Christensenella minuta Alleviates Acetaminophen-Induced Hepatotoxicity by Regulating Phenylalanine Metabolism.

Acetaminophen (APAP)-induced liver injury (AILI), even liver failure, is a significant challenge due to the limited availability of therapeutic medicine. Christensenella minuta (C. minuta), as a probiotic therapy, has shown promising prospects in metabolism and inflammatory diseases. Our research aimed to examine the influence of C. minuta on AILI and explore the molecular pathways underlying it. We found that administration of C. minuta remarkably alleviated AILI in a mouse model, as evidenced by decreased levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) and improvements in the histopathological features of liver sections. Additionally, there was a notable decrease in malondialdehyde (MDA), accompanied by restoration of the reduced glutathione/oxidized glutathione (GSH/GSSG) balance, and superoxide dismutase (SOD) activity. Furthermore, there was a significant reduction in inflammatory markers (IL6, IL1ß, TNF-α). C. minuta regulated phenylalanine metabolism. No significant difference in intestinal permeability was observed in either the model group or the treatment group. High levels of phenylalanine aggravated liver damage, which may be linked to phenylalanine-induced dysbiosis and dysregulation in cytochrome P450 metabolism, sphingolipid metabolism, the PI3K-AKT pathway, and the Integrin pathway. Furthermore, C. minuta restored the diversity of the microbiota, modulated metabolic pathways and MAPK pathway. Overall, this research demonstrates that supplementing with C. minuta offers both preventive and remedial benefits against AILI by modulating the gut microbiota, phenylalanine metabolism, oxidative stress, and the MAPK pathway, with high phenylalanine supplementation being identified as a risk factor exacerbating liver injury.

Exosomes and circular RNAs: promising partners in hepatocellular carcinoma from bench to bedside.

Hepatocellular carcinoma (HCC) is characterized by high morbidity and mortality, and a low 5-year survival rate. Exploring the potential molecular mechanisms, finding diagnostic biomarkers with high sensitivity and specificity, and determining new therapeutic targets for HCC are urgently needed. Circular RNAs (circRNAs) have been found to play a key role in the occurrence and development of HCC, while exosomes play an important role in intercellular communication; thus, the combination of circRNAs and exosomes may have inestimable potential in early diagnosis and curative therapy. Previous studies have shown that exosomes can transfer circRNAs from normal or abnormal cells to surrounding or distant cells; thereafter, circRNAs influence target cells. This review summarizes the recent progress regarding the roles of exosomal circRNAs in the diagnosis, prognosis, occurrence and development and immune checkpoint inhibitor and tyrosine kinase inhibitor resistance of HCC to provide inspiration for further research.

Validation of the hepatocellular carcinoma early detection screening algorithm Doylestown and aMAP in a cohort of Chinese with cirrhosis.

BACKGROUND: Previous studies have developed some blood-based biomarker algorithms such as the Doylestown algorithm and aMAP score to improve the detection of Hepatocellular carcinoma (HCC). However, no one has studied the application of the Doylestown algorithm in the Chinese. Meanwhile, which of these two screening models is more suitable for people with liver cirrhosis remains to be investigated. METHODS: In this study, HCC surveillance was performed by radiographic imaging and testing for tumor markers every 6 months from August 21, 2018, to January 12, 2021. We conducted a retrospective study of 742 liver cirrhosis patients, and among them, 20 developed HCC during follow-up. Samples from these patients at three follow-up time points were tested to evaluate alpha-fetoprotein (AFP), the Doylestown algorithm, and aMAP score. RESULTS: Overall, 521 liver cirrhosis patients underwent semiannual longitudinal follow-up three times. Five patients were diagnosed with HCC within 0-6 months of the third follow-up. We found that for these liver cirrhosis patients, the Doylestown algorithm had the highest accuracy for HCC detection, with areas under the receiver operating characteristic curve (AUCs) of 0.763, 0.801, and 0.867 for follow-ups 1-3, respectively. Compared with AFP at 20 ng/ml, the Doylestown algorithm increased biomarker performance by 7.4%, 21%, and 13% for follow-ups 1-3, respectively. CONCLUSIONS: Our findings show that the Doylestown algorithm performance appeared to be optimal for HCC early screening in the Chinese cirrhotic population when compared with the aMAP score and AFP at 20 ng/ml.

