Targeting PML-RARα and Oncogenic Signaling Pathways by Chinese Herbal Mixture Tien-Hsien Liquid in Acute Promyelocytic Leukemia NB4 Cells

Tien-Hsien Liquid (THL) is a Chinese herbal mixture that has been used worldwide as complementary treatment for cancer patients in the past decade. Recently, THL has been shown to induce apoptosis in various types of solid tumor cells in vitro. However, the underlying molecular mechanisms have not yet been well elucidated. In this study, we explored the effects of THL on acute promyelocytic leukemia (APL) NB4 cells, which could be effectively treated by some traditional Chinese remedies containing arsenic trioxide. The results showed THL could induce G2/M arrest and apoptosis in NB4 cells. Accordingly, the decrease of cyclin A and B1 were observed in THL-treated cells. The THL-induced apoptosis was accompanied with caspase-3 activation and decrease of PML-RARα fusion protein. Moreover, DNA methyltransferase 1 and oncogenic signaling pathways such as Akt/mTOR, Stat3 and ERK were also down-regulated by THL. By using ethyl acetate extraction and silica gel chromatography, an active fraction of THL named as EAS5 was isolated. At about 0.5–1% of the dose of THL, EAS5 appeared to have most of THL-induced multiple molecular targeting effects in NB4 cells. Based on the findings of these multi-targeting effects, THL might be regarding as a complementary and alternative therapeutic agent for refractory APL

A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response.

The major histocompatibility complex (MHC) is most closely associated with nasopharyngeal carcinoma (NPC), but the complexity of its genome structure has proven challenging for the discovery of causal MHC loci or genes. We conducted a targeted MHC sequencing in 40 Cantonese NPC patients followed by a two-stage replication in 1065 NPC cases and 2137 controls of Southern Chinese descendent. Quantitative RT-PCR analysis (qRT-PCR) was used to detect gene expression status in 108 NPC and 43 noncancerous nasopharyngeal (NP) samples. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) were used to assess the transcription factor binding site. We discovered that a novel SNP rs117565607_A at TRIM26 displayed the strongest association (OR = 1.909, Pcombined = 2.750 × 10-19 ). We also observed that TRIM26 was significantly downregulated in NPC tissue samples with genotype AA/AT than TT. Immunohistochemistry (IHC) test also found the TRIM26 protein expression in NPC tissue samples with the genotype AA/AT was lower than TT. According to computational prediction, rs117565607 locus was a binding site for the transcription factor Yin Yang 1 (YY1). We observed that the luciferase activity of YY1 which is binding to the A allele of rs117565607 was suppressed. ChIP data showed that YY1 was binding with T not A allele. Significance analysis of microarray suggested that TRIM26 downregulation was related to low immune response in NPC. We have identified a novel gene TRIM26 and a novel SNP rs117565607_A associated with NPC risk by regulating transcriptional process and established a new functional link between TRIM26 downregulation and low immune response in NPC

Insights into the functional role of tea microbes on tea growth, quality and resistance against pests and diseases

Tea is an economical and most widely used beverage across the globe owing to its unique fragrance and flavor. Plant microbe interaction has emerged as an important topic which got the attention of scientists to improve plant performance. Tea microbes remained a prominent research topic for scientists over the years as tea microbes helps in nutrient cycling and stress management which in turn improve the tea growth, yield and quality. The roots of tea plants are colonized by various microbes including arbuscular mycorrhizal fungi (AMF), bacterial communities, and endophytes increase root growth, development and nutrient uptake which in turn improve tea growth, yield and quality. These microbes also increase the concentration of nutrients, amino acids, soluble proteins, flavonoids, catechuic acid, glucose, fructose, sucrose contents caffeine, and polyphenols concentration in tea plants. Besides this, these microbes also protect the tea plants from harmful pest and diseases which in turn leads to an appreciable improvement in plant growth and development. The most important goal of any farming system is to establish a system with production of maximum food while minimizing impacts on the environment. The present review article highlights the role of various microbes in improving the growth, yield and quality of tea plants. In addition, we also discussed the research gaps to improve our understanding about the role of tea microbes in improving tea growth, yield, pest and diseases resistance. We believe that this review will provide a better insight into the existing knowledge of tea microbes in improving tea growth and yield

High energy Millihertz quasi-periodic oscillations in 1A 0535+262 with Insight-HXMT challenge current models

We studied the millihertz quasi-periodic oscillation (mHz QPO) in the 2020 outburst of the Be/X-ray binary 1A 0535+262 using Insight-HXMT data over a broad energy band. The mHz QPO is detected in the 27-120 keV energy band. The QPO centroid frequency is correlated with the source flux, and evolves in the 35-95 mHz range during the outburst. The QPO is most significant in the 50-65 keV band, with a significance of ~ 8 sigma, but is hardly detectable (<2 sigma) in the lowest (1-27 keV) and highest (>120 keV) energy bands. Notably, the detection of mHz QPO above 80 keV is the highest energy at which mHz QPOs have been detected so far. The fractional rms of the mHz QPO first increases and then decreases with energy, reaching the maximum amplitude at 50-65 keV. In addition, at the peak of the outburst, the mHz QPO shows a double-peak structure, with the difference between the two peaks being constant at ~0.02 Hz, twice the spin frequency of the neutron star in this system. We discuss different scenarios explaining the generation of the mHz QPO, including the beat frequency model, the Keplerian frequency model, the model of two jets in opposite directions, and the precession of the neutron star, but find that none of them can explain the origin of the QPO well. We conclude that the variability of non-thermal radiation may account for the mHz QPO, but further theoretical studies are needed to reveal the physical mechanism.Comment: 13 pages, 7 figures. Accepted for publication in MNRA

Coronin 1B Regulates S1P-Induced Human Lung Endothelial Cell Chemotaxis: Role of PLD2, Protein Kinase C and Rac1 Signal Transduction

Coronins are a highly conserved family of actin binding proteins that regulate actin-dependent processes such as cell motility and endocytosis. We found that treatment of human pulmonary artery endothelial cells (HPAECs) with the bioactive lipid, sphingosine-1-phosphate (S1P) rapidly stimulates coronin 1B translocation to lamellipodia at the cell leading edge, which is required for S1P-induced chemotaxis. Further, S1P-induced chemotaxis of HPAECs was attenuated by pretreatment with small interfering RNA (siRNA) targeting coronin 1B (∼36%), PLD2 (∼45%) or Rac1 (∼50%) compared to scrambled siRNA controls. Down regulation PLD2 expression by siRNA also attenuated S1P-induced coronin 1B translocation to the leading edge of the cell periphery while PLD1 silencing had no effect. Also, S1P-induced coronin 1B redistribution to cell periphery and chemotaxis was attenuated by inhibition of Rac1 and over-expression of dominant negative PKC δ, ε and ζ isoforms in HPAECs. These results demonstrate that S1P activation of PLD2, PKC and Rac1 is part of the signaling cascade that regulates coronin 1B translocation to the cell periphery and the ensuing cell chemotaxis

The 5-Hydroxymethylcytosine Landscape of Prostate Cancer

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease. SIGNIFICANCE: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.publishedVersionPeer reviewe