Liver Hepatocellular Carcinoma Research Articles

System analysis based on the lysosome-related genes identifies HPS4 as a novel therapy target for liver hepatocellular carcinoma.

Liver cancer is a leading cause of cancer-related deaths worldwide. Lysosomal dysfunction is implicated in cancer progression; however, prognostic prediction models based on lysosome-related genes (LRGs) are lacking in liver cancer. This study aimed to establish an LRG-based model to improve prognosis prediction and explore potential therapeutic targets in liver cancer. Expression profiles of 61 LRGs were analyzed in The Cancer Genome Atlas liver cancer cohorts. There were 14 LRGs identified, and their association with clinical outcomes was evaluated. Unsupervised clustering, Cox regression, and functional assays were performed. Patients were classified into high-risk and low-risk subgroups based on the 14 LRGs. The high-risk group had significantly worse overall survival. Aberrant immune infiltration and checkpoint expression were observed in the high-risk group. Furthermore, HPS4 was identified as an independent prognostic indicator. Knockdown of HPS4 suppressed liver cancer cell proliferation and induced apoptosis. This study developed an LRG-based prognostic model to improve risk stratification in liver cancer. The potential value of HPS4 as a therapeutic target and biomarker was demonstrated. Regulation of HPS4 may offer novel strategies for precision treatment in liver cancer patients.

The diagnostic or prognostic values of FADD in cancers based on pan‑cancer analysis.

Previous studies have determined that aberrant expression of the fas-associated death domain (FADD) contributes to the development of cancer. However, no pan-cancer analysis has been reported to explore the relationship between FADD and various cancers. Multiple databases were screened to identify cancer datasets for the present study and to validate the expression of FADD in various tumors. The association of FADD alteration with cancer prognosis, clinical features and tumor immunity was also evaluated. Reverse transcription-quantitative PCR (RT-qPCR) was utilized to confirm the expression of FADD in breast, colon, liver and gastric cancer cells. Analysis of Gene Expression Omnibus database and The Cancer Genome Atlas database indicated that FADD was highly expressed in breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma, cholangiocarcinoma, colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD) and prostate adenocarcinoma, whereas RT-qPCR results revealed that FADD was highly expressed in breast cancer and colon cancer. Further analyses demonstrated that FADD expression was significantly altered in ESCA, head and neck squamous cell carcinoma (HNSC), lung squamous cell carcinoma and BRCA. FADD expression was observed to be a risk factor of the overall survival in patients with HNSC, LIHC and LUAD as demonstrated by Kaplan-Meier and Cox regression analyses. The results of the present study demonstrated that FADD is highly expressed in numerous malignancies and can be utilized as a biomarker for the diagnosis of BRCA, COAD, LIHC and stomach adenocarcinoma. Moreover, FADD expression is a predictive risk factor for the development of HNSC, LIHC and LUAD and can potentially be used as a prognostic marker for these cancers.

The Current Status of the Liver Liquid Biopsy in MASH Related HCC: Overview and Future Directions.

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the major risk factors for chronic liver disease and hepatocellular carcinoma (HCC). The incidence of MASH in Western countries continues to rise, driving HCC as the third cause of cancer-related death worldwide. HCC has become a major global health challenge, partly from the obesity epidemic promoting metabolic cellular disturbances but also from the paucity of biomarkers for its early detection. Over 50% of HCC cases are clinically present at a late stage, where curative measures are no longer beneficial. Currently, there is a paucity of both specific and sensitive biological markers for the early-stage detection of HCC. The search for biological markers in the diagnosis of early HCC in high-risk populations is intense. We described the potential role of surrogates for a liver biopsy in the screening and monitoring of patients at risk for nesting HCC.