The value of transthoracic echocardiography in the detection of extra-cardiac lesions.

OBJECTIVE: Transthoracic echocardiography (TTE) is generally recognized as the top choice for detecting myocardial and cardiac cavity lesions. Sonographers mostly focus on myocardium, cardiac cavity and cardiac hemodynamics, whereas the abnormal extra-cardiac lesions are easily remain unrecognized. The aim of this study was to investigate the ultrasonic image features in abnormal extra-cardiac lesions and the value of TTE in the detection of extra-cardiac lesions. METHODS: 49 cases of abnormal extra-cardiac lesion detected by TTE from January 2014 to December 2019 were collected, which were confirmed by surgical pathology. The two-dimensional ultrasonic characteristics and the relationships with the cardiac and great vessels were summarized on the basis of multi-view by TTE. All patients were also examined by computed tomography (CT). RESULTS: In 49 patients with abnormal extra-cardiac lesions, 37 malignant cases and 12 benign cases were included. There were 41 cases (41/49, 86.67%) of mediastinal lesions and 8 cases (8/49, 16.33%) of lung lesions. The maximum diameter ranged from 3.2 cm to 13.66 cm, and the median diameter was about 7.4 cm, among which 29 cases (29/49, 59.18%) were larger than 5 cm. 4 cases (4/49, 8.16%) of cystic anechoic lesions were pericardial cyst. 2 cases (2/49, 4.08%) of cystic-solid echogenic lesions were teratoma. The remaining 43 cases (43/49, 87.76%) presented as solid hypoechoic or heterogeneous masses. 6 cases compressed the heart and 21 cases encroached on the heart and vessels. Diagnosis coincidence rates of TTE and CT were respectively 77.55% and 93.88%, with a statistical difference (p = 0.012). CONCLUSION: Although the diagnostic coincidence rate of TTE is slightly lower than that of CT, TTE has certain diagnostic value for extra-cardiac lesions.

Diagnostic and prognostic value of serum Chitinase 3-like protein 1 in hepatocellular carcinoma.

The serum Chitinase 3-like protein 1 (CHI3L1) protein level can distinguish the stages of liver fibrosis to a great extent. However, the diagnostic and prognostic significance of serum CHI3L1 in hepatocellular carcinoma (HCC) is not clarified. To evaluate the diagnostic and prognostic value of CHI3L1 in HCC, a total of 128 HCC patients treated in the HwaMei Hospital, University of Chinese Academy of Sciences, from December 2018 to April 2020 were collected retrospectively. Matched age and gender subjects, 40 patients with liver cirrhosis, 40 patients with chronic hepatitis, and 40 healthy subjects were enrolled in the control group. The relevant clinical laboratory and examination data and the overall survival time (OS) of the HCC patients were collected. The serum CHI3L1 expression level is related to α-fetoprotein (AFP), tumor-node-metastasis (TNM) stage, maximum tumor diameter, liver cirrhosis, and HCC patient's OS (p < 0.05). The area under the curve (AUC) of CHI3L1 was 0.7875 with the cutoff value of 91.36 ng/ml. Combining the serum CHI3L1 and α-fetoprotein (AFP) by a binary logistic regression model can increase the diagnostic sensitivity to 97.5%. Multivariate Cox regression analysis indicated that CHI3L1 is an independent prognostic factor in patients with HCC.

Circular RNAs in liver diseases: Mechanisms and therapeutic targets.

Circular RNAs (circRNAs) are formed from the genome through diverse back splicing and feature the closed loop. circRNAs are widely available in a variety of cells and characterized by conservation, structural stability, high abundance and tissue-specific or developmental-specific expression. Recent studies have shown that circRNAs are closely related to liver diseases, such as metabolic-associated fatty liver disease, hepatitis, liver cirrhosis and hepatocellular carcinoma. circRNAs play an important role in the progression of liver diseases, are potential diagnostic and prognostic markers, and have translational value in therapy. This article reviews the research on circRNAs in liver diseases, with a view to providing a theoretical basis and new ideas for future research and treatment of liver diseases.

