Background and Aims
Aristolochic acid (AA) exposure has been statistically associated with human liver cancers. However, direct evidence of AA exposure–induced liver cancer is absent. This study aims ...to establish a direct causal relationship between AA exposure and liver cancers based on a mouse model and then explores the AA‐mediated genomic alterations that could be implicated in human cancers with AA‐associated mutational signature.
Approach and Results
We subjected mice, including phosphatase and tensin homolog (Pten)‐deficient ones, to aristolochic acid I (AAI) alone or a combination of AAI and CCl4. Significantly, AAI exposure induced mouse liver cancers, including hepatocellular carcinoma (HCC) and combined HCC and intrahepatic cholangiocarcinoma, in a dose‐dependent manner. Moreover, AAI exposure also enhanced tumorigenesis in these CCl4‐treated or Pten‐deficient mice. AAI led to DNA damage and AAI‐DNA adduct that could initiate liver cancers through characteristic adenine‐to‐thymine transversions, as indicated by comprehensive genomic analysis, which revealed recurrent mutations in Harvey rat sarcoma virus oncogene. Interestingly, an AA‐associated mutational signature was mainly implicated in human liver cancers, especially from China. Moreover, we detected the AAI‐DNA adduct in 25.8% (16/62) of paratumor liver tissues from randomly selected Chinese patients with HCC. Furthermore, based on phylogenetic analysis, the characteristic mutations were found in the initiating malignant clones in the AA‐implicated mouse and human liver cancers where the mutations of tumor protein p53 and Janus kinase 1 were prone to be significantly enriched in the AA‐affected human tumors.
Conclusions
This study provides evidence for AA‐induced liver cancer with the featured mutational processes during malignant clonal evolution, laying a solid foundation for the prevention and diagnosis of AA‐associated human cancers, especially liver cancers.
The differentiation and maturation trajectories of fetal liver stem/progenitor cells (LSPCs) are not fully understood at single-cell resolution, and a priori knowledge of limited biomarkers could ...restrict trajectory tracking.
We employed marker-free single-cell RNA-Seq to characterize comprehensive transcriptional profiles of 507 cells randomly selected from seven stages between embryonic day 11.5 and postnatal day 2.5 during mouse liver development, and also 52 Epcam-positive cholangiocytes from postnatal day 3.25 mouse livers. LSPCs in developing mouse livers were identified via marker-free transcriptomic profiling. Single-cell resolution dynamic developmental trajectories of LSPCs exhibited contiguous but discrete genetic control through transcription factors and signaling pathways. The gene expression profiles of cholangiocytes were more close to that of embryonic day 11.5 rather than other later staged LSPCs, cuing the fate decision stage of LSPCs. Our marker-free approach also allows systematic assessment and prediction of isolation biomarkers for LSPCs.
Our data provide not only a valuable resource but also novel insights into the fate decision and transcriptional control of self-renewal, differentiation and maturation of LSPCs.
Both E2F transcription factor and cyclin-dependent kinases (CDKs), which increase or decrease E2F activity by phosphorylating E2F or its partner, are involved in the control of cell proliferation, ...and some circRNAs and miRNAs regulate the expression of E2F and CDKs. However, little is known about whether dysregulation among E2Fs, CDKs, circRNAs and miRNAs occurs in human PCa.
The expression levels of CDK13 in PCa tissues and different cell lines were determined by quantitative real-time PCR and Western blot analysis. In vitro and in vivo assays were preformed to explore the biological effects of CDK13 in PCa cells. Co-immunoprecipitation anlysis coupled with mass spectrometry was used to identify E2F5 interaction with CDK13. A CRISPR-Cas9 complex was used to activate endogenous CDK13 and circCDK13 expression. Furthermore, the mechanism of circCDK13 was investigated by using loss-of-function and gain-of-function assays in vitro and in vivo.
