) and acute cellular rejection (ACR). RESULTS: A total of 153 cases were enrolled from January 2015 to February 2021. Serum anti-HCV antibody titers were assessed before and after (day 30) LT. Among all recipients, 31/153 (20.3%) had pre-LT DAA therapy (the DAA group) and 122/153 (79.7%) did not undergo pre-LT DAA therapy (the DAA-naïve group). A higher incidence of post-LT BCs was observed in the DAA group (p = 0.028). Compared with the DAA-naïve group, the DAA group had a significantly higher mean level of anti-HCV titer upregulation (p = 0.0024); furthermore, among the recipients with BCs (n = 28) and ACR (n = 41), those in the DAA group exhibited significantly higher mean levels of anti-HCV antibody titer upregulation (p < 0.005). CONCLUSIONS: In conclusion, we speculate that the upregulation of anti-HCV antibody titers, which might have been induced via the restoration of HCV-specific immune responses through pre-LT DAA therapy, was associated with post-LT allograft injury.
Background: Acute jaundice remains a critical problem following liver transplantation. MicroRNAs (miRNAs) are involved in regulating gene expression related to various disease phenotypes and statuses. Aims: To differentiate acute jaundice etiology after living donor liver transplantation (LDLT), we examined the hepatic miRNA expression patterns in several liver graft pathologies. Methods: Eighty liver transplant recipients undergoing post-LDLT graft biopsy for the evaluation of acute jaundice were enrolled in this 1-year prospective study. Using a real-time quantitative reverse transcription-polymerase chain reaction profiling assay, we identified hepatic miRNA (miRNA-122, miRNA-301, miRNA-133a, and miRNA-21) signatures in various allografts pathologies. Results: Pathologic findings of the 80 recipients were as follows: acute cholangitis (AC), 37 (46%); acute rejection (AR), 20 (25%); recurrent hepatitis (RH), 12 (15%); non-specific pathological change, 6 (8%); and fatty change (FC), 5 (6%). None of these identified hepatic miRNAs expression pattern was significantly correlated with serum parameters, including neutrophil-lymphocyte ratio. In AC, hepatic miRNA-122, miRNA-301, miRNA-133a, and miRNA-21 expression was significantly downregulated (p < 0.05). MicroRNA-122 expression was elevated in cases of AR and RH (p < 0.05); miRNA-301 and miRNA-21 expression was higher in RH than in AC (p < 0.05); and miRNA-133a expression was higher in FC than in AR (p < 0.05). Conclusions: Our study suggests that specific hepatic miRNA expression patterns as a checklist may be useful for differential diagnosis of acute jaundice following liver transplantation.
BACKGROUND: Most cases of advanced liver diseases are associated with low serum 25-hydroxyvitamin D and vitamin D deficiency. This phenomenon may occur in living donor liver transplantation (LDLT). AIMS: We conducted this study to explore the interplay between VDR and CYP2R1 in liver graft and compared our findings with the pathological interpretation of serum 25(OH)D concentration. METHODS: In total, 60 patients received liver graft biopsy after LDLT and were separated (1:1) into two groups: graft rejection group and graft non-rejection group. We extracted both of the recipients' and donors' serum DNA to investigate the vitamin D receptor (VDR) rs2228530 and CYP2R1 rs10741657 single nucleotide polymorphisms (SNPs) using real-time polymerase chain reaction. We also extracted DNA from liver graft tissues to explore the genetic alleles of VDR rs2228530 and CYP2R1 rs10741657 after LDLT. Serum biochemistry profile and 25(OH)D concentrations were measured before and after LDLT. RESULTS: There were no significant differences in serum VDR rs2228530 and CYP2R1 rs10741657 genetic alleles between recipients and donors. The percentage of genetic modification was 33.4% (10/30) for the rejection and non-rejection groups in VDR rs2228530, and 66.7% (20/30) for both groups in CYP2R1 rs10741657. Serum 25(OH)D concentrations were significantly lower after LDLT D30 than that before LDLT in the rejection (p = 0.0001) and non-rejection graft pathology (p = 0.0017) groups. CONCLUSIONS: The presence of low serum 25(OH)D concentrations after LDLT suggested that post-transplant low serum 25(OH)D concentrations may develop with the homogenous phenomenon of VDR rs2228530 and CYP2R1 rs10741657 genetic modifications in recipients regardless of graft pathology.