Retro-miRs: novel and functional miRNAs originating from mRNA retrotransposition

BackgroundReverse-transcribed gene copies (retrocopies) have emerged as major sources of evolutionary novelty. MicroRNAs (miRNAs) are small and highly conserved RNA molecules that serve as key post-transcriptional regulators of gene expression. The origin and subsequent evolution of miRNAs have been addressed but not fully elucidated.ResultsIn this study, we performed a comprehensive investigation of miRNA origination through retroduplicated mRNA sequences (retro-miRs). We identified 17 retro-miRs that emerged from the mRNA retrocopies. Four of these retro-miRs had de novo origins within retrocopied sequences, while 13 retro-miRNAs were located within exon regions and duplicated along with their host mRNAs. We found that retro-miRs were primate-specific, including five retro-miRs conserved among all primates and two human-specific retro-miRs. All retro-miRs were expressed, with predicted and experimentally validated target genes except miR-10527. Notably, the target genes of retro-miRs are involved in key biological processes such as metabolic processes, cell signaling, and regulation of neurotransmitters in the central nervous system. Additionally, we found that these retro-miRs play a potential oncogenic role in cancer by targeting key cancer genes and are overexpressed in several cancer types, including liver hepatocellular carcinoma and stomach adenocarcinoma.ConclusionsOur findings demonstrated that mRNA retrotransposition is a key mechanism for the generation of novel miRNAs (retro-miRs) in primates. These retro-miRs are expressed, conserved, have target genes with important cellular functions, and play important roles in cancer.

Small-interfering RNA targeting proprotein convertase subtilisin/kexin type 9 might promote fatty liver disease and hepatocellular carcinoma through upregulation of CD36.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low-density lipoprotein (LDL) receptor and fatty acid translocase CD36, inducing lysosomal degradation of these two receptors in the liver cells. Both monoclonal antibody (mAb) and small-interfering RNA (siRNA) targeting PCSK9 have been designed for treatment of familial hypercholesterolemia recently, with elevating LDL receptors on the liver cell surface and increasing LDL uptake as the main beneficial mechanism. However, given that the binding domains of PCSK9 for LDL receptor and CD36 are different, and PCSK9 mAb only attacks the domain for LDL receptor, CD36 expression remains partially controlled under PCSK9 mAb treatment. In contrast, PCSK9 siRNA brings on complete loss of PCSK9, resulting in overexpression of CD36. Based on the fact that CD36 is a key factor in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and subsequent hepatocellular carcinoma (HCC), the risk of developing NAFLD and HCC on long-term use of PCSK9 siRNA is thus raised as a hypothesis. Additionally, because CD36 is also involved in the promotion of malignant diseases other than HCC, such as acute myeloid leukemia, gastric cancer, breast cancer, and colorectal cancer, the speculative danger of flourishing these malignancies by PCSK9 siRNA is discussed as well.

Liver stiffness in Fontan patients: the effect of respiration and food intake.