Here we show that CDK13 is significantly upregulated in human PCa tissues. CDK13 depletion and overexpression in PCa cells decrease and increase, respectively, cell proliferation, and the pro-proliferation effect of CDK13 is strengthened by its interaction with E2F5. Mechanistically, transcriptional activation of endogenous CDK13, but not the forced expression of CDK13 by its expression vector, remarkably promotes E2F5 protein expression by facilitating circCDK13 formation. Further, the upregulation of E2F5 enhances CDK13 transcription and promotes circCDK13 biogenesis, which in turn sponges miR-212-5p/449a and thus relieves their repression of the E2F5 expression, subsequently leading to the upregulation of E2F5 expression and PCa cell proliferation.
These findings suggest that CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 is responsible for PCa development. Targeting this newly identified regulatory axis may provide therapeutic benefit against PCa progression and drug resistance.
As a chronic progressive autoimmune disease, rheumatoid arthritis (RA) is characterized by mainly damaging the synovium of peripheral joints and causing joint destruction and early disability. RA is ...also associated with a high incidence rate and mortality of cardiovascular disease. Recently, the relationship between lipid metabolism and RA has gradually attracted attention. Plasma lipid changes in RA patients are often detected in clinical tests, the systemic inflammatory status and drug treatment of RA patients can interact with the metabolic level of the body. With the development of lipid metabolomics, the changes of lipid small molecules and potential metabolic pathways have been gradually discovered, which makes the lipid metabolism of RA patients or the systemic changes of lipid metabolism after treatment more and more comprehensive. This article reviews the lipid level of RA patients, as well as the relationship between inflammation, joint destruction, cardiovascular disease, and lipid level. In addition, this review describes the effect of anti-rheumatic drugs or dietary intervention on the lipid profile of RA patients to better understand RA.
Chronic inflammation is one of the definite factors leading to the occurrence and development of tumors, including prostate cancer (PCa). The androgen receptor (AR) pathway is essential for PCa ...tumorigenesis and inflammatory response. However, little is known about the AR‐regulated NACHT, LRR, and PYD domain‐containing protein 3 (NLRP3) inflammasome pathway in human PCa. In this study, we explored the expression of inflammatory cytokine and AR in high‐grade PCa and observed that NLRP3 inflammasome‐associated genes were upregulated in high‐grade PCa compared with that in low‐grade PCa and benign prostatic hyperplasia and were associated with AR expression. In addition, we identified circAR‐3—a circRNA derived from the AR gene—which is involved in the AR‐regulated inflammatory response and cell proliferation by activating the NLRP3 inflammatory pathway. While circAR‐3 overexpression promoted cell proliferation and the inflammatory response, its depletion induced opposite effects. Mechanistically, we noted that circAR‐3 mediated the acetylation modification of NLRP3 by KAT2B and then promoted NLRP3 inflammasome complex subcellular distribution and assembly. Disturbing NLRP3 acetylation or blocking inflammasome assembly with an inhibitor suppressed the progression of PCa xenograft tumors. Our findings provide the first evidence that targeting NLRP3 acetylation or inflammasome assembly may be effective in inhibiting PCa progression.
Frame insertion, deletion and duplication are common inter-frame tampering operations in digital videos. In this paper, based on similarity analysis, a passive-blind forensics scheme for video shots ...is proposed to detect inter-frame forgeries. This method is composed of two parts: HSV (Hue-Saturation-Value) color histogram comparison and SURF (Speeded Up Robust Features) feature extraction together with FLANN (Fast Library for Approximate Nearest Neighbors) matching for double-checking. We mainly calculate H-S and S-V color histograms of every frame in a video shot and compare the similarity between histograms to detect and locate tampered frames in the shot. Then we utilize SURF feature extraction and FLANN matching to further confirm the forgery types in the tampered locations. Experimental results demonstrate that the proposed detection method is efficient and accurate in terms of forgery identification and localization. In contrast to other inter-frame forgery detection methods, our scheme can detect three kinds of forgery operations and has its own superiority and applicability as a passive-blind detection method.
•Porous (kelp) and non-porous (sludge) biochar were used for Cd adsorption.•TMT-102 coating and NaOH soaking were compared to enhance Cd adsorption.•The Cd adsorption by tested biochar are dominated ...by chemisorption.•TMT-102 coating is an efficient modification method for non-porous biochar.