CHI3L1 in the pathophysiology and diagnosis of liver diseases.

Chitinase 3-like protein 1(CHI3L1) participates in physiological and pathophysiological process, such as cell survival, cell proliferation, tissue remodeling, angiogenesis, etc. Some studies demonstrated that CHI3L1 is liver-enriched and has better application value in staging liver fibrosis than platelet ratio index(APRI) and fibrosis-4 index(FIB-4) and that CHI3L1 can be used in monitoring the prognosis of hepatocellular carcinoma (HCC). In this review, we summarized the pathophysiological role and the diagnostic value of CHI3L1 in liver fibrosis in different background and HCC.

The clinical significance of serum chitinase 3-like 1 in hepatitis B-related chronic liver diseases.

AIM: In the present study, we purposed to determine serum chitinase 3-like 1 (CHI3L1) expression characteristics in chronic liver diseases monoinfected with hepatitis B virus and analyze its diagnostic value in liver fibrosis. METHODS: A total of 467 chronic hepatitis B (CHB) patients, 312 liver cirrhosis (LC) patients, and 104 hepatocellular carcinoma (HCC) patients at our institution were enrolled, and clinical indicators were analyzed. RESULTS: Our data have shown that the expression level of serum CHI3L1 was steadily increased from CHB to LC to HCC (P < .001). Serum CHI3L1 expression levels were positively associated with liver stiffness measurement (LSM), fibrosis-4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and HCC stage. The receiver operating characteristic (ROC) curve proved that serum CHI3L1 was superior to other noninvasive methods (LSM, FIB-4, and APRI) with an area under the ROC curve (AUC) of 0.97 in diagnosing significant fibrosis. CONCLUSIONS: Serum CHI3L1 harbors significant clinical value in chronic liver diseases infected with hepatitis B virus, especially in the diagnosis of fibrosis.

Hsa_circ_0028502 and hsa_circ_0076251 are potential novel biomarkers for hepatocellular carcinoma.

Circular RNAs (circRNAs) have been increasingly revealed to be desirable biomarkers for some tumors, including hepatocellular carcinoma (HCC). Combined with our previous microarray screening results, we aimed to determine the hsa_circ_0028502 and hsa_circ_0076251 expression features in HCC, analyze the relationship between their expression level and clinical and pathological characteristics, and investigate their diagnostic and prognostic values. Our data demonstrated that the hsa_circ_0028502 and hsa_circ_0076251 levels were considerably lower in HCC tissues than in adjacent paracancerous tissues (P < .001). Further study revealed that hsa_circ_0028502 expression levels were related to tumor node metastasis (TNM) stage (P = .015) and that hsa_circ_0076251 expression levels were related to Barcelona Clinic Liver Cancer (BCLC) stage (P = .038), comorbidity with type 2 diabetes mellitus (P = .023) and the presence of serum HbsAg (P = .044). Furthermore, the degree of expression of both hsa_circ_0028502 and hsa_circ_0076251 increased from HCC to liver cirrhosis (LC) to chronic hepatitis (CH). The receiver operating characteristic (ROC) curve demonstrated that hsa_circ_0028502 and hsa_circ_0076251 could serve as fairly accurate markers to distinguish HCC tissues from CH tissues and LC tissues, as well as distinguishing LC tissues from CH tissues. Cox regression analysis showed that low expression of has_circ_0076251 was associated with unfavorable survival rates in HCC (HR = 0.46; 95% CI = 0.22-0.98; P < .05). These findings implied that hsa_circ_0028502 and hsa_circ_0076251 were potentially valuable biomarkers for HCC diagnosis, whereas hsa_circ_0076251 could be used as a prognostic indicator for HCC.

Differential expression of circular RNAs in hepatic tissue in a model of liver fibrosis and functional analysis of their target genes.