Background: Atypical antipsychotics such as olanzapine often cause metabolic side effects such as obesity and diabetes, leading to an increased risk of nonalcoholic fatty liver disease. The aim of the present study was to investigate the effects of olanzapine treatment on hepatic lipid metabolism and its possible relationship with adipose tissue status. Methods: Using a female rat model, we investigated the effects of chronic olanzapine administration on the regulation of carbohydrate and lipid metabolism including lipid biosynthesis, oxidation, efflux, and lipolysis in liver and adipose tissue. Results: The body weight, liver mass and visceral adiposity after olanzapine treatment (2 mg/kg) for five weeks were not significantly different compared with vehicle controls. The serum level of triglycerides was higher in the vehicle controls than in olanzapine-treated rats. Unexpectedly, olanzapine treatment did not reduce glucose tolerance in our model. The expression of functional thermogenic protein uncoupling protein 1 (UCP1) was increased in brown adipose tissue (BAT) of the olanzapine group. Additionally, olanzapine treatment also reduced adipose inflammation in white adipose tissue (WAT). The transcription factor sterol regulatory element-binding protein (SREBP)-1c, a key early regulator of lipogenesis, was downregulated following olanzapine treatment. The expression of genes related to the triglycerides synthesis apparatus in the liver was upregulated in the olanzapine group. Olanzapine treatment induced genes involved in PPAR-α signaling and mitochondrial fatty acid oxidation in response to increased ATGL-mediated lipolysis in the liver. Conclusion: Together, our findings suggest a complicated link between olanzapine therapy and metabolic disturbance and may garner interest in assessing the action of antipsychotic-induced metabolic disturbances.
BACKGROUND: Hepatocellular carcinoma (HCC) ranks many tasks in clinical oncology due to possibly developing a general tumor in men and, usually lead to malignant to death within years. Researches had reported about major factors for being HCC was male sex and HCC associated with cirrhosis in childhood was found more common in males than females. In certain mouse strains as studied, breeding with testosterone significantly increases the development of HCC. Furthermore, castration of male mice diminished the frequency of the development of liver tumors. Meanwhile male hepatitis B virus transgenic mice have a greater occurrence of HCC than females. METHODS: We apply degenerate priming PCR to observe the expression of various steroid receptors in livers. Yeast-two hybrid screening to search a novel RNA fragment helps to find a new full-length gene by RACE experiment. RT-PCR is applied to detect various expressions in tissues and cell lines. In situ hybridization detects DNA in Chromosome mapping. GFP-constructs transfection proves the gene localization in cells. Immunoprecipitation pulldown assay verifies protein interaction. Gene transfection followed with luciferase assay demonstrates the interaction of genes within cellular signaling. Genomic alignment analysis for observing sequences data perform from NCBI database website (http://www.ncbi.nim.nih.gov/genebank/). RESULTS: The androgen receptor (AR) expression level is found at the highest level among the steroid receptors families detected in liver tumors. By yeast-two hybrid screening, we cloned an Androgen Receptor Complex Associated Protein (ARCAP), of 95 Kd in molecular weight and its cDNA. ARCAP locates at Chromosome 1. Our findings indicate ARCAP is highly expressed in hepatoma cell lines and liver tumors and their adjacent tumors as observed. Yeast two-hybrid assay and in vitro immunoprecipitation assays demonstrated an interaction between AR and ARCAP. CONCLUSION: We aim to search for different types and levels of steroid receptors expressed within human HCCs and in the adjacent liver tissues. To verify possible molecular mechanisms by which AR might affect hepatoma cells, we had characterized a novel protein ARCAP which functions as a coregulator to interact with AR within liver. The ligand-dependent AR with its cofactor, ARCAP, can induce a signal cascade by transactivation.