For several years, patients with single ventricle hearts have been palliated according to the Fontan principle. One well known long-term consequence in these patients is the Fontan-associated liver disease and fibrosis, which occurs due to the chronically increased Central Venous Pressure (CVP) after Fontan palliation. It carries an increased risk of liver cirrhosis and hepatocellular carcinoma over time. Liver elastography (LE) is a non-invasive, safe, and feasible ultrasound method to determine liver stiffness and the stage of liver fibrosis. Usually, this examination must be performed in a sober condition and strict inspiratory hold to optimize the results and may therefore be difficult to perform on children as a routine examination. However, the influence of food intake and respiration on these results in Fontan patients is unclear. To optimize the implementation for this examination especially in children, the effects of food intake and breathing maneuvers on liver stiffness in patients with Fontan circulation were investigated. For this prospective study, 25 Fontan patients (group 1) and 50 healthy volunteers (group 2) were examined. The two groups were additionally divided into two age categories (group 1a: 10-19 years; group 1b: 20-29 years; group 2a: 15-19 years; group 2b: 20-25 years). Liver stiffness was measured by liver elastography once before food intake (=T0, with 6 h of fasting). Subsequently the participants consumed a standardized chocolate drink (500 mL) with nutritional distribution corresponding to a standardized meal (600 kcal). Liver stiffness was then determined 15, 30, 45, 60, 90, 120, 150, and 180 min after ingestion. Each measurement of liver stiffness was performed during maximal inspiratory and expiratory holds. The study was reviewed and approved by the responsible ethics committee. In group 2 there was a significant increase in liver stiffness after food intake at T15, T30, and T45 during inspiration measurements (T0 = 4.0 kPa vs. T15 = 4.9 kPa, difference = 22.5%; T0 = 4.0 kPa vs. T30 = 4.9 kPa difference = 22.5%; T0 = 4.0 kPa vs. T45 = 4.3 kPa difference = 7.5%), as well as during expiration at T15 and T30 (T0 = 4.5 kPa vs. T15 = 5.1 kPa, difference = 14.7%; T0 = 4.5 kPa vs. T30 = 4.9 kPa difference = 7.8%). Whereas in Fontan patients (group 1) liver stiffness did not differ significantly at any time between fasting (T0) and postprandial values. The respiratory maneuvers in the healthy subjects (group 2) differed significantly only before food intake (T0) (group 2: insp = 3.97 kPa vs. exp. = 4.48 kPa difference = 11.3%). In the Fontan group (group 1), there was no significant difference between the respiratory phases at any point. The different age categories showed no significant difference in liver stiffness. With these results we could demonstrate for the first time that in Fontan patients the time of food intake (i.e., fasting) has no clinical significance for the values obtained in liver elastography. We could also demonstrate that the breathing maneuvers during the examination had only minimal clinical impact on the results of liver elastography in patients with normal circulation and no effect in patients with Fontan-circulation. Consequently, liver elastography for Fontan patients is reliable independently of food intake and breathing maneuvers and can also be performed on younger patients, who are unable to follow breathing commands or longer fasting periods, without any impairment of the results. These results should encourage a routine use of LE in the follow-up of Fontan patients.

ESTIMATION OF PREVALENCE OF HEPATITIS C VIRUS INFECTION BY SEROLOGICAL TEST AND REAL TIME RT-PCR TEST AMONG SUSPECTED VIRAL HEPATITIS CASES ATTENDING TERTIARY CARE HOSPITAL, KOLKATA

Objective: Hepatitis C virus (HCV) infection is a major public health problem in India and worldwide. Majority remain asymptomatic until they develop serious complications like liver cirrhosis or hepatocellular carcinoma with fatal outcome. Hence, early diagnosis of active HCV infection and prompt initiation of treatment is important. Treatment with directly acting antivirals (DAAs) resulted in high sustained virological response (SVR) rates of >95% globally. This study was done to estimate seroprevalence and prevalence of active HCV infection among study population. After initiation of treatment, SVR rates were estimated. Methods: This was hospital-based, cross-sectional, and observational study. Screening was done by third-generation Enzyme-linked immunosorbent assay to detect anti-HCV antibody, then confirmatory real-time reverse transcription-polymerase chain reaction (RT-PCR) test was done for detection of active cases and determining their viral load. Treatment of 12-week duration was initiated by DAAs and followed up to estimate SVR by doing real-time RT-PCR after 12 weeks of treatment completion. Result: Among 17,752 consecutive non-repetitive blood samples, seroprevalence was 1.78%. The prevalence of active cases was 1.52%. HCV active infection was prevalent more among male (64.21%) and among 40–60 years age group. History of multiple blood transfusion (58%) was the most common risk factor, followed by multiple sex partners (13.3%). Coinfections with Hepatitis B virus and Human immunodeficiency virus were seen in 13.65% of cases. About 92% of patients completed their treatment. SVR was 97.87%. Conclusion: High SVR of 97.87% is evidence-based data that support that proper treatment can eliminate HCV infection. Detection by real-time RT-PCR and highly effective DAA has made a paradigm shift to approach of HCV diagnosis and management in recent times

Comprehensive analysis of P2Y family genes expression, immune characteristics, and prognosis in pan-cancer