AIM: To measure the expression profile of circular RNA (circRNA) in hepatic tissues in a liver fibrosis model and to explore their function using molecular biology and bioinformatic techniques. METHODS: The classic CCl4 mouse liver fibrosis model was established alongside a normal control group. The circRNA expression profile of hepatic tissue from the two groups was compared using a high-throughput circRNA microarray. The differentially expressed circRNAs were identified, and real-time quantitative polymerase chain reaction (RT-qPCR) was used to verify a subset of the differentially expressed circRNAs (target genes). At the same time, the mouse oxidative stress injury, macrophage inflammation, and hepatic stellate cell activation models were established, and the expression of target circRNA in the above cells was measured by RT-qPCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to predict the biological functions of target genes. Finally, one of the circRNAs was selected and its cellular function was verified using siRNA. RESULTS: A total of 10 389 circRNAs were analyzed by microarray. Compared with the normal group, there were 69 circRNAs that were differentially expressed in the liver fibrosis model group (>2-fold differential expression, P < 0.05), of which 14 were upregulated and 55 were downregulated. Five circRNAs and their differential expression were verified by RT-qPCR, and the findings were consistent with the microarray results. Of these, three circRNAs were differentially expressed (P < 0.05) in the JS1 model, one circRNA was differentially expressed (P < 0.05) in the AML12 model, and four circRNAs were differentially expressed (P < 0.05) in the RAW264.7 model. The GO analysis showed that the differentially expressed circRNAs might be involved in cell autophagy, composition of extracellular matrix components, synthesis and metabolism of retinoic acid, retinol dehydrogenase activity, ubiquitin-like protein ligase activity, histone methylation, and other biological functions. The KEGG analysis showed that the target genes of the differentially expressed circRNAs might be involved in transforming growth factor-ß1/smads, Hippo, Rap1, vascular endothelial growth factor, and other signaling pathways. Lipofection experiments showed that the expression of α-smooth muscle actin (α-SMA) in JS1 cells increased significantly after the expression of mmu_circ_34116 was decreased. CONCLUSION: The circRNA expression profile in liver fibrosis tissue shows significant changes. Partially differentially expressed circRNA could be involved in hepatic fibrosis related to hepatic oxidative stress injury, macrophage inflammation, and stellate cell activation. For instance, mmu_circ_34116 can significantly inhibit the activation of hepatic stellate cells.

Circular RNAs in hepatocellular carcinoma: Functions and implications.

At present, as hotspot members of the noncoding RNA network, circular RNAs (circRNAs) with distinct properties and diverse pathophysiological functions are being increasingly delineated. CircRNAs play roles at the epigenetic, transcriptional and posttranscriptional regulatory levels. Major studies have focused on their functions as efficient microRNA sponges. The validated number of endogenous circRNAs involved in hepatocellular carcinoma (HCC) continues to increase. Altered circRNA expression is associated with HCC occurrence, invasion, and metastasis. Moreover, the aberrant expression of circRNAs is also significantly related to HCC tumor stage, size, differentiation and metastasis. Because they are exceptionally stable, highly conserved and have tissue-specific expression patterns, some circRNAs, including hsa_circ_0004018, hsa_circ_0003570, and hsa_circ_0005075, may be potential markers for the diagnosis of HCC. We herein summarize the current knowledge of HCC-associated circRNAs and present their implications for carcinogenesis and their potential value as diagnostic and prognostic biomarkers. Finally, we discuss the future directions of studies on HCC-associated circRNAs.

Circular RNA 0068669 as a new biomarker for hepatocellular carcinoma metastasis.

BACKGROUND: Circular RNAs (circRNAs) play important roles in disease occurrence. However, the roles of circRNAs in the diagnosis of hepatocellular carcinoma (HCC) are largely unknown. The aim of this study is to investigate the clinical diagnostic values of hsa_circ_0068669 (Alias: hsa_circ_103561), one of the representative HCC-associated circRNAs. METHODS: Hsa_circ_0068669 expression levels in HCC tissues, HCC cell lines, and chronic hepatitis tissues were detected by real-time quantitative reverse transcription-polymerase chain reaction. Its expression levels between HCC tissues and adjacent non-tumorous tissues were analyzed using paired t test. Independent t test and one-way analysis of variance (ANOVA) were performed to analyze the relationships between hsa_circ_0068669 expression levels and clinicopathological factors of patients with HCC. A receiver operating characteristic (ROC) curve was established to estimate the value of hsa_circ_0068669 as a biomarker in HCC. RESULTS: Hsa_circ_0068669 expression was significantly downregulated in HCC tissues and HCC cell lines compared with paired non-tumorous tissues and normal hepatic cell line, respectively. Moreover, hsa_circ_0068669 expression in HCC tissues was decreased comparing with chronic hepatitis tissues. Furthermore, hsa_circ_0068669 expression was correlated with microvascular invasion and TNM stages. CONCLUSIONS: Our findings indicate that hsa_circ_0068669 might be served as a novel potential biomarker for HCC metastasis.

