Following partial hepatectomy (PH), the complex process of liver regeneration is initiated, which encompasses the synchronized induction of hepatocyte proliferation. Hepatocyte proliferation can be regulated by multiple stimuli, including long non‑coding RNAs (lncRNAs) and Wnt/β‑catenin signaling, although the underlying mechanism of lncRNA/Wnt in liver regeneration remains unclear. In the present study, a liver regeneration‑associated functional lncRNA was identified, and its function was delineated in vitro and in vivo; lncRNA small nucleolar RNA host gene 12 (SNHG12) was revealed to be upregulated at various time‑points after 2/3 PH. The expression of SNHG12 was also increased in normal liver cell lines treated with different concentrations of hepatocyte growth factor (HGF). Functionally, SNHG12 enhanced hepatocyte proliferation in vitro and in vivo, and the liver/body weight ratio of SNHG12‑overexpressing mice was significantly higher than that of the control mice. Overexpression of SNHG12 promoted the activation of Wnt/β‑catenin signaling in hepatocytes. Furthermore, specific inhibition of Wnt/β‑catenin signaling significantly attenuated SNHG12‑induced hepatocyte proliferation and the affected liver/body weight ratio. Collectively, the results of the present study indicated that SNHG12 contributes to liver regeneration by activating Wnt/β‑catenin signaling. Therefore, drugs that regulate the SNHG12/Wnt axis may be beneficial for liver regeneration following PH.

Diabetic liver injury (DLI) can result in several diseases of the liver, including steatohepatitis, liver fibrosis, cirrhosis, and liver cancer. Low‑dose ionizing radiation (LDIR) has hormetic effects in normal/disease conditions. However, whether LDIR has a beneficial effect on DLI has not been assessed previously. MicroRNA (miR)‑155 and its target gene suppressor of cytokine signaling 1 (SOCS1) play critical roles in modulating hepatic proliferation, apoptosis, and immunity. However, whether a miR‑155‑SOCS1 axis is involved in high glucose (HG) induced hepatic damage remains to be determined. In the present study, mouse hepatocyte AML12 cells were treated with 30 mM glucose (HG), 75 mGy X‑ray (LDIR), or HG plus LDIR. The expression levels of miR‑155 and SOCS1 were determined by reverse transcription‑quantitative PCR and western blotting. Additionally, apoptosis was measured using flow cytometry. The release of inflammatory factors, including TNF‑α, IL‑1β, IL‑6, IL‑10, and IFN‑γ, after HG and/or LDIR treatment was detected by ELISA. The results showed that HG may induce hepatic apoptosis by upregulating the levels of miR‑155 and downregulating the levels of SOCS1. HG also stimulated the secretion of TNF‑α, IL‑1β, IL‑6, and IL‑10. However, LDIR blocked the HG‑induced activation of a miR‑155‑SOCS1 axis and suppressed the release of inflammatory factors. These results indicated that a miR‑155‑SOCS1 axis plays a role in HG‑induced liver injury, and LDIR may exert a hepatoprotective effect by regulating the miR‑155‑SOCS1 axis.

Previous studies have shown that long noncoding RNAs (lncRNAs) are capable of regulating cell differentiation and pluripotency. The objective of the present study was to explore the effect of lncRNA cancer upregulated drug resistant (CUDR) on the hepatic differentiation of human umbilical cord mesenchymal stem cells (HuMSCs). HuMSCs were subjected to a hepatogenic differentiation protocol. The level of CUDR was monitored by reverse transcription‑quantitative PCR (RT‑qPCR) following certain stages of hepatic differentiation. Lentivirus transfection was used to achieve CUDR overexpression. The hepatocyte‑related proteins and mRNAs were then examined by immunofluorescence, ELISA and RT‑qPCR analyses. The results showed that CUDR was upregulated during the hepatic differentiation of HuMSCs. Upregulation of CUDR can improve hepatic differentiation of HuMSCs, including hepatocyte‑related genes and proteins. In addition, it was also found that liver‑enriched transcription factors were upregulated after CUDR overexpression. Moreover, there was an association between the Wnt/β‑catenin pathway and CUDR. In summary, these results demonstrated that the overexpression of CUDR could improve the hepatic differentiation of HuMSCs, therefore it could be an ideal source for regenerative therapy.

