QingFeiPaiDu decoction (QFPDD) treatment benefits patients with coronavirus disease 2019 (COVID-19). This study aims to elucidate the mechanisms that underlie the anti-inflammatory effects of QFPDD.

Based on the clinical symptoms of COVID-19 patients, a component-target-disease network was constructed using the network pharmacology method, and the potential active components, targets, and molecular mechanisms of QFPDD for the treatment of COVID-19 were screened using topology parameter analysis. The best molecules that were affected by QFPDD were validated using Real-Time quantitative polymerase chain reaction (RT-qPCR) in a cellular inflammation model.

In total, 376 active ingredients were identified in QFPDD, and 18,833 potential anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets. The principal targets included PIK3CA, PIK3R1, APP, SRC, MAPK1, MAPK3, AKT1, HSP90AA1, EP300, and CDK1. Overall, 574 gene oncology entries and 214 signal pathways were identified. QFPDD affected the cellular response to nitrogen compounds, protein kinase activity, and membrane rafts. QFPDD modulated pathways that are associated with cancer, endocrine resistance, PI3K-Akt signaling, and proteoglycans in cancer. Molecular docking indicated that the core ingredients of QFPDD had a strong binding affinity for SARS-CoV-2 3-chymotrypsin-like cysteine protease (3CLpro) and angiotensin-converting enzyme 2 (ACE2). QFPDD treatment significantly mitigated the lipopolysaccharides-induced five targeted gene transcription in A549 cells.

Our findings preliminarily elucidated that through its active ingredients QFPDD targeted 3CLpro and ACE2 to modulate many factors and pathways that are associated with the pathogenesis of COVID-19. The identified potential molecular mechanism, relevant factors, and key genes QFPDD targeted might help in the design of new and specific antiviral drugs.

Previous studies have reported that the single nucleotide polymorphisms (SNPs) of SAMM50-rs738491, PARVB-rs5764455 and PNPLA3-rs738409 are associated with nonalcoholic fatty liver disease (NAFLD). However, no studies have examined the effect of interactions between these three genotypes to affect liver disease severity. We assessed the effect of these three SNPs on nonalcoholic steatohepatitis (NASH) and also examined the gene-gene interactions in a Chinese population with biopsy-confirmed NAFLD.

We enrolled 415 consecutive adult individuals with biopsy-proven NAFLD. Multivariable logistic regression analysis was undertaken to test associations between NASH and SNPs in SAMM50-rs738491, PARVB-rs5764455 and PNPLA3-rs738409. Gene-gene interactions were analyzed by performing a generalized multifactor dimensionality reduction (GMDR) analysis.

The mean ± standard deviation age of these 415 patients was 41.3±12.5 years, and 75.9% were men. Patients with SAMM50-rs738491 TT, PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes had a higher risk of NASH, even after adjustment for age, sex and body mass index. GMDR analysis showed that the combination of all three SNPs was the best model for predicting NASH. Additionally, the odds ratio of the haplotype T-A-G for predicting the risk of NASH was nearly three times higher than that of the haplotype G-C-C.

NAFLD patients carrying the SAMM50-rs738491 TT, PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes are at greater risk of NASH. These three SNPs may synergistically interact to increase susceptibility to NASH.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new term from nonalcoholic fatty liver disease (NAFLD) and is a positive diagnosis based on histopathology, imaging, or blood biomarkers. MAFLD is one of the common causes of liver dysfunction worldwide, likely due to the increase in metabolic syndrome as well as the high burden of disease and its relationship to other extrahepatic conditions. However, effective pharmacological therapeutic agents are still lacking; current management largely focuses on weight reduction and lifestyle modification. The purpose of this review was to summarize the updated evidence of novel therapies targeting different pathogenetic pathways in MAFLD.

Chronic kidney disease (CKD) usually occurs during the chronic infection of hepatitis B virus (HBV). However, the risk factors of CKD in an HBV population have not been completely demonstrated. Our present study aimed to investigate the risk factors of CKD in chronic HBV infection using a hospital based cross-sectional study in the northern area of China.