Decreased expression of hsa_circ_0003570 in hepatocellular carcinoma and its clinical significance.

BACKGROUND: Circular RNAs (circRNAs) constitute a class of non-coding RNAs recently discovered to be widespread and abundant in mammalian cells. However, the expression features of most of circRNAs in hepatocellular carcinoma (HCC) are unraveled. In this study, we focused on hsa_circ_0003570, which was found to be down-regulated in HCC tissues in our previous microarray screening. METHODS: The hsa_circ_0003570 levels in HCC cell lines, HepG2, SMMC-7721, MHCC97L, MHCC97H, and HCCLM3, and human normal hepatic cell line L02 were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Then, its levels in 107 paired HCC tissues and adjacent non-tumor tissues, 60 liver biopsy samples from patients with chronic liver diseases were detected by qRT-PCR. The receiver operating characteristic curve (ROC) was used to evaluate the diagnostic value of hsa_circ_0003570 for HCC. RESULTS: Hsa_circ_0003570 was not only first found down-regulated in HCC cell lines (P<.001) but also in HCC tissues (P<.001). Moreover, hsa_circ_0003570 was gradually decreased from chronic hepatitis (CH), to liver cirrhosis (LC) and to HCC tissues (P<.01). Its expression levels were significantly correlated with tumor diameter (P=.035), differentiation (P=.013), microvascular invasion (P=.045), Barcelona Clinic Liver Cancer stages (P=.011), tumor-node-metastasis stages (P=.016), and serum alpha-fetoprotein levels (P=.031). The ROC curve demonstrated that hsa_circ_0003570 had poor performance for differentiating HCC from LC and CH, but had relatively good performance for differentiating LC from CH. CONCLUSIONS: These results indicated that hsa_circ_0003570 expression levels were associated with HCC clinicopathological characteristics.

Plasma circular RNA profiling of patients with gastric cancer and their droplet digital RT-PCR detection.

To observe the diagnostic values of circular RNAs (circRNAs), their expression profiles between gastric cancer patients' plasma and healthy controls were first assessed by circRNA microarray. Then, circRNA levels were measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and RT-droplet digital PCR (RT-ddPCR), respectively. A total of 343 differentially expressed circRNAs were found. The top 10 elevated circRNAs in patients were hsa_circ_0088300, hsa_circ_0075825, hsa_circ_0019172, hsa_circ_0000220, hsa_circ_0035277, hsa_circ_0000301, hsa_circ_0000189, hsa_circ_0090080, hsa_circ_0001888, and hsa_circ_0001874. The top 10 reduced circRNAs were hsa_circ_0004771, hsa_circ_0001190, hsa_circ_0061276, hsa_circ_0092337, hsa_circ_0058495, hsa_circ_0061274, hsa_circ_0075829, hsa_circ_0080845, hsa_circ_0001006, and hsa_circ_0003764. In cancer and dysplasia tissues, hsa_circ_0001017 and hsa_circ_0061276 were downregulated. Their levels were significantly associated with distal metastasis. The area under receiver operating characteristic curve in combinative use was 0.966 with 95.5% sensitivity and 95.7% specificity. Patients with low plasma hsa_circ_0001017 or hsa_circ_0061276 had a much shorter overall survival than those with high levels. Patients whose plasma hsa_circ_0001017 or hsa_circ_0061276 levels recovered to normal after operation had a longer disease-free survival. Finally, the in vitro model indicated gastric cancer cells secreting circRNAs into plasma. In conclusion, RT-ddPCR is a potent non-invasive and absolute quantification method for simultaneous detection of multiple circRNAs. Hsa_circ_0001017 and hsa_circ_0061276 are new potential biomarkers for gastric cancer. KEY MESSAGE: A total of 343 circRNAs are differentially expressed between gastric cancer patients' plasma and healthy controls. Hsa_circ_0001017 and hsa_circ_0061276 are downregulated in gastric cancer tissues. The RT-ddPCR is a potent method for simultaneous detection of multiple circRNAs in plasma. Hsa_circ_0001017 and hsa_circ_0061276 are potential biomarkers for gastric cancer.

