Molecular Mechanisms of Hepatocellular Carcinoma Related to Aflatoxins: An Update

Hepatocellular carcinoma (hepatocarcinoma) is a major type of primary liver cancer and one of the most frequent human malignant neoplasms. Aflatoxins are I-type chemical carcinogen for hepatocarcinoma. Increasing evidence has shown that hepatocarcinoma induced by aflatoxins is the result of interaction between aflatoxins and hereditary factor. Aflatoxins can induce DNA damage including DNA strand break, adducts formation, oxidative DNA damage, and gene mutation and determine which susceptible individuals feature cancer. Inheritance such as alterations may result in the activation of proto-oncogenes and the inactivation of tumor suppressor genes and determine individual susceptibility to cancer. Interaction between aflatoxins and genetic susceptible factors commonly involve in almost all pathologic sequence of hepatocarcinoma: chronic liver injury, cirrhosis, atypical hyperplastic nodules, and hepatocarcinoma of early stages. In this review, we discuss the biogenesis, toxification, and epidemiology of aflatoxins and signal pathways of aflatoxin-induced hepatocarcinoma. We also discuss the roles of some important genes related to cell apoptosis, DNA repair, drug metabolism, and tumor metastasis in hepatocarcinogenesis related to aflatoxins

CBX4 Expression and AFB1-Related Liver Cancer Prognosis

Background: Previous studies have shown that chromobox 4 (CBX4) expression may involve in the progression of liver cancer, however, it is unclear whether it affects the prognosis of hepatocellular carcinoma (HCC) related to aflatoxin B1 (AFB1)

Effects of Sangu Decoction on Osteoclast Activity in a Rat Model of Breast Cancer Bone Metastasis

Bone metastasis (BM) is a major clinical problem for which current treatments lack full efficacy. The Traditional Chinese Medicine (TCM) Sangu Decoction (SGD) has been widely used to treat BM in China. However, no in vivo experiments to date have investigated the effects of TCM on osteoclast activity in BM. In this study, the protective effect and probable mechanism of SGD were evaluated. The model was established using the breast cancer MRMT-1 cells injected into the tibia of rat. SGD was administrated, compared with Zoledronic acid as a positive control. The development of the bone tumor and osteoclast activity was monitored by radiological analysis. TRAP stain was used to identify osteoclasts quantity and activity. TRAP-5b in serum or bone tumor and TRAP mRNA were also quantified. Radiological examination showed that SGD inhibited tumor proliferation and preserved the cortical and trabecular bone structure. In addition, a dramatic reduction of TRAP positive osteoclasts was observed and TRAP-5b levels in serum and bone tumor decreased significantly. It also reduced the mRNA expression of TRAP. The results indicated that SGD exerted potent antiosteoclast property that could be directly related to its TRAP inhibited activity. In addition it prevented bone tumor proliferation in BM model

The N-terminal Phosphodegron Targets TAZ/WWTR1 Protein for SCF β-TrCP -dependent Degradation in Response to Phosphatidylinositol 3-Kinase Inhibition

The Hippo tumor suppressor pathway plays a major role in development and organ size control, and its dysregulation contributes to tumorigenesis. TAZ (transcriptional co-activator with PDZ-binding motif; also known as WWTR1) is a transcription co-activator acting downstream of the Hippo pathway, and increased TAZ protein levels have been associated with human cancers, such as breast cancer. Previous studies have shown that TAZ is inhibited by large tumor suppressor (LATS)-dependent phosphorylation, leading to cytoplasmic retention and ubiquitin-dependent degradation. The LATS kinase, a core component of the Hippo pathway, phosphorylates the C-terminal phosphodegron in TAZ to promote its degradation. In this study, we have found that the N-terminal phosphodegron of TAZ also plays a role in TAZ protein level regulation, particularly in response to different status of cellular PI3K signaling. GSK3, which can be inhibited by high PI3K via AKT-dependent inhibitory phosphorylation, phosphorylates the N-terminal phosphodegron in TAZ, and the phosphorylated TAZ binds to β-TrCP subunit of the SCFβ-TrCP E3 ubiquitin ligase, thereby leading to TAZ ubiquitylation and degradation. We observed that the TAZ protein level is elevated in tumor cells with high PI3K signaling, such as in PTEN mutant cancer cells. This study provides a novel mechanism of TAZ regulation and suggests a role of TAZ in modulating tissue growth and tumor development in response to PI3K signaling