During January 2013 to December 2017, a total of 94 patients with CKD complicated by chronic HBV infection were consecutively enrolled in the study, as well as 548 age- and sex-matched hepatitis B patients without CKD who were enrolled as controls. Univariate and multivariate regression analyses were used to determine the effects of each variable after adjusting for cofounding factors.

Multivariate analysis showed that HBeAg-positive status (odds ratio [OR]=2.099, 95% CI 1.128–3.907), dyslipidemia (OR: 3.025, 95% CI 1.747–5.239), and hypertension (OR: 12.523, 95% CI 6.283–24.958) were independently associated with the incidence of CKD, while duration of HBV infection (≥240 months) (OR: 0.401, 95% CI 0.179–0.894), Log10 HBsAg (OR: 0.514, 95% CI 0.336–0.786), and coronary heart disease (OR: 0.078, 95% CI 0.008–0.768) were protective factors for the incidence of CKD. Duration of HBV infection, Log10 HBsAg, HBeAg-positive status and dyslipidemia remained the risk factors for CKD after adjusting for diabetes mellitus, hypertension, and coronary heart disease.

Duration of HBV infection, Log10 HBsAg, HBeAg-positive status and dyslipidemia contributed to the incidence of CKD during chronic HBV infection in a Chinese population.

AT-rich interactive domain-containing protein 1A (ARID1A) is frequently mutated or deficient in hepatocellular carcinoma (HCC). However, the role of ARID1A in HCC remains unclear. Therefore, the biological role of ARID1A in HCC was evaluated and a potential mechanism was investigated.

Arid1a was knocked out in the livers of mice using the CRISPR/Cas9 system delivered by hydrodynamic tail vein injection. The development of HCC was observed in different mouse models. The correlation of ARID1A and prognosis in patients with HCC was analyzed using cBioPortal. The effect of ARID1A on cell proliferation was assessed by MTT assay following the manipulation of candidate genes.

ARID1A deficiency alone did not cause HCC in mice, but knockout of ARID1A accelerated liver tumorigenesis in response to diethylnitrosamine (DEN) or when a combination knockout of phosphatase and tensin homolog (Pten) plus tumor protein P53 (p53) was introduced. ARID1A mutations were associated with a poorer prognosis in HCC patients. The mRNA level of MYC was significantly higher in patients with an ARID1A mutation compared to those without a mutation. Ectopic expression of ARID1A inhibited HCC cell proliferation. ARID1A knockout increased HCC cell growth and resulted in disruptions to DNA damage repair and apoptosis following radiation stress. Furthermore, mechanistic studies revealed that ARID1A inhibited the proliferation of HCC cells via transcriptional down-regulation of MYC.

These results describe ARID1A as a tumor suppressor in the liver. A deficiency in ARID1A predicts worse survival in HCC patients and promotes HCC progression via up-regulation of MYC transcription.

The diagnosis of metabolic-associated fatty liver disease is based on the detection of liver steatosis together with the presence of metabolic dysfunction. According to this new definition, the diagnosis of metabolic-associated fatty liver disease is independent of the amount of alcohol consumed. Actually, alcohol and its metabolites have various effects on metabolic-associated abnormalities during the process of alcohol metabolism. Studies have shown improved metabolic function in light to moderate alcohol drinkers. There are several studies focusing on the role of light to moderate alcohol intake on metabolic dysfunction. However, the results from studies are diverse, and the conclusions are often controversial. This review systematically discusses the effects of alcohol consumption, focusing on light to moderate alcohol consumption, obesity, lipid and glucose metabolism, and blood pressure.

Liver imaging reporting and data system (LI-RADS) provides standardized lexicon and categorization for diagnosing hepatocellular carcinoma (HCC). However, there is limited knowledge about the effect of LI-RADS training. We prospectively explored whether the systematic training of LI-RADS v2018 on magnetic resonance imaging (MRI) can effectively improve the diagnostic performances of different radiologists for HCC.

A total of 20 visiting radiologists and the multiparametric MRI of 70 hepatic observations in 61 patients with high risk of HCC were included in this study. The LI-RADS v2018 training procedure included three times of thematic lectures (each lasting for 2.5 h) given by a professor specialized in imaging diagnosis of liver, with an interval of a month. After each seminar, the radiologists had a month to adopt the algorithm into their daily work. The diagnostic performances and interobserver agreements of these radiologists adopting the algorithm for HCC diagnosis before and after training were compared.