Cadmium (Cd) is a toxic heavy metal and has been recognized to be teratogenic and carcinogenic to human. Although different biochars have been developed for cadmium adsorption, interactions between the modification process and biochars’ pore structure, as well as their effect on heavy metal adsorption capacity have been overlooked. By using trithiocyanuric acid trisodium salt (TMT-102) and NaOH soaking, cadmium adsorption by non-porous sludge and porous kelp biochar were compared. The modified biochars were characterized by SEM, FTIR, BET, EDS and Zeta potential analysis, while their performance were evaluated under various adsorption time, pH and with the existence of coexisting ions. The results proved that TMT-102 modification could enlarge sludge biochar's surface area and improve its adsorption capacity significantly. It also suggests that TMT-102 modification is more suitable for non-porous sludge biochar than porous kelp biochar. The results also suggest that Ca2+, Mg2+, C5H7O5COO− and CH3COO− could reduce Cd removal efficiency significantly, suggesting the necessity of considering interfering ions in future adsorption experiments.
A binary noble-metal-free cocatalyst consisting of ZnIn2S4 and In(OH)3 was developed via a facile one-step hydrothermal method. The ZnIn2S4/In(OH)3 modified ZnWO4 nanocomposite exhibited enhanced ...photocatalytic H2 evolution activity compared to all the related pure samples and binary composite photocatalysts under visible light irradiation. The enhanced photocatalytic hydrogen production activities can be attributed to the synergistic effects of the favorable light trapping ability and efficient spatial charge separation. The photocatalytic hydrogen evolution activity over other semiconductors, such as Zn2SnO4 and TiO2, can also be significantly increased by loading ZnIn2S4/In(OH)3 as a cocatalyst. The results clearly demonstrated that ZnIn2S4/In(OH)3 is discovered as a new class of earth-abundant cocatalyst for water-splitting under visible light irradiation. It is expected that our work could provide a new strategy to improve the visible light response of semiconductors and facilitate their application in water splitting.
Pre-existing Ca
2+
handling abnormalities constitute the arrhythmogenic substrate in patients developing postoperative atrial fibrillation (POAF), a common complication after cardiac surgery. ...Postoperative interleukin (IL)-6 levels are associated with atrial fibrosis in several animal models of POAF, contributing to atrial arrhythmias. Here, we hypothesize that IL-6-mediated-Ca
2+
handling abnormalities contribute to atrial fibrillation (AF) in sterile pericarditis (SP) rats, an animal model of POAF. SP was induced in rats by dusting atria with sterile talcum powder. Anti-rat-IL-6 antibody (16.7 μg/kg) was administered intraperitoneally at 30 min after the recovery of anesthesia.
In vivo
electrophysiology,
ex vivo
optical mapping, western blots, and immunohistochemistry were performed to elucidate mechanisms of AF susceptibility. IL-6 neutralization ameliorated atrial inflammation and fibrosis, as well as AF susceptibility
in vivo
and the frequency of atrial ectopy and AF with a reentrant pattern in SP rats
ex vivo
. IL-6 neutralization reversed the prolongation and regional heterogeneity of Ca
2+
transient duration, relieved alternans, reduced the incidence of discordant alternans, and prevented the reduction and regional heterogeneity of the recovery ratio of Ca
2+
transient. In agreement, western blots showed that IL-6 neutralization reversed the reduction in the expression of ryanodine receptor 2 (RyR2) and phosphorylated phospholamban. Acute IL-6 administration to isolated rat hearts recapitulated partial Ca
2+
handling phenotype in SP rats. In addition, intraperitoneal IL-6 administration to rats increased AF susceptibility, independent of fibrosis. Our results reveal that IL-6-mediated-Ca
2+
handling abnormalities in SP rats, especially RyR2-dysfunction, independent of IL-6-induced-fibrosis, early contribute to the development of POAF by increasing propensity for arrhythmogenic alternans.
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