The Diagnostic and Prognostic Potential of MicroRNAs for Hepatocellular Carcinoma

Hepatocellular carcinoma (also termed hepatocarcinoma) is the third cancer-related cause of death worldwide. To our knowledge, markers such as α-fetoprotein display poor performance in the early diagnosis and prognosis prediction of hepatocarcinoma. MicroRNAs are an evolutionarily conserved class of small noncoding single-stranded RNA typically consisting of 18–24 nucleotides. They have been reported to act as tumor suppressors or oncogenes via reversely regulating gene expression. Recent evidence has revealed that microRNAs, especially in body fluids such as the blood and urine, display important diagnostic and prognostic potential for hepatocarcinoma. Here, we reviewed currently available data on microRNAs and hepatocarcinoma, with emphasis on the biogenesis and function of microRNAs and their potential diagnostic and prognostic value for hepatocarcinoma. We also discussed the clinical utility perspectives of microRNAs in hepatocarcinoma and possible challenges

DNA barcoding of Scomberomorus (Scombridae, Actinopterygii) reveals cryptic diversity and misidentifications

The genus Scomberomorus is economically important; however, the taxonomic status and phylogenetic relationships in this genus are not clearly resolved, making it difficult to effectively protect and exploit fish resources. To clarify the taxonomic status of Scomberomorus species, mitochondrial cytochrome c oxidase I (COI) gene sequences of 150 samples were analyzed. The average genetic distance among 14 species was approximately 11 times greater than the distances within species, in accordance with the ‘10× rule’ of species identification. Five of the 14 species did not form monophyletic clades based on a Bayesian inference gene tree. The application of four DNA-based species delimitation methods (automatic barcode gap discovery, barcode index numbers, Poisson tree process, and the K/θ method) yielded several key results. (1) Cryptic species were detected within Scomberomorus commerson. (2) A Scomberomorus queenslandicus sample from Australia was misidentified as S. commerson in the Barcode of Life Data System (BOLD). (3) Specimens originally identified as Scomberomorus guttatus was differentiated into four OTUs or species, two in the Yellow, South China, and Java seas, and two in geographically distant areas, one each in the Arabian Sea and the Bay of Bengal. (4) Six specimens from South Africa originally identified as S. plurilineatus most likely do not belong to the species. (5) Specimens identified as S. maculatus and S. regalis were conspecific; however, introgression cannot be ruled out. Our findings revealed cryptic diversity and difficulties in morphological identification of species in the genus Scomberomorus. This study provides scientifically based support for the conservation of germplasm resources of the genus Scomberomorus

Genetic Single Nucleotide Polymorphisms (GSNPs) in the DNA Repair Genes and Hepatocellular Carcinoma Related to Aflatoxin B1 among Guangxiese Population

Aflatoxin B1 (AFB1) is an important environmental carcinogen for the development of hepatocellular carcinoma (HCC). HCC is a complex disease likely resulting from genetic single nucleotide polymorphisms (GSNPs) of multiple interacting genes and gene-environment interactions. Recent efforts have been made to analyze the associations between risk of this malignancy and GSNPs in genes involved in the repair of DNA damage induced by AFB1. Here, we reviewed the results of published case-control studies that have examined the effects of common alleles of all susceptible DNA repair genes, including XRCC1, XRCC3, XRCC4, XRCC7, XPC, and XPD, on risk of AFB1-related HCC among Guangxi population. Statistically significant differences in genotype frequencies found in case-control comparisons were rs25487, rs80309960, rs861539, rs7003908, rs28383151, rs3734091, rs13181, and rs2228001 polymorphism. The overall effects of these GNSPs were moderate in terms of relative risk, with ORs ranging from 2 to 10. Furthermore, some evidence of the interaction of GSNPs in DNA repair genes and AFB1 exposure modulate risk of this cancer was also found, although the results require confirmation with larger sample size studies