Carcinoma, Hepatocellular/physiopathology , Liver Neoplasms , Liver/metabolism , Liver/physiopathology , Receptors, Androgen/metabolism , Animals , Hepatitis B virus , Male , Mice , Receptors, Androgen/genetics
OBJECTIVE: To compare hepatitis C virus (HCV) RNA levels from serum and explanted native liver samples from patients undergoing living donor liver transplantation (LDLT). METHODS: This was a prospective observational study. Serum and liver samples were collected from consecutive serum anti-HCV-positive transplant recipients between February 2016 to August 2019. HCV RNA was extracted from liver samples and subjected to one-step reverse-transcription qPCR. using the TopScript One Step qRT-PCR Probe Kit with HCV qPCR probe assay and human GAPDH qPCR probe assay on a ViiA7 Real-Time PCR System. RESULTS: Among the 80 patients, 36% (29/80) were HCV RNA positive in serum and 85% (68/80) had positive hepatic HCV RNA. Post-liver transplantation, 4% (3/80) patients were serum positive. CONCLUSIONS: Our study suggests that pre-transplant serum HCV RNA levels may give an underestimate of the number of positive HCV RNA cases and that hepatic HCV RNA data may be more accurate.
Hepatitis C , Liver Transplantation , Hepacivirus/genetics , Humans , Liver , Living Donors , RNA , RNA, Viral/genetics
Increasing evidence has suggested that elevated systemic inflammation with a high neutrophil-lymphocyte ratio (NLR) is associated with poor prognosis after liver transplantation (LT). The ongoing molecular events involved in poor survival remain unclear. This retrospective study evaluated LT recipients whose data was collected at Kaohsiung Chang Gung Memorial Hospital between 2005 and 2014. Clinical records of 347 patients with hepatocellular carcinoma from seven days before LT to 30 days after LT illustrated that longitudinal values of lymphocytes, RBC, and hemoglobin were persistently low in patients with peritransplant high NLR (PTH-NLR, pre-LT ≥ 4 and post-LT ≥ 5), which indicated a significantly worse survival rate in association with increased RDW-CV and pancytopenia when compared to other patients (p = 0.008). We further found that PTH-NLR patients had decreased DNA damage response (DDR) genes and detoxifying enzymes of ADH and ALDH families, and increased mitochondrial stress response genes in their liver tissues. Reduced lineage markers of liver progenitor cells were also observed in PTH-NLR patients signifying the presence of unresolved impairments after LT. Our results demonstrate the association between hematopoietic deficiencies and lack of protection against DDR with PTH-NLR in LDLT recipients with HCC and may imply abnormal hematological and organismal defects in those patients.
The liver plays a central role in energy metabolism. Dysregulated hepatic lipid metabolism is a major cause of non-alcoholic fatty liver disease (NAFLD), a chronic liver disorder closely linked to obesity and insulin resistance. NAFLD is rapidly emerging as a global health problem with currently no approved therapy. While early stages of NAFLD are often considered benign, the disease can progress to an advanced stage that involves chronic inflammation, with increased risk for developing end-stage disease including fibrosis and liver cancer. Hence, there is an urgent need to identify potential pharmacological targets. Ca2+ is an essential signaling molecule involved in a myriad of cellular processes. Intracellular Ca2+ is intricately compartmentalized, and the Ca2+ flow is tightly controlled by a network of Ca2+ transport and buffering proteins. Impaired Ca2+ signaling is strongly associated with endoplasmic reticulum stress, mitochondrial dysfunction and autophagic defects, all of which are etiological factors of NAFLD. In this review, we describe the recent advances that underscore the critical role of dysregulated Ca2+ homeostasis in lipid metabolic abnormalities and discuss the feasibility of targeting Ca2+ signaling as a potential therapeutic approach.