The present study investigated the effects and molecular mechanism of the second mitochondria‑derived activator of caspase (SMAC) mimetic birinapant on the proliferation and apoptotic rate of liver cancer cells. Western blotting and reverse transcription‑quantitative PCR were used to detect the protein and mRNA expression levels of cellular inhibitor of apoptosis 1 (cIAP1) and tumor necrosis factor receptor‑associated factor 3 (TRAF3) in the liver cancer cell lines Huh7, H22 and HepG2, and the hepatocyte line AML12. Annexin V‑FITC and Transwell assays were used to assess the effect of birinapant pretreatment on the apoptotic rate and invasive ability of liver cancer cells. Lentivirus‑mediated silencing of TRAF3 was performed in liver cancer cells. Western blotting was used to detect the lentivirus silencing efficiency. A subcutaneous hepatocellular carcinoma model was established in nude mice and 15 days after tumor induction the subcutaneous tumors were measured in each group. Immunohistochemistry assays were used to detect the protein expression levels of proliferating cell nuclear antigen and caspase‑3. The results suggested that the expression levels of cIAP1 and TRAF3 were lower in Huh7, H22 and HepG2 cells compared with AML12 cells. Pretreatment with birinapant promoted apoptosis and inhibited invasion of liver cancer cells by activating the cIAP1/TRAF3 axis. Birinapant also promoted apoptosis and inhibited the growth of subcutaneous hepatocellular carcinoma tumors in nude mice. The present results suggested that the SMAC mimetic birinapant may promote apoptosis, and inhibit the proliferation and invasion of liver cancer cells. The molecular mechanism responsible for the effects of birinapant may be related to activation of the cIAP1/TRAF3 signaling pathway by birinapant in liver cancer cells.

Due to the lack of potential organs, hepatocellular transplantation has been considered for treating end-stage liver disease. Induced pluripotent stem cells (iPSCs) are reverted from somatic cells and are able to differentiate into hepatocytes. The present study aimed to investigate the mechanisms underlying iPSC differentiation to hepatocytes. GSE66076 was downloaded from the Gene Expression Omnibus; this database includes data from 3 undifferentiated (T0), 3 definitive endoderm (T5), and 3 early hepatocyte (T24) samples across hepatic‑directed differentiation of iPSCs. Differentially expressed genes (DEGs) between T0 and T5 or T24 samples were identified using the linear models for microarray data package in Bioconductor, and enrichment analyses were performed. Using the weighted correlation network analysis package in R, clusters were identified for the merged DEGs. Cytoscape was used to construct protein‑protein interaction (PPI) networks for DEGs identified to belong to significant clusters. Using the ReactomeFI plugin in Cytoscape, functional interaction (FI) networks were constructed for the common genes. A total of 433 and 1,342 DEGs were identified in the T5 and T24 samples respectively, compared with the T0 samples. Blue and turquoise clusters were identified as significant gene clusters. In the PPI network for DEGs in the blue cluster, the key node fibroblast growth factor 2 (FGF2) could interact with bone morphogenetic protein 2 (BMP2). Cyclin‑dependent kinase 1 (CDK1) was demonstrated to have the highest degree (degree=71) in the PPI network for DEGs in the turquoise cluster. Enrichment analysis for the common genes, including hepatocyte nuclear factor 4α (HNF4A) and epidermal growth factor (EGF), in the FI network indicated that EGF and FGF2 were enriched in the Ras and Rap1 signaling pathways. The present results suggest that FGF2, BMP2, CDK1, HNF4A and EGF may participate in the differentiation of iPSCs into hepatocytes.

Intracranial aneurysm (IA) is a severe clinical condition of primary concern and currently, there is no effective therapeutic reagent. The present study aimed to investigate the molecular mechanism of IA via bioinformatic analysis. Various gene expression profiles (GSE26969) were downloaded from the Gene Expression Omnibus database, including 3 IA and 3 normal superficial temporal artery samples. Firstly, the limma package in R language was used to identify differentially expressed genes (DEGs; P‑value <0.01 and |log2 FC|≥1). Secondly, the database for annotation, visualization and integrated discovery software was utilized to perform pathway and functional enrichment analyses (false discovery rate ≤0.05). Finally, protein‑protein interaction (PPI) network and sub‑network clustering analyses were performed using the biomolecular interaction network database and ClusterONE software, respectively. Following this, a transcription factor regulatory network was identified from the PPI network. A total of 1,124 DEGs were identified, of which 989 were upregulated and 135 downregulated. Pathway and functional enrichment analyses revealed that the DEGs primarily participated in RNA splicing, functioning of the spliceosome, RNA processing and the mRNA metabolic process. Following PPI network analysis, 1 hepatocyte nuclear factor (HNF) 4A (transcription factor)‑centered regulatory network and 5 DEG‑centered sub‑networks were identified. On analysis of the transcription factor regulatory network, 6 transcription factors (HNF6, HNF4A, E2F4, YY1, H4 and H31T) and a regulatory pathway (HNF6‑HNF4‑E2F4) were identified. The results of the present study suggest that activating transcription factor‑5, Jun proto‑oncogene, activator protein‑1 transcription factor subunit, HNF6, HNF4 and E2F4 may participate in IA progression via vascular smooth muscle cell apoptosis, inflammation, vessel wall remodeling and damage and the tumor necrosis factor‑β signaling pathway. However, further experimental studies are required to validate these predictions.