A total of 20 radiologists (male/female, 12/8; with an average age of 36.75±4.99 years) were enrolled. After training, the interobserver agreements for the LI-RADS category for all radiologists (p=0.005) were increased. The sensitivity, specificity, positive predictive value, negative predictive value, and coincidence rate of all radiologists for HCC diagnosis before and after training were 43% vs. 54%, 86% vs. 88%, 74% vs. 81%, 62% vs. 67%, and 65% vs. 71%, respectively. The diagnostic performances of all radiologists (p<0.001) showed improvement after training.

The systematic training of LI-RADS can effectively improve the diagnostic performances of radiologists with different experiences for HCC.

To explore how insulin resistance promotes colorectal adenomas by disrupting the balance of glucose and lipid metabolism.

All the clinical data were collected for retrospective analysis were divided into five groups. Clinical chemical analysis was run by automatic biochemical analyzer. An enzyme-linked immunosorbent assay was used to detect peripheral blood insulin levels, and RT-qPCR was used to detect mRNA expression of insulin pathway-related genes, including INSR, KCNJ11, and PIK3CA). Moreover, the expression levels of all genes were also obtained from the GEO database and compared.

In the adenoma groups, only TG, HDL-C levels, and HOMA-IR scores were statistically increased comparing the control group, but TC was statistically different among the adenoma groups. Chi-square results showed that the presence of fatty liver increased adenoma generation and progression, and the ROC curve revealed that HOMA-IR scores had high diagnostic value for progressive and non-progressive adenomas. Gene analysis showed that INSR, KCNJ11, and PIK3CA all had a significantly lower expression in colorectal adenocarcinoma tissues compared with the control group. GEO bioinformatics analysis revealed that INSR was statistically increased in the GSE 37364 dataset, and PIK3CA was significantly different between adenoma and controls in the GSE 41657 dataset, while KCNJ11 was elevated when comparing colorectal carcinoma to controls in the GSE 41657 dataset.

Through clinical pathological data analysis, bioinformatics mining, and molecular biology experiments, INSR, KCNJ11, and PIK3CA were shown to act on colorectal adenomas through the insulin resistance pathway and may be used as distinguished potential biomarkers for tumorigenesis.

Chronic hepatitis B virus (HBV) infection is a serious health problem worldwide. Evaluating liver injury in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) with detectable HBV DNA and normal alanine aminotransferase (ALT) is crucial to guide their clinical management. We aimed to investigate the stages of liver inflammation and fibrosis as well as the predictive accuracy of gamma-glutamyl transpeptidase-to-platelet ratio (GPR) in these patients.

A total of 184 treatment-naïve HBeAg-negative CHB patients with detectable HBV DNA and normal ALT were enrolled. The Scheuer scoring system was used to classify liver inflammation and fibrosis.

The distribution of patients with different liver inflammation grades were as follows: G0, 0 (0%); G1, 97 (52.7%); G2, 68 (37.0%); G3, 12 (6.5%); and G4, 7 (3.8%). The distribution of patients with different liver fibrosis stages were as follows: S0, 22 (12.0%); S1, 72 (39.1%); S2, 42 (22.8%); S3, 19 (10.3%); and S4, 29 (15.8%). The areas under the receiver operating characteristic (AUROC) curves of GPR in predicting significant inflammation, severe inflammation, and advanced inflammation were 0.723, 0.895, and 0.952, respectively. The accuracy of GPR was significantly superior to that of ALT in predicting liver inflammation. The AUROCs of GPR in predicting significant fibrosis, severe fibrosis, and cirrhosis were 0.691, 0.780, and 0.803, respectively. The predictive accuracy of GPR was significantly higher than that of aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4) in identifying advanced fibrosis and cirrhosis, and it was superior to FIB-4 but comparable to APRI in identifying significant fibrosis.

Nearly half of the HBeAg-negative CHB patients with detectable HBV DNA and normal ALT levels had significant liver inflammation or fibrosis. GPR can serve as an accurate predictor of liver inflammation and fibrosis in these patients.