Calcium Signaling , Non-alcoholic Fatty Liver Disease/metabolism , Animals , Endoplasmic Reticulum/metabolism , Homeostasis , Humans , Mitochondria/metabolism , Molecular Targeted Therapy
Liver transplantation (LT) is an essential treatment for end-stage alcoholic liver disease (ALD). The patients' psychosocial condition plays a vital role in post-transplantation prognosis. A survey of the candidates' psychosocial wellbeing is necessary before LT. This study aims to investigate the psychosocial characteristics, including the depression degree, family function, alcohol use duration, and alcohol abstinence period, of LT candidates with ALD. In addition, 451 candidates for LT due to ALD were enrolled. They received psychosocial evaluations, including depression scale (Hamilton depression rating scale) and family functioning assessment (adaptability, partnership, growth, affection, resolve (APGAR) index). The test scores were analyzed according to age, alcohol use duration, and alcohol abstinence period. The Hamilton depression rating scale (HAM-D) score and the family APGAR index score differentiated significantly according to the age, alcohol use duration, and abstinence period of the LT candidates. The patients with shorter alcohol use duration tended to have more severe depressive symptoms and poorer family support. The younger patients showed a significantly shorter abstinence period, more severe depression, and poorer family functioning than older patients. The younger ALD patients and patients with shorter alcohol use duration showed an increased severity of depression before transplantation. They need more mental health care over time.
Liver Diseases, Alcoholic , Liver Transplantation , Adult , Female , Humans , Liver Diseases, Alcoholic/epidemiology , Liver Diseases, Alcoholic/surgery , Liver Transplantation/psychology , Male , Middle Aged , Recurrence , Retrospective Studies , Risk Factors , Taiwan/epidemiology
Alcohol-associated liver disease (ALD) is a common indication for liver transplantation (LT). Alcohol relapse after LT is associated with graft loss and worse prognosis. Over the past 20 years, the number and prevalence of living donor liver transplantations (LDLTs) have increased in Taiwan. The aims of this retrospective study are to analyze the incidence and risk factors of alcohol relapse after LT at a single center in Taiwan. A total of 98 patients with ALD who underwent LT from January 2012 to December 2018 were retrospectively evaluated by chart review. Pre-transplant characteristics as well as psychosocial and alcoholic history were used to test the possible associations among the risk factors studied and post-LT alcohol relapse. The incidence of post-LT alcohol relapse was 16.3%. The median duration of alcohol relapse after liver transplantation was 28.1 months (range: 1-89.4 months). The cumulative incidence was 12% and 19% at 1 year and 3 years after LT, respectively. The most powerful risk factors were a pre-LT abstinence period less than 6 months and younger age of starting alcohol. For predicting alcohol relapse, the accuracy rate of abstinence less than 6 months was up to 83.7%. In summary, pre-abstinence period plays a role in predicting post-LT alcohol relapse. Post-LT interventions should be considered specifically for the patients with short abstinence period. Long-term follow-up, patient-centered counseling, and enhancement of healthy lifestyle are suggested to prevent alcohol relapse.
MicroRNAs (miRNAs) are a class of short non-coding RNAs that play a significant role in biological processes in various cell types, including mesenchymal stem cells (MSCs). However, how miRNAs regulate the immunomodulatory functions of adipose-derived MSCs (AD-MSCs) remains unknown. Here, we showed that modulation of miR-301a in AD-MSCs altered macrophage polarization. Bone marrow (BM)-derived macrophages were stimulated with LPS (1 µg/ml) and co-cultured with miRNA transfected AD-MSCs for 24 h. The expression of M1 and M2 markers in macrophages was analyzed. Inhibition of miR-301a induced M2 macrophage with arginase-1, CD163, CD206, and IL-10 upregulation. Additionally, toll-like receptor (TLR)-4 mRNA expression in macrophages was downregulated in co-cultures with AD-MSCs transfected with a miR-301a inhibitor. Nitric oxide (NO) in the supernatant of AD-MSC/macrophage co-culture was also suppressed by inhibition of miR-301a in AD-MSCs. We further found that suppression of miR-301a in AD-MSCs increased prostaglandin E2 (PGE2) concentration in the conditioned medium of the co-culture. Taken together, the results of our study indicate that miR-301a can modulate the immunoregulatory functions of AD-MSCs that favor the applicability as a potential immunotherapeutic agent.