The present study was aimed at screening the key genes associated with abdominal aortic aneurysm (AAA) in the neck, and to investigate the molecular mechanism underlying the development of AAA. The gene expression profile, GSE47472, including 14 AAA neck samples and eight donor controls, was downloaded from the Gene Expression Omnibus database. The total AAA samples were grouped into two types to avoid bias. Differentially expressed genes (DEGs) were screened in patients with AAA and subsequently compared with donor controls using linear models for microarray data, or the Limma package in R, followed by gene ontology enrichment analysis. Furthermore, a protein‑protein interaction (PPI) network based on the DEGs was constructed to detect highly connected regions using a Cytoscape plugin. In total, 388 DEGs in the AAA samples were identified. These DEGs were predominantly associated with limb development, including embryonic limb development and appendage development. Nuclear receptor co‑repressor 1 (NCOR1), histone 4 (H4), E2F transcription factor 4 (E2F4) and hepatocyte nuclear factor 4α (HNF4A) were the four transcription factors associated with AAA. Furthermore, HNF4A indirectly interacted with the other three transcription factors. Additionally, six clusters were selected from the PPI network. The DEG screening process and the construction of an interaction network enabled an understanding of the mechanism of AAA to be gleaned. HNF4A may exert an important role in AAA development through its interactions with the three other transcription factors (E2F4, NCOR1 and H4), and the mechanism of this coordinated regulation of the transcription factors in AAA may provide a suitable target for the development of therapeutic intervention strategies.

Berberine (BBR) is an isoquinoline alkaloid, reported to have multiple pharmacological functions. However, its effects against CCl4‑induced oxidative damage remain poorly studied. Therefore, the present study investigated the protective action of BBR, and its antioxidant mechanisms, against CCl4‑induced liver injury in rats. A total of 48 rats were randomly arranged into six groups: Control; model; positive control (PC); BBR low‑dose (BL); BBR middle‑dose (BM); and BBR high‑dose (BH). The BL, BM and BH animals received BBR (5, 10 and 15 mg/kg by weight, respectively) orally for 7 consecutive days. Rats in the PC group were given silymarin (150 mg/kg), and the control and model groups were administered distilled water orally. At the end of the experiment, blood samples and livers were collected. To measure the liver biochemical indices, the reactive oxygen species (ROS) generation and the expression levels of related genes and protein, the following methods were used: An automatic biochemical analyzer; flow cytometry; spectrophotometry; reverse transcription‑quantitative PCR; western blotting; and hematoxylin and eosin staining. The results revealed that BBR significantly decreased the serum levels of alanine transaminase, aspartate transaminase and alkaline phosphatase, and increased those of glutathione and superoxide dismutase, but decreased malondialdehyde activity in hepatic tissue, and significantly decreased the reactive oxygen species level in hepatocytes. In hepatic tissue, the expressions of nuclear factor erythroid 2‑related factor 2 (Nrf2), kelch‑like ECH‑associated protein 1 (Keap-1), NAD(P)H quinone dehydrogenase 1 (NQO-1), heme oxygenase 1 (HO‑1), Bcl‑2 and Bcl‑xL mRNA, and HO‑1 protein were elevated, and the expression of p53 mRNA was decreased, particularly in the BH group (15 mg/kg). In conclusion, BBR exerts a protective action against CCl4‑induced acute liver injury in rats via effectively regulating the expression of Nrf2‑Keap1‑antioxidant responsive element‑related genes and proteins, and inhibiting p53 pathway‑mediated hepatocyte apoptosis.

Adipose tissue‑derived mesenchymal stem cells (ADSCs) have been considered to be attractive and readily available adult mesenchymal stem cells, and they are becoming increasingly popular for use in regenerative cell therapy, as they are readily accessible through minimally invasive techniques. The present study investigated whether autologous ADSC transplantation promoted liver regeneration following a repeat partial hepatectomy in rats. The rats were divided into three groups as follows: 70% partial hepatectomy (PH) group; repeat PH (R‑PH) group and R‑PH/ADSC group, subjected to R‑PH and treated with autologous ADSCs via portal vein injection. In each group, the rats were sacrificed at different time points postoperatively in order to evaluate the changes in liver function and to estimate the liver regenerative response. The expression of proliferating cell nuclear antigen (PCNA) labeling index in the liver was measured using immunohistochemistry. The expression levels of hepatocyte growth factor (HGF) mRNA were measured using reverse transcription polymerase chain reaction. The results showed that regeneration of the remaining liver following R‑PH was significantly promoted by ADSC transplantation, as shown by a significant increase in liver to body weight ratio and the PCNA labeling index at 24 h post‑hepatectomy. Additionally, ADSC transplantation markedly inhibited the elevation of serum levels of alanine aminotransferase, aspartate aminotransferase and total bilirubin, increased HGF content and also attenuated hepatic vacuolar degeneration 24 h postoperatively. Furthermore, the liver was found to almost fully recover from hepatocellular damage due to hepatectomy among the three groups at 168 h postoperatively. These results indicated that autologous ADSC transplantation enhanced the regenerative capacity of the remnant liver tissues in the early phase following R‑PH.