Numerous studies have explored the important role of N6-methyladenosine (m6A) in cancer. Nonetheless, the interaction between m6A and long noncoding RNAs (lncRNAs) is poorly investigated. Herein, we systematically analyzed the role and prognostic value of m6A-related lncRNAs in hepatocellular carcinoma (HCC).

The m6A-related lncRNAs were identified based on the correlation coefficients with m6A-related genes in HCC from The Cancer Genome Atlas. Subsequently, a novel risk score model was determined using the least absolute shrinkage and selection operator Cox regression analyses. Univariate and multivariate Cox analyses were used to identify independent prognostic factors for overall survival (OS) of HCC; thereafter, a prognostic nomogram was constructed.

A total of 259 lncRNAs showed significant correlations with m6A in HCC, while 29 lncRNAs had prognostic significance. Further, six critical m6A-related lncRNAs (NRAV, SNHG3, KDM4A-AS1, AC074117.1, AC025176.1, and AL031985.3) were screened out to construct a novel risk score model which classified HCC patients into high- and low-risk groups. Survival analyses revealed that patients in the high-risk group exhibited worse OS, both in the training and validation groups. The risk score was also identified as an independent prognostic factor of OS, and a nomogram was established and verified with superior prediction capacity. Besides, the risk score significantly correlated with the expression of immune checkpoint genes and immune subtypes.

These findings indicated the significant role of m6A-related lncRNAs in HCC and the potential application of the novel risk score model for prognostic prediction.

Reducing reactive oxygen species (ROS) production has proven an effective way for alleviating oxidative stress during ischemia-reperfusion injury (IRI). Moreover, inhibition of Rac1 could reduce ROS production and prevent oxidative stress injury. Previous studies have suggested a positive interactivation feedback loop between Rac1 and hypoxia-inducible factor (HIF)-1α, the latter being up-regulated early during ischemia. The positive inter-activation between Rac1 and HIF-1α would aggravate ROS production, thereby promoting IRI. This study was designed to verify the effects of Rac1 inhibition on hepatic IRI both at animal and cellular levels and to explore the interaction between Rac1 and HIF-1α during hepatic IRI.

C57B/6 mice and AML-12 cells were used for the construction of hepatic IRI animal and cell models. Rac1 inhibition was achieved by NSC23766 (a specific Rac1 inhibitor). Lentiviral vectors were used for Rac1 knockdown. At designated time points, serum and liver tissues were collected from the mice and treated cells were collected for further analysis.

NSC23766 treatment significantly alleviated the hepatic IRI in mice, manifesting as lower vacuolation score and less apoptosis cells, lower ROS and serum/liver alanine aminotransferase/aspartate aminotransferase levels, and fewer activated inflammatory cells. IRI of AML-12 was also alleviated by 50 µM NSC23766 or Rac1-knockdown, manifesting as reduced cell apoptosis, less extensive interruption of mitochondrial membrane potential, down-regulation of apoptosis, and effects on DNA damage-related proteins. Interestingly, Rac1 knockdown also down-regulated the expression level of HIF-1α.

Our study supports a protective effect of Rac1 inhibition on hepatic IRI. Aside from the classic topics of reducing ROS production and oxidative stress, our study showed an interaction between Rac1 and HIF-1α signaling during hepatic IRI.

Although activation of hepatic stellate cells (HSCs) plays a central role in the development of liver fibrosis, the mechanism underlying the activation of HSCs remains unclear. Keratin 17 (KRT17), a member of the intermediate filament family, can regulate tumor cell proliferation and migration. The current study aimed to elucidate the role of KRT17 in the activation of HSCs and the mechanisms underlying liver fibrosis.

The expression of KRT17 was determined using immunohistochemistry in tissue microarray. Western blotting and qRT-PCR assays were used to determine the KRT17 expression in fibrotic liver tissues obtained from human subjects and mice. LX-2 cells were treated with TGF-β1 recombinant protein and adipocyte differentiation mixture (MDI) mix to induce and reverse LX-2 cell activation, respectively, in order to explore the correlation between KRT17 and HSC activation. Additionally, cell proliferation and migration abilities of LX-2 cells transfected with KRT17-overexpressing plasmid or small interfering RNA were determined using CCK-8, flow cytometry, Transwell, and wound healing assays. Finally, rescue assay was used to explore the role of KRT17 in HSC activation and epithelial-mesenchymal transition (EMT).