BackgroundP2Y receptors are a family of G protein-coupled receptor genes that have an important function in cancer development and metastasis. However, systematic studies have not been conducted on human tumors. This study attempted to explore the role of P2Y family genes (P2Ys) in pan-cancer. MethodsGene expression and clinical data were downloaded from The Cancer Genome Alas dataset. Gene differential expression, mutation, prognosis, tumor microenvironment (TME) (containing immune cells infiltration, Estimate/immune/stromal scores, immune checkpoints, immune and molecular subtypes, DNA repair genes and methyltransferase), clinical correlation, protein-protein interaction network and functional enrichment analysis were performed. In addition, experiments such as western blots were performed for validation. ResultsEight P2Ys were differentially expressed in most tumor and normal tissues, and their abnormal expression in a variety of cancers could significantly reduce the survival rate of patients. Expression levels of P2Ys, especially P2Y6, P2Y12, P2Y13, P2Y14, were correlated significantly with immune cells, immune checkpoint genes, immune and molecular subtypes and Estimate/immune/stromal scores in a variety of cancers such as uveal melanoma, liver hepatocellular carcinoma, stomach adenocarcinoma, colorectal cancer (CRC), prostate adenocarcinoma, breast invasive carcinoma and uterine corpus endometrial carcinoma (all p < 0.05). P2Ys play an important role in TME and are involved in immune regulation. In addition, enrichment analysis and western blots showed that the levels of P2Y2 and P2Y6 expression regulate the Akt/GSK-3β/β-catenin pathway in CRC, thereby affecting epithelial-to-mesenchymal transition. ConclusionP2Ys may be used as potential pan-cancer biomarkers in prognosis and immunology. They may also be new targets for tumor immunotherapy, which has wide clinical implications.

Recapitulation of patient-specific 3D chromatin conformation using machine learning

Regulatory networks containing enhancer-gene edges define cellular states. Multiple efforts have revealed these networks for reference tissues and cell lines by integrating multi-omics data. However, the methods developed cannot be applied for large patient cohorts due to the infeasibility of chromatin immunoprecipitation sequencing (ChIP-seq) for limited biopsy material. We trained machine-learning models using chromatin interaction analysis with paired-end tagsequencing(ChIA-PET) and high-throughput chromosome conformation capture combined with chromatin immunoprecipitation (HiChIP) data that can predict connections using only assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA-seq data as input, which can be generated from biopsies. Our method overcomes limitations of correlation-based approaches that cannot distinguish between distinct target genes of given enhancers or between active vs. poised states in different samples, a hallmark of network rewiring in cancer. Application of our model on 371 samples across 22 cancer types revealed 1,780 enhancer-gene connections for 602 cancer genes. Using CRISPR interference (CRISPRi), we validated enhancers predicted to regulate ESR1 in estrogen receptor (ER)+ breast cancer and A1CF in liver hepatocellular carcinoma.

Widespread 8-oxoguanine modifications of miRNA seeds differentially regulate redox-dependent cancer development.

Oxidative stress contributes to tumourigenesis by altering gene expression. One accompanying modification, 8-oxoguanine (o8G) can change RNA-RNA interactions via o8G•A base pairing, but its regulatory roles remain elusive. Here, on the basis of o8G-induced guanine-to-thymine (o8G > T) variations featured in sequencing, we discovered widespread position-specific o8Gs in tumour microRNAs, preferentially oxidized towards 5' end seed regions (positions 2-8) with clustered sequence patterns and clinically associated with patients in lower-grade gliomas and liver hepatocellular carcinoma. We validated that o8G at position 4 of miR-124 (4o8G-miR-124) and 4o8G-let-7 suppress lower-grade gliomas, whereas 3o8G-miR-122 and 4o8G-let-7 promote malignancy of liver hepatocellular carcinoma by redirecting the target transcriptome to oncogenic regulatory pathways. Stepwise oxidation from tumour-promoting 3o8G-miR-122 to tumour-suppressing 2,3o8G-miR-122 occurs and its specific modulation in mouse liver effectively attenuates diethylnitrosamine-induced hepatocarcinogenesis. These findings provide resources and insights into epitranscriptional o8G regulation of microRNA functions, reprogrammed by redox changes, implicating its control for cancer treatment.

Corrected and republished from: Metabolic associated liver disease.