Screening differential circular RNA expression profiles reveals hsa_circ_0004018 is associated with hepatocellular carcinoma.

Circular RNAs (circRNAs) have been emerged as an indispensable part of endogenous RNA network. However, the expression significance of circRNAs in hepatocellular carcinoma (HCC) is rarely revealed. The aim of this study was to determine the circRNA expression profile in HCC, and to investigate their clinical significances and relevant mechanisms for cancer progression. The global circRNA expression profile in HCC was measured by circRNA microarray. Levels of one representative circRNAs, hsa_circ_0004018, were confirmed by real-time reverse transcription-polymerase chain reaction. The expression levels of hsa_circ_0004018 in HCC were significantly lower compared with para-tumorous tissue (P<0.001). Our data further showed that lower expression of hsa_circ_0004018 was correlated with serum alpha-fetoprotein (AFP) level, tumor diameters, differentiation, Barcelona Clinic Liver Cancer stage and Tumor-node-metastasis stage. More importantly, we detected liver tissues from chronic hepatitis, cirrhosis and HCC patients; and found that hsa_circ_0004018 harbored HCC-stage-specific expression features in diverse chronic liver diseases (P<0.001). The area under receiver operating characteristic curve was up to 0.848 (95% CI=0.803-0.894, P<0.001). The sensitivity and specificity were 0.716 and 0.815, respectively. Finally, hsa_circ_0004018 might be involved in cancer-related pathways via interactions with miRNAs.

Investigation on left ventricular multi-directional deformation in patients of hypertension with different LVEF.

BACKGROUND: This study is aimed at investigating myocardial multi-directional systolic deformation in hypertensive with different left ventricular ejection fraction (LVEF), and exploring its contribution to LVEF. METHODS: One hundred and twenty-three patients with primary hypertension (HT) were divided into group A (LVEF ≥ 55%), group B (45% ≤ LVEF < 50%, or 50% ≤ LVEF < 55% + LVEDVI ≥ 97 ml/m2), and group C (LVEF < 45%). Two-dimensional strain echocardiography (2DSE) including LV longitudinal strain (SL), radial strain (SR) and circumferential strain (SC) were measured. RESULTS: SL decreased gradually from group A, B to C (all p < 0.05) while SR and SC were reduced only in group B and C (all p < 0.05). All strain measurements correlated to LVEF, with the strongest correlation in SC (r = -0.82, p < 0.01) and the second in SL (r = -0.76). The diastolic E/e increased from group A, B to C. CONCLUSIONS: Left ventricular multi-directional deformation correlated well to LVEF in hypertension and particularly SC, indicating that it was SC, not SL or SR, that makes the prominent contribution to left ventricular pump function.

Hsa_circ_0005986 inhibits carcinogenesis by acting as a miR-129-5p sponge and is used as a novel biomarker for hepatocellular carcinoma.

Circular RNAs (circRNAs), a class of long-time-ignored noncoding RNA, have been revealed as multifunctional RNAs in recent years. However, the diagnostic values and the mechanism of most circRNAs in hepatocellular carcinoma (HCC) remain unknown. In this study, we revealed that the expression level of hsa_circ_0005986 in HCC was significantly lower than that in adjacent non-tumorous tissues (P < 0.001). Its levels in HCC cell lines, HepG2, SMMC7721, Huh7, MHCC97L, MHCC97H, and HCCLM3 were significantly lower than those in human normal hepatic cell line L02 (P < 0.001). In addition, the low expression level of hsa_circ_0005986 was correlated with chronic hepatitis B family history (P = 0.001), tumor diameters (P < 0.001), microvascular invasion (P = 0.026), and Barcelona Clinic Liver Cancer (BCLC) stage (P < 0.001). Further experiments demonstrated that both hsa_circ_0005986 and Notch1mRNA were targets of miR-129-5p, and that hsa_circ_0005986 downregulation liberated miR-129-5p and decreased the expression level of Notch1mRNA. More importantly, hsa_circ_0005986 downregulation accelerated cell proliferation by promoting the G0/G1 to S phase transition. We conclude that hsa_circ_0005986 function as microRNA sponge in tumorigenesis and can be used as a novel biomarker for HCC.