The expression of KRT17 was higher in the human and mouse fibrotic liver tissues than in healthy liver tissues, and it was positively correlated with HSC activation. Upregulated KRT17 enhanced proliferation, migration, HSC activation and EMT in LX-2 cells, while knockdown of KRT17 reversed these effects. TGF-β1 recombinant protein accelerated KRT17-mediated EMT, HSC activation and proliferation, while TGF-β1 inhibitor counteracted the effect of KRT17 in vitro.

KRT17 promoted HSC activation, proliferation and EMT in hepatic fibrosis probably via TGF-β1 signaling, and KRT17 might serve as a therapeutic target for the treatment of liver fibrosis.

Endovascular implantation of iodine-125 (125I) seeds strand combined with stent is an effective method of treatment for portal vein tumor thrombosis. The aim of this study was to develop a novel endovascular brachytherapy stent (EVB-Stent) and to evaluate its feasibility of use.

An EVB-Stent was implanted into the main portal vein (MPV) in a live porcine model via the percutaneous transhepatic route. Blood samples were collected and tested before and after operation, as well as before euthanasia. Single-photon emission computed tomography (SPECT) combined with CT (SPECT/CT) scan were performed directly after operation and CT scan was performed 2 months after implantation. After the CT scan was performed, all animals were euthanized and histologically examined.

The novel stent was successfully positioned in all six pigs. No deterioration of liver function was observed during the 2-month follow-up period. SPECT/CT revealed the uniform distribution of radiation around the seeds strand, and the hottest spot was near the center of the MPV. The patency of the stented MPV was confirmed using CT scans. The tissue-accumulated absorbed dose was 31,822.11 mGy at 10 mm transversely away from the midpoint of the 125I seeds strand, with a half-life of 59.4 days. Pathological examination results showed no significant atrophy or inflammation of adjunct liver tissue, and no obvious intima thickening or thrombosis were detected in the stented MPV.

A liver porcine model was used to demonstrate that the transhepatic placement of a novel endovascular brachytherapy stent, EVB-Stent, is both technically feasible and safe.

Microvascular invasion (MVI) affects recurrence after treatment of small hepatocellular carcinoma (sHCC) of ≤3 cm in size. The present study aimed to investigate whether abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and intermuscular adipose tissue (IMAT) are associated with MVI in patients with sHCC.

A total of 124 patients with pathologically-confirmed sHCC diagnosed on surgical resection at the First Hospital Affiliated to Army Military University were recruited and divided into two groups according to MVI classification criteria (i.e., MVI-positive or MVI-negative). The SAT, VAT, and IMAT areas at the lumbar 3 vertebral level were imaged with abdominal computed tomography and measured using ImageJ software. Their association with MVI in sHCC was analyzed.

Of the 124 patients with sHCC, 67 were MVI-positive and 57 were MVI-negative. Univariate analysis revealed a significant difference in the abdominal VAT and SAT between the MVI-positive and MVI-negative groups (p<0.05), with an area under the receiver operating characteristic curve of 0.76 and 0.65, respectively.

The results of this study suggest that the areas of abdominal SAT and VAT are of significant clinical value because they can effectively predict the MVI status in patients with sHCC.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy that causes a poor survival. We aimed to identify its prognostic factors and to develop a nomogram that will predict survival of ICC patients among all stages.

A total of 442 patients with pathology-proven ICC registered at the Fifth Medical Center of PLA General Hospital between July 2007 and December 2019 were enrolled. Subjects were followed for survival status until June 30, 2020. A prognostic model visualized as a nomogram was constructed in the training cohort using multivariate cox model, and was then validated in the validation cohort.