Alcohol consumption (AC) and metabolic syndrome (MS) represent the first cause of liver disease, hepatocellular carcinoma and liver transplantation. The habit of consuming alcoholic beverages and the presence of MS and non-alcoholic fatty liver disease (NAFLD) often coexist in the same patient. The histoclinical boundaries between alcohol related liver disease (ALD) and NAFLD are often not well defined. The co-presence of AC and MS increases the risk of hepatic and extra-hepatic disease. The terminological evolution from NAFLD to metabolic associated fatty liver disease (MAFLD) is certainly a useful advance. However, it is known that the appearance of liver fibrosis increases oncologic and cardiovascular disease risk, which in the case of cirrhosis can be present even in the absence of steatosis and that the mechanisms of fibrogenesis can act independently of the presence of steatosis/steatohepatitis. For this reason, as already stated recently, a further terminological evolution can be hypothesized. This article was originally published with mistakes in the text. The new corrected citable version appears below.

The emerging role of lipid nanosystems and nanomicelles in liver diseases.

Nanoparticles (NPs) exhibit remarkable potential in the diagnosis and treatment of various liver ailments, including primary liver cancer or hepatocellular carcinoma (HCC), liver cirrhosis, viral hepatitis, and alcoholic and non-alcoholic liver diseases. High surface area-to-volume ratio with distinct physicochemical and bio-pharmaceutical properties have contributed numerous benefits to NPs, such as high intracellular uptake and efficient drug delivery capabilities stemming from their ability to encapsulate a diverse range of drugs. Lipid-based nanosystems have demonstrated significant potential as reliable and efficient transport vehicles for a variety of actives, including small interfering RNA, targeting the liver, owing to their excellent in vivo compatibility, biodegradable nature, and non-toxic properties. Multiple aspects of various lipid-based materials, lipid nanosystems like solid lipid NPs, nanovesicles such as nanoemulsions, liposomes, and nanomicelles for liver-specific active targeting have been comprehensively reviewed. Ongoing and completed clinical trials of lipid nanosystems developed for HCC, hepatic fibrosis, and hepatitis are tabulated. Types of receptors and ligands typically used for active liver targeting in HCC are extensively discussed. The US FDA's recent approval for the use of Onpattro (Patisiran) injection to treat polyneuropathy in adult patients is indicative of the rapid development of lipid nanosystems employed for hepatic targeting. Nanoemulsions loaded with diagnostic imaging agents for multi-modal liver imaging were briefly discussed. Emerging technologies are being developed to integrate desirable properties of nanoparticles (NPs), including high stability, efficient drug loading, opsonization avoidance, active liver targeting, and facilitation of endosomal escape. Clinical translations of many lipid NPs for drug and gene therapy applications targeting different liver diseases are expected in the near future.

Experience with direct-acting antivirals in genotype 1-5 infected chronic hepatitis C patients in Turkey.

Hepatitis C virus (HCV) can cause chronic liver disease, hepatic cirrhosis, hepatocellular carcinoma, liver transplantation, and death. Early diagnosis and treatment are thus vital. We aimed to investigate the sustained virological response (SVR) rates in chronic hepatitis C patients infected with different genotypes, receiving different direct-acting antiviral treatments (DAAs). Retrospective, observational SETTING: Clinic for infectious diseases and clinical microbiology PATIENTS AND METHODS: Patients diagnosed with chronic hepatitis C who applied to our outpatient clinic between January 2016 and November 2022 and were treated with a DAA were included in the study. Treatment responses were evaluated after each patient was treated with either ledipasvir plus sofosbuvir (LDV/SOF), LDV/SOF + ribavirin (RBV), SOF+RBV, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r±DSV) ±RBV, or glecaprevir plus pibrentasvir (GLE/PIB). Sustained virological response (SVR) rates at 12 weeks (SVR12) post-treatment. 360 patients. Of 360 patients who met the inclusion criteria, 218 (60.6%) were male and 142 (39.4%) were female with no statistically significant differences in SVR between sexes (P=.252). Nearly all had a SVR (n=353, 98.1%). The median (IQR) age of the patients was 56 (30.3) years. There were 42 (11.7%), 199 (55.3%), 4 (1.1%), 106 (29.4%), 8 (2.2%) and 1 (0.3%) patient with genotypes 1a, 1b, 2, 3, 4 and 5, respectively, and SVR12 did not differ significantly between genotypes (P=.066). SVR12 response was higher in 246 (68.3%) non-injecting drug users compared to 114 (31.7%) injecting drug users (P=.005). The SVR12 response was achieved in 100% of patients with genotypes 1a, 2, 4, and 5. SVR12 response could not be obtained in 1 of 199 genotype 1b patients and 6 of 106 genotype 3 patients. The common feature of 6 reinfection patients with genotype 3 was that they were using intravenous drugs. These 6 patients were reinfected due to their continued intravenous drug use. In conclusion, DAAs provide high SVR12 rates in cirrhotic/non-cirrhotic, pegylated interferon-naive/experienced patient groups and in patients infected with all genotypes. DAAs have a high SVR12 rate in patients with chronic hepatitis C. Retrospective, single-center.