Abdominal Fat/cytology , Cell Communication , Cell Plasticity , Macrophages/metabolism , Mesenchymal Stem Cells/metabolism , MicroRNAs/metabolism , Animals , Biomarkers/metabolism , Cells, Cultured , Coculture Techniques , Gene Expression Regulation , Macrophages/immunology , Mesenchymal Stem Cells/immunology , MicroRNAs/genetics , Phenotype , Rats, Inbred Lew , Signal Transduction
Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver diseases worldwide, ranges from simple steatosis to steatohepatitis, with the risk for progressive fibrosis or even cirrhosis. While simple steatosis is a relatively benign condition, the buildup of toxic lipid metabolites can induce chronic inflammation, ultimately triggering disease progression. Pigment epithelium-derived factor (PEDF) is a secreted, multifunctional glycoprotein with lipid metabolic activities. PEDF promotes lipolysis through binding to adipose triglyceride lipase (ATGL), a key enzyme for triglyceride breakdown. In the current study, we aimed to delineate how changes in PEDF expression affect hepatic lipid accumulation. Our data revealed that hepatic PEDF was downregulated in a mouse NAFLD model. We further showed that decreased PEDF levels in hepatocytes in vitro resulted in elevated fatty acid uptake and lipid droplet formation, with concomitant upregulation of fatty acid transport proteins CD36 and fatty acid binding protein 1 (FABP1). RNA sequencing analysis of PEDF knocked down hepatocytes revealed an alteration in gene expression profile toward lipid accumulation. Additionally, decreased PEDF promotes mobilization of fatty acids, an observation distinct from blocking ATGL activity. Taken together, our data suggest that hepatic PEDF downregulation causes molecular changes that favor triglyceride accumulation, which may further lead to NAFLD progression.
Eye Proteins/metabolism , Fatty Acids/metabolism , Hepatocytes/metabolism , Lipid Droplets/metabolism , Liver/metabolism , Nerve Growth Factors/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , Serpins/metabolism , Animals , CD36 Antigens/metabolism , Cell Line, Tumor , Disease Models, Animal , Disease Progression , Down-Regulation , Eye Proteins/genetics , Fatty Acid-Binding Proteins/metabolism , Hepatocytes/pathology , Humans , Liver/pathology , Male , Mice, Inbred C57BL , Nerve Growth Factors/genetics , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/pathology , Serpins/genetics
The International Liver Transplantation Society (ILTS) 2019 Annual Congress was held in Toronto, Canada, in May 2019. Members of the ILTS Basic and Translational Research Committee attended all sessions of the meeting and selected the most promising, innovative, and novel research presented. A total of 900 abstracts were presented at the meeting. The percentage of abstracts presented at the ILTS Congress that contains basic or translational research continues to increase, accounting for 15% of all the abstracts in 2019, up from 10% in 2018. Here, we summarize the "what's hot what's new" in 5 main themes: liver immunobiology and tolerance, ischemia/reperfusion injury and organ preservation, bioengineering and liver regeneration, hepatic primary tumor biology, and pathophysiology of liver failure.
Biomedical Research/trends , Congresses as Topic , International Cooperation , Liver Transplantation/trends , Allografts/immunology , Bioengineering/trends , Canada , Graft Rejection/immunology , Graft Survival/immunology , Humans , Liver/immunology , Liver Failure/etiology , Liver Failure/pathology , Liver Failure/surgery , Liver Neoplasms/etiology , Liver Neoplasms/pathology , Liver Neoplasms/surgery , Liver Transplantation/adverse effects , Organ Preservation/methods , Organ Preservation/trends , Regeneration/immunology , Reperfusion Injury/etiology , Societies, Medical , Tissue and Organ Procurement/methods , Tissue and Organ Procurement/trends , Transplantation Tolerance
A recurrence of hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) is one of the major concerns reflecting the higher mortality of HCC. This study aimed to explore the impact of circulating exosomes on HCC development and recurrence. One-shot transfusion of hepatoma serum to naïve rats induced liver cancer development with gradual elevation of alpha-fetoprotein (AFP), but exosome-free hepatoma serum failed to induce AFP elevation. The microarray analysis revealed miR-92b as one of the highly expressing microribonucleic acids in hepatoma serum exosomes. Overexpression of miR-92b enhanced the migration ability of liver cancer cell lines with active release of exosomal miR-92b. The hepatoma-derived exosomal miR-92b transferred to natural killer (NK) cells, resulting in the downregulation of CD69 and NK cell-mediated cytotoxicity. Furthermore, higher expression of miR-92b in serum exosomes was confirmed in HCC patients before LDLT, and its value at 1 month after LDLT was maintained at a higher level in the patients with posttransplant HCC recurrence. In summary, we demonstrated the impact of circulating exosomes on liver cancer development, partly through the suppression of CD69 on NK cells by hepatoma-derived exosomal miR-92b. The value of circulating exosomal miR-92b may predict the risk of posttransplant HCC recurrence.
Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/diagnosis , Liver Transplantation/adverse effects , MicroRNAs/genetics , Neoplasm Recurrence, Local/diagnosis , Postoperative Complications/diagnosis , Animals , Carcinoma, Hepatocellular/etiology , Cell Proliferation , Exosomes , Female , Gene Expression Regulation, Neoplastic , Liver Neoplasms, Experimental/diagnosis , Liver Neoplasms, Experimental/etiology , Male , Mice , Mice, Inbred BALB C , Neoplasm Recurrence, Local/etiology , Postoperative Complications/etiology , Rats
Liver Transplantation , Science/trends , Bioengineering , Bioprinting , Carcinoma, Hepatocellular/surgery , Humans , Liver Neoplasms/surgery , Liver Transplantation/adverse effects , Liver, Artificial , Organ Preservation , Reperfusion Injury/prevention & control , Societies, Medical , Transplantation, Heterologous
Adipogenesis is a tightly regulated cellular process that involves the action of multiple signaling pathways. Characterization of regulators that are associated with adipose development is crucial to understanding the mechanisms underlying obesity and other metabolic disorders. Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein that was first described as a neurotrophic factor. The role of PEDF in lipid metabolism was established when adipose triglyceride lipase (ATGL), a major triglyceride hydrolase, was characterized as its binding partner. In this study, we investigated the downstream effects of PEDF on adipogenic differentiation using rat adipose-derived stem cells (AdSCs) and the mouse pre-adipocyte cell line 3T3-L1. Knocking down PEDF in differentiating cells resulted in elevated levels of ATGL and CD36, as well as other adipogenic markers, with a concomitant increase in adipocyte number. CD36, a scavenger receptor for a variety of ligands, regulated proliferation and lipogenic gene expression during adipogenesis. The CD36 increase due to PEDF down-regulation might be a result of elevated PPARγ. We further demonstrated that PEDF expression was regulated by dexamethasone, a synthetic glucocorticoid that is widely used for adipogenesis at the transcriptional level. Taken together, our findings highlight that PEDF negatively regulates adipogenesis through the regulation of various signaling intermediates, and it may play a crucial role in lipid metabolic disorders.
Adipogenesis/drug effects , CD36 Antigens/metabolism , Cell Differentiation/drug effects , Eye Proteins/metabolism , Nerve Growth Factors/metabolism , Serpins/metabolism , 3T3-L1 Cells , Adipose Tissue/cytology , Animals , Cells, Cultured , Dexamethasone/pharmacology , Lipase/metabolism , Mice , Rats , Stem Cells/cytology , Stem Cells/drug effects
OBJECTIVE: : Coagulation factor VII (FVII) triggers the extrinsic pathway of blood coagulation. In our previous study, we showed that FVII plays an important role in tumorigenesis of hepatocellular carcinoma (HCC). However, the role of FVII polymorphism in HCC is still unknown. The present study aimed to investigate the relationship between HCC carcinogenesis and single nucleotide polymorphism of FVII. METHODS: : Thirty-seven HCC patients and 30 healthy donors were recruited in this study. Four common FVII gene polymorphisms - a decanucleotide insertion at position -323 (-323ins10-bp), a G to T substitution at position -401 (-401G/T), a G to A substitution at position -402 (-402G/A), and a T to C substitution at position -122 (-122T/C) - were analyzed by sequencing or commercialized assays using genomic DNA isolated from blood samples. Clinicopathological parameters between control and HCC subjects were compared according to the specific genotypes. RESULTS: : The most common nucleotide variation was -402G/A. However, no statistically significant difference was observed between healthy controls and HCC subjects for all four polymorphisms in terms of genotype distribution and allele frequencies, indicating that these polymorphisms may not affect HCC tumorigenesis. Furthermore, no association was found between -402G/A polymorphisms and tumor stage, recurrence, and overall survival. CONCLUSIONS: : Our results indicate that FVII polymorphisms may not be a key factor that clinically impact tumorigenesis and outcomes of HCC, although further investigations should be conducted to confirm our findings.