The median age was 55 years. With a median follow-up of 50.4 months, 337 patients died. The median survival was 11.6 months, with 1-, 3- and 5-year survival rates of 48.3%, 22.7% and 16.2%, respectively. Factors associated with overall survival were multiple tumors, lymph node involvement, vascular invasion, distant metastasis, decreased albumin, elevated lactate dehydrogenase (LDH), decreased iron, elevated fibrinogen, elevated CA125 and elevated CA19-9. A nomogram predicting survival of ICC patients at the time of diagnosis achieved a Harrel’s c-statistic of 0.758, significantly higher than the 0.582 of the TNM stage alone. Predicted median survivals of those within the low, mid and high-risk subgroups were 35.6, 12.1 and 6.2 months, respectively.

A nomogram based on imaging data and serum biomarkers at diagnosis showed good ability to predict survival in patients with all stages of ICC. Further studies are needed to validate the prognostic capability of our new model.

This study aimed to evaluate the diagnostic performance of high frame rate contrast-enhanced ultrasound (H-CEUS) of focal liver lesions (FLLs).

From July 2017 to June 2019, conventional contrast-enhanced ultrasound (C-CEUS) and H-CEUS were performed in 78 patients with 78 nodules. The characteristics of C-CEUS and H-CEUS in malignant and benign groups and the differences between different lesion sizes (1–3 cm, 3–5 cm, or >5 cm) of C-CEUS and H-CEUS were examined. The diagnostic performance of C-CEUS and H-CEUS was analyzed. The chi-square test or Fisher’s exact test was used to assess inter-group differences. The receiver operating characteristic curve was plotted to determine the diagnostic performance of C-CEUS and H-CEUS.

There were significant differences in the enhancement area, fill-in direction and vascular architecture between C-CEUS and H-CEUS for both benign and malignant lesions (all p=0.000–0.008), but there were no significant differences in washout results (p=0.566 and p=0.684, respectively). For lesions 1–3 cm in size, the enhancement area, fill-in direction, and vascular architecture on C-CEUS and H-CEUS were significantly different (all p=0.000), unlike for lesions 3–5 cm or >5 cm in size. For differentiation of malignant from benign FLLs in the 1–3 cm group, H-CEUS showed sensitivity, specificity, accuracy, and positive and negative predictive values of 92.86%, 95.0%, 96.3%, 90.48% and 93.75%, respectively, which were higher than those for C-CEUS (75.0%, 70.0%, 77.78%, 66.67% and 72.91%, respectively).

H-CEUS provided more vascular information which could help differentiate malignant from benign FLLs, especially for lesions 1–3 cm in size.

Long non-coding RNA small nucleolar RNA host genes (SNHGs) play a critical role in the occurrence and development of tumors. In this study, we aimed to investigate the role of SNHG4 in hepatocellular carcinoma (HCC) and its underlining mechanism.

Datasets were acquired from The Cancer Genome Atlas (TCGA) database. lncLocator 2.0 was used to identify the distribution of SNHG4 in HCC cells. Gene expression, Kaplan-Meier survival, microRNA and transcription factor target analyses were performed with the University of Alabama Cancer (UALCAN) Database, Kaplan-Meier Plotter, LinkedOmics, WebGestalt and gene set enrichment analysis, respectively. Gene Ontology and pathway enrichment analyses and assessment of RNA binding proteins were performed by R software, circlncRNAnet and Encyclopedia of RNA Interactomes (ENCORI). In addition, CirclncRNAnet and ENCORI were used to find the correlation between SNHG4 and important proteins, while the prognostic value was assessed with the Human Protein Atlas database and Kaplan-Meier Plotter.

Expression of SNHG4 in HCC is higher in HCC tissue than in normal healthy liver tissues and is mainly distributed in the nucleus. SNHG4 positively correlated with poor prognosis (p<0.01 for overall survival and recurrence-free survival). Functional enrichment analysis revealed SNHG4 involvement with regulation of ribosomal RNA synthesis and the RNA processing and surveillance pathway. SNHG4 is closely associated with miR-154 and miR-206, transcription factor target E2F family and the signaling pathway for MAPK/ERK and mTOR. U2 auxiliary factor 2 (U2AF2) showed strong correlation with SNHG4, while low-expression of U2AF2 showed good prognosis.

Based on our findings, we infer SNHG4 may play a role in the formation of HCC via regulation of tumor-related pathways.