Histone lysine‐specific demethylase 1 (LSD1) is the first discovered and reported histone demethylase by Dr. Shi Yang's group in 2004. It is classified as a member of amine oxidase superfamily, the ...common feature of which is using the flavin adenine dinucleotide (FAD) as its cofactor. Since it is located in cell nucleus and acts as a histone methylation eraser, LSD1 specifically removes mono‐ or dimethylated histone H3 lysine 4 (H3K4) and H3 lysine 9 (H3K9) through formaldehyde‐generating oxidation. It has been indicated that LSD1 and its downstream targets are involved in a wide range of biological courses, including embryonic development and tumor‐cell growth and metastasis. LSD1 has been reported to be overexpressed in variety of tumors. Inactivating LSD1 or downregulating its expression inhibits cancer‐cell development. LSD1 targeting inhibitors may represent a new insight in anticancer drug discovery. This review summarizes recent studies about LSD1 and mainly focuses on the basic physiological function of LSD1 and its involved mechanisms in pathophysiologic conditions, as well as the development of LSD1 inhibitors as potential anticancer therapeutic agents.
Lysine specific demethylase 1 (LSD1) and Histone deacetylases (HDACs) are promising drug targets for cancers. Recent studies reveal an important functional interplay between LSD1 and HDACs, and there ...is evidence for the synergistic effect of combined LSD1 and HDAC inhibitors on cancers. Therefore, development of inhibitors targeting both LSD1 and HDACs might be a promising strategy for epigenetic therapy of cancers. We report herein the synthesis of a series of tranylcypromine derivatives as LSD1/HDACs dual inhibitors. Most compounds showed potent LSD1 and HDACs inhibitory activity, especially compound 7 displayed the most potent inhibitory activity against HDAC1 and HDAC2 with IC50 of 15 nM and 23 nM, as well as potent inhibition against LSD1 with IC50 of 1.20 μM. Compound 7 demonstrated stronger anti-proliferative activities than SAHA with IC50 values ranging from 0.81 to 4.28 μM against MGC-803, MCF-7, SW-620 and A-549 human cancer cell lines. Further mechanistic studies showed that compound 7 treatment in MGC-803 cells dose-dependently increased cellular H3K4 and H3K9 methylation, as well as H3 acetylation, decreased the mitochondrial membrane potential and induced remarkable apoptosis. Docking studies showed that compound 7 can be well docked into the active binding sites of LSD1 and HDAC2. This finding highlights the potential for the development of LSD1/HDACs dual inhibitors as novel anticancer drugs.
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•A series of tranylcypromine derivatives were discovered as novel LSD1/HDACs dual inhibitors.•Compound 7 exhibited potent dual LSD1/HDACs inhibition with strong antiproliferative activity.•Compound 7 dose-dependently increased cellular H3K4 and H3K9 methylation, as well as H3 acetylation.•Compounds 7 induced remarkable apoptosis and decreased mitochondrial membrane potential.
The endometrium plays a critical role in embryo implantation and pregnancy, and a thin uterus is recognized as a key factor in embryo implantation failure. Umbilical cord mesenchymal stem cells ...(UC-MSCs) have attracted interest for the repair of intrauterine adhesions. The current study investigated the repair of thin endometrium in rats using the UC-