First principle study of intrinsic defects in hexagonal tungsten carbide

The characteristics of intrinsic defects are important for the understanding of self-diffusion processes, mechanical strength, brittleness, and plasticity of tungsten carbide, which present in the divertor of fusion reactors. Here, we use first-principles calculations to investigate the stability of point defects and their complexes in WC. Our calculation results confirm that the formation energies of carbon defects are much lower than that of tungsten defects. The outward relaxations around vacancy are found. Both interstitial carbon and interstitial tungsten atom prefer to occupy the carbon basal plane projection of octahedral interstitial site. The results of isolated carbon defect diffusion show that the carbon vacancy stay for a wide range of temperature because of extremely high diffusion barriers, while carbon interstitial migration is activated at lower temperatures for its considerable lower activation energy. These results provide evidence for the presumption that the 800K stage is attributed by the annealing out of carbon vacancies by long-range migration.Comment: Submitted to Journal of Nuclear Material

High Prevalence and Genetic Heterogeneity of Rodent-Borne Bartonella Species on Heixiazi Island, China

We performed genetic analysis of Bartonella isolates from rodent populations from Heixiazi Island in northeast China. Animals were captured at four sites representing grassland and brushwood habitats in 2011 and examined for the prevalence and genetic diversity of Bartonella species, their relationship to their hosts, and geographic distribution. A high prevalence (57.7%) and a high diversity (14 unique genotypes which belonged to 8 clades) of Bartonella spp. were detected from 71 rodents comprising 5 species and 4 genera from 3 rodent families. Forty-one Bartonella isolates were recovered and identified, including B. taylorii, B. japonica, B. coopersplainsensis, B. grahamii, B. washoensis subsp. cynomysii, B. doshiae, and two novel Bartonella species, by sequencing of four genes (gltA, the 16S rRNA gene, ftsZ, and rpoB). The isolates of B. taylorii and B. grahamii were the most prevalent and exhibited genetic difference from isolates identified elsewhere. Several isolates clustered with strains from Japan and far-eastern Russia; strains isolated from the same host typically were found within the same cluster. Species descriptions are provided for Bartonella heixiaziensis sp. nov. and B. fuyuanensis sp. nov

Sweroside Alleviated Aconitine-Induced Cardiac Toxicity in H9c2 Cardiomyoblast Cell Line

Aconitine is the main bioactive ingredient of Aconitum plants, which are well-known botanical herbs in China. Aconitine is also notorious for its high cardiotoxicity, as it can induce life-threatening ventricular arrhythmias. Unfortunately, there are few effective antidotes to aconitine toxicity. This study aimed to evaluate the potent protective effects of the ingredients from V. baillonii on aconitine toxicity on H9c2 cell line. Cell viability was assessed by methylthiazoltetrazolium bromide (MTT). Intracellular Ca2+ concentration alteration and reactive oxygen species (ROS) generation were observed by confocal microscopy and flow cytometry, respectively. Cellular oxidative stress was analyzed by measuring malondialdehyde (MDA) and superoxide dismutase (SOD) levels. Mitochondrial membrane potential (ΔΨ) was determined using JC-1 kit. RT-PCR and Hoechst staining techniques were conducted to determine the levels of autophagy/apoptosis. The mRNA levels of dihydropyridine receptor (DHPR), ryanodine receptors (RyR2) and sarcoplasmic reticulum Ca2+-ATPase (SERCA) were measured by RT-PCR. We screened six components from V. baillonii, among which, sweroside exhibited the strongest protective effects on aconitine-induced cardiac toxicity. Sweroside suppressed the aconitine-induced mRNA expressions of NaV1.5 (encoded by SCN5A), RyR2 and DHPR, and reversed the aconitine-induced decrease in mRNA level of SERCA, thus preventing the aconitine-induced persistent intracellular Ca2+ accumulation and avoiding intracellular Ca2+ overload. We further found that sweroside restabilized the aconitine-disrupted mitochondrial membrane potential (ΔΨ) and reversed the aconitine-induced increase in the mRNA levels of cell autophagy-related factors (Beclin-1, Caspase-3, and LC3- II) in H9c2 cells. In the whole-animal experiments, we observed that sweroside (50 mg/kg) alleviated effectively aconitine-induced arrhythmias by analysis of electrocardiogram (ECG) recording in rats. Our results demonstrate that sweroside may protect cardiomyocytes from aconitine toxicity by maintaining intracellular Ca2+ homeostasis, restabilizing mitochondrial membrane potential (ΔΨ) and avoiding cell autophagy/apoptosis