BACKGROUND: Living donor liver transplantation (LDLT) has been developed as one of gold standard treatments for end-stage liver disease. Mental health is a required selection criterion for adult living liver donors and may influence the quality of life after operation. PATIENTS AND METHODS: A total of 1,210 potential living donor candidates for liver transplantation (LT) underwent psychosocial evaluation that included a semi-structured interview, multi-choice self-reported inventory (Beck Depression Inventory-2nd edition [BDI-II], Beck Anxiety Inventory [BAI]), and the family APGAR (Adaptability, Partnership, Growth, Affection, Resolve) index. The test results were compared by family relationships, and subgroups were classified based on the donation type: 1) parents to children, 2) grown children to parents, 3) siblings to siblings, 4) spouses to spouses, and 5) other relatives to other relatives. RESULTS: The BDI-II (P < 0.001) and BAI differed considerably according to the donation type in potential donor candidates. Compared with other subgroups, parents donating to their children suffered the most severe psychological stress before LDLT and exhibited more depressive (P < 0.001) and anxiety symptoms. However, the stress associated with grown children donating to their parents, siblings, and spouses was not significantly higher than it was for other relatives. Furthermore, a significant negative correlation existed between family APGAR scores and the severity of depression and anxiety (P < 0.001) among potential donor candidates. CONCLUSION: These results indicate the importance of understanding potential donor candidates' psychological characteristics before LT. Greater anxiety and depression may be exhibited by parent donors due to the distress from fears of death or illness of the recipients, or their guilty feeling for their child. Additionally, family dysfunction also revealed more depression and anxiety. Such donor candidates should be given more extensive pre-donation counseling for minimizing pre-LDLT psychological stress.
The physiological role of autophagy in the catabolic process of the body involves protein synthesis and degradation in homeostasis under normal and stressed conditions. In hepatocellular carcinoma (HCC), the role of tumor microenvironment (TME) has been concerned as the main issue in fighting against this deadly malignancy. During the last decade, the crosstalk between tumor cells and their TME in HCC extensively accumulated. However, a deeper knowledge for the actual function of autophagy in this interconnection which involved in supporting tumor development, progression and chemoresistance in HCC is needed but still largely unknown. Recent studies have shown that coagulants tissue factor (TF) and factor VII (FVII) has a pathological role in promoting tumor growth by activating protease-activated receptor 2 (PAR2). Autophagy-associated LC3A/B-II formation was selectively suppressed by FVII/PAR2 signaling which mediated by mTOR activation through Atg7 but not Atg5/Atg12 axis. The coagulant-derived autophagic suppression seemed potentiate a vicious circle of malignancy in producing more FVII and PAR2 which facilitate in vivo and in vitro tumor progression of HCC and the investigations are consistent with the clinical observations. In this review, we briefly summarize the current understanding of autophagy and discuss recent evidence for its role in HCC malignancy.
Autophagy/physiology , Liver Neoplasms/etiology , Tumor Microenvironment , Blood Coagulation , Factor VII/physiology , Humans , Liver Neoplasms/pathology , MicroRNAs/physiology , Receptor, PAR-2 , Receptors, G-Protein-Coupled/physiology , Thromboplastin/physiology , Trans-Activators/physiology , Viral Regulatory and Accessory Proteins