Circular RNAs: Biogenesis, properties, roles, and their relationships with liver diseases.

Circular RNAs (circRNAs) are a class of new-found RNA molecules that have a special covalent loop structure without a 5' cap and 3' tail. Researchers have found that circRNAs may be generated by intron-pairing-driven or lariat-driven circularization. They are cleared up by way of extracellular vesicles. They have some advantages such as stability, conservation, and tissue specificity. By serving as sponges of microRNAs, interacting with long non-coding RNAs, mRNA, or proteins, circRNAs regulate gene expression at transcriptional and post-transcriptional levels and contribute to carcinogenesis. In recent years, circRNAs have been found to be correlated with many cancers including hepatocellular carcinoma, one of the most common cancers with high mortality. This article will first introduce the biogenesis, properties, and functions of circRNAs. Then we focus on the molecular mechanisms underlying some circRNAs, including hsa_circ_0001649, hsa_circ_0005075, and cerebellar degeneration-related protein 1 antisense, on hepatocellular carcinoma metastasis.

Molecular mechanisms of long noncoding RNAs on gastric cancer.

Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. Aberrant expression of lncRNAs has been found associated with gastric cancer, one of the most malignant tumors. By complementary base pairing with mRNAs or forming complexes with RNA binding proteins (RBPs), some lncRNAs including GHET1, MALAT1, and TINCR may mediate mRNA stability and splicing. Other lncRNAs, such as BC032469, GAPLINC, and HOTAIR, participate in the competing endogenous RNA (ceRNA) network. Under certain circumstances, ANRIL, GACAT3, H19, MEG3, and TUSC7 exhibit their biological roles by associating with microRNAs (miRNAs). By recruiting histone-modifying complexes, ANRIL, FENDRR, H19, HOTAIR, MALAT1, and PVT1 may inhibit the transcription of target genes in cis or trans. Through these mechanisms, lncRNAs form RNA-dsDNA triplex. CCAT1, GAPLINC, GAS5, H19, MEG3, and TUSC7 play oncogenic or tumor suppressor roles by correlated with tumor suppressor P53 or onco-protein c-Myc, respectively. In conclusion, interaction with DNA, RNA and proteins is involved in lncRNAs' participation in gastric tumorigenesis and development.

Plumbagin Ameliorates CCl 4 -Induced Hepatic Fibrosis in Rats via the Epidermal Growth Factor Receptor Signaling Pathway.

Epidermal growth factor (EGF) and its signaling molecules, EGFreceptor (EGFR) and signal transducer and activator of transcription factor 3 (STAT3), have been considered to play a role in liver fibrosis and cirrhosis. Plumbagin (PL) is an extracted component from the plant and has been used to treat different kinds of cancer. However, its role in regulation of EGFR and STAT3 during liver fibrosis has not been investigated. In this study, the effects of PL on the regulation of EGFR and STAT3 were investigated in carbon tetrachloride (CCl4) induced liver fibrosis and hepatic stellate cells (HSC-T6). PL significantly attenuated liver injury and fibrosis in CCl4 treated rats. At concentrations of 2 to 6 µM, PL did not induce significant cytotoxicity of HSC-T6 cells. Moreover, PL reduced phosphorylation of EGFR and STAT3 in both fibrotic liver and heparin-binding EGF-like growth factor (HB-EGF) treated HSC-T6 cells. Furthermore, PL reduced the expression of α-SMA, EGFR, and STAT3 in both fibrotic liver and HB-EGF treated HSC-T6 cells. In conclusion, plumbagin could ameliorate the development of hepatic fibrosis through its downregulation of EGFR and STAT3 in the liver, especially in hepatic stellate cells.