Expression Profile and Gene Regulation Network of NUSAP1 in Pan Cancers Based on Integrated Bioinformatics Analysis.

Nucleolar and spindle-associated protein 1 (NUSAP1) plays key roles in microtubules and chromosomes in normal cells both structurally and functionally. In malignancies, NUSAP1 is frequently dysregulated and mutated. However, the expression profiles and biological functions of NUSAP1 in tumors remain unclear. NUSAP1 expression in BALB/c mice and human normal or tumor tissues was examined using immunohistochemistry. Kaplan-Meier survival analysis was utilized to assess the prognostic significance of NUSAP1 in tumors, and principal component analysis and co-expression analysis were performed to explore the unique roles of NUSAP1. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed with DAVID. The relevance between NUSAP1 and tumor-infiltrating immune cells was investigated using TIMER. A transcriptional regulation network was constructed using data from The Cancer Genome Atlas. NUSAP1 expression levels in various mice tissues were different. Compared with normal tissues, NUSAP1 was strongly expressed in several human tumor tissues. We believe that NUSAP1 distinctly impacts the prognosis of several cancers and plays various roles in thymoma and testicular germ cell tumors. Further, NUSAP1 expression levels were significantly positively associated with diverse infiltrating levels of immune cells, including B cells, CD4+ and CD8+ T cells, dendritic cells, and macrophages, in thymoma. The expression level of NUSAP1 demonstrated strong relevance with various immune markers in thymoma. Finally, the miR-1236-5p-NUSAP1 and TCF3-NUSAP1 network revealed the tumor-promoting role of NUSAP1 and pertinent underlying mechanisms in human liver hepatocellular carcinoma. NUSAP1 may be regarded as a therapeutic target or potential prognostic biomarker for various cancer types.

ZBTB34 is a hepatocellular carcinoma-associated protein with a monopartite nuclear localization signal.

ZBTB34 is a novel zinc finger protein with an unknown function. In this study, the gene expression and survival prognosis of ZBTB34 were analyzed across tumors based on the TCGA datasets. According to the bioinformatics analysis and qPCR results, liver hepatocellular carcinomas exhibit a high level of ZBTB34 expression. Additionally, the experiment supported the bioinformatics analysis findings that ZBTB34 expression was regulated by miR-125b-5p and that ZBTB34 affected ZBTB10, POLR1B, and AUH expression in HepG2 cells. Biological software analysis further revealed that ZBTB34 contains a monopartite nuclear localization signal (NLS). Arginine and lysine inside the putative NLS were substituted using the alanine-scanning mutagenesis method. The findings showed that the ability of ZBTB34 to enter the nucleus was abolished by the alanine substitution of the sequence 320RGGRARQKRA329 and the mutation of Lys327 and Arg328 residues. ZBTB34 was co-immunoprecipitated with importin α1, importin α3, importin α4, and importin β1, according to the results of the co-immunoprecipitation assay. In conclusion, ZBTB34 is a hepatocellular carcinoma-associated protein with a monopartite NLS. The nuclear import of ZBTB34 is mediated by importin α1, importin α3, importin α4, and importin β1. ZBTB34 performs its biological functions via a putative miR-125b-5p/ZBTB34/(ZBTB10, POLR1B, and AUH) signaling axis in HepG2 cells.

Therapeutic potential of sulforaphane in liver diseases: a review.

The burden of liver diseases such as metabolic-associated fatty liver diseases and hepatocellular carcinoma has increased rapidly worldwide over the past decades. However, pharmacological therapies for these liver diseases are insufficient. Sulforaphane (SFN), an isothiocyanate that is mainly found in cruciferous vegetables, has been found to have a broad spectrum of activities like antioxidation, anti-inflammation, anti-diabetic, and anticancer effects. Recently, a growing number of studies have reported that SFN could significantly ameliorate hepatic steatosis and prevent the development of fatty liver, improve insulin sensitivity, attenuate oxidative damage and liver injury, induce apoptosis, and inhibit the proliferation of hepatoma cells through multiple signaling pathways. Moreover, many clinical studies have demonstrated that SFN is harmless to the human body and well-tolerated by individuals. This emerging evidence suggests SFN to be a promising drug candidate in the treatment of liver diseases. Nevertheless, limitations exist in the development of SFN as a hepatoprotective drug due to its special properties, including instability, water insolubility, and high inter-individual variation of bioavailability when used from broccoli sprout extracts. Herein, we comprehensively review the recent progress of SFN in the treatment of common liver diseases and the underlying mechanisms, with the aim to provide a better understanding of the therapeutic potential of SFN in liver diseases.

Prognosis after splenectomy plus pericardial devascularization vs transjugular intrahepatic portosystemic shunt for esophagogastric variceal bleeding.

Portal hypertension combined with esophagogastric variceal bleeding (EGVB) is a serious complication in patients with hepatitis B virus (HBV)-related cirrhosis in China. Splenectomy plus pericardial devascularization (SPD) and transjugular intrahepatic portosystemic shunt (TIPS) are effective treatments for EGVB. However, a comparison of the effectiveness and safety of those methods is lacking. To compare the prognosis after SPD vs TIPS for acute EGVB after failure of endoscopic therapy or secondary prophylaxis of variceal rebleeding (VRB) in patients with HBV-related cirrhosis combined with portal hypertension. This retrospective cohort study included 318 patients with HBV-related cirrhosis and EGVB who underwent SPD or TIPS at West China Hospital of Sichuan University during 2009-2013. Propensity score-matched analysis (PSM), the Kaplan-Meier method, and multivariate Cox regression analysis were used to compare overall survival, VRB rate, liver function abnormality rate, and hepatocellular carcinoma (HCC) incidence between the two patient groups. The median age was 45.0 years (n = 318; 226 (71.1%) males). During a median follow-up duration of 43.0 mo, 18 (11.1%) and 33 (21.2%) patients died in the SPD and TIPS groups, respectively. After PSM, SPD was significantly associated with better overall survival (OS) (P = 0.01), lower rates of abnormal liver function (P < 0.001), and a lower incidence of HCC (P = 0.02) than TIPS. The VRB rate did not differ significantly between the two groups (P = 0.09). Compared with TIPS, SPD is associated with higher postoperative OS rates, lower rates of abnormal liver function and HCC, and better quality of survival as acute EGVB treatment after failed endoscopic therapy or as secondary prophylaxis of VRB in patients with HBV-related cirrhosis combined with portal hypertension. There is no significant between-group difference in VRB rates.

Antiviral Therapy Favors a Lower Risk of Liver Cirrhosis in HBeAg-negative Chronic Hepatitis B with Normal Alanine Transaminase and HBV DNA Positivity.

Direct evidence on the outcomes of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients with normal alanine transaminase after long-term antiviral treatment is lacking. HBeAg-negative patients with normal ALT and positive HBV DNA (≥20 IU/mL) were retrospectively enrolled. The endpoints included virological response (HBV DNA<100 IU/mL), changes in aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 index (FIB-4), and the incidence of liver nodules, cirrhosis, and hepatocellular carcinoma (HCC). This cohort (n=194) was divided into three subgroups, untreated (n=67), treatment-continued (n=87), and treatment-discontinued patients (n=40), with a median follow-up of 54 months. The treatment-continued group achieved 100% (95% CI: 94.7-100) virological response, and significantly reduced APRI and FIB-4 scores (both p<0.001). The risk of liver nodules and cirrhosis in that group was reduced by 76% (HR: 0.24, 95% CI: 0.11-0.54, p<0.001) and 89% (HR: 0.11, 95% CI: 0.14-0.91, p=0.041) vs. the untreated group and by 77% (HR: 0.23, 95% CI: 0.10-0.49, p<0.001) and 95% (HR: 0.05, 95% CI: 0.01-0.44, p=0.006) vs. the treatment-discontinued group. For patients with HBV DNA≥2,000 IU/mL, adherence to treatment lowered the risks of liver cirrhosis by 92% (95% CI: 0.01-0.67) and 93% (95% CI: 0.01-0.53) vs. the untreated and treatment-discontinued patients, respectively. No patient adhering to treatment developed HCC, but one in each of the remaining groups did. Continuous nucleos(t)ide analog (NA) treatment has a satisfactory effectiveness and helps to lower the risk of liver cirrhosis in HBeAg-negative CHB patients with normal alanine transaminase, especially in those with HBV DNA≥2,000 IU/mL.

Integrative analysis of mitochondrial metabolic reprogramming in early-stage colon and liver cancer.

Gastrointestinal malignancies, including colon adenocarcinoma (COAD) and liver hepatocellular carcinoma (LIHC), remain leading causes of cancer-related deaths worldwide. To better understand the underlying mechanisms of these cancers and identify potential therapeutic targets, we analyzed publicly accessible Cancer Genome Atlas datasets of COAD and LIHC. Our analysis revealed that differentially expressed genes (DEGs) during early tumorigenesis were associated with cell cycle regulation. Additionally, genes related to lipid metabolism were significantly enriched in both COAD and LIHC, suggesting a crucial role for dysregulated lipid metabolism in their development and progression. We also identified a subset of DEGs associated with mitochondrial function and structure, including upregulated genes involved in mitochondrial protein import and respiratory complex assembly. Further, we identified mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) as a crucial regulator of cancer cell metabolism. Using a genome-scale metabolic model, we demonstrated that HMGCS2 suppression increased glycolysis, lipid biosynthesis, and elongation while decreasing fatty acid oxidation in colon cancer cells. Our study highlights the potential contribution of dysregulated lipid metabolism, including ketogenesis, to COAD and LIHC development and progression and identifies potential therapeutic targets for these malignancies.

Giant mitochondria in human liver disease.

This thematic review aims to provide an overview of the current state of knowledge about the occurrence of giant mitochondria or megamitochondria in liver parenchymal cells. Their presence and accumulation are considered to be a major pathological hallmark of the health and fate of liver parenchymal cells that leads to overall tissue deterioration and eventually results in organ failure. The first description on giant mitochondria dates back to the 1960s, coinciding with the availability of the first generation of electron microscopes in clinical diagnostic laboratories. Detailed accounts on their ultrastructure have mostly been described in patients suffering from alcoholic liver disease, chronic hepatitis, hepatocellular carcinoma and non-alcoholic fatty liver disease. Interestingly, from this extensive literature survey, it became apparent that giant mitochondria or megamitochondria present themselves with or without highly organised crystal-like intramitochondrial inclusions. The origin, formation and potential role of giant mitochondria remain to-date largely unanswered. Likewise, the biochemical composition of the well-organised crystal-like inclusions and their possible impact on mitochondrial function is unclear. Herein, concepts about the possible mechanism of their formation and three-dimensional architecture will be approached. We will furthermore discuss their importance in diagnostics, including future research outlooks and potential therapeutic interventions to cure liver disease where giant mitochondria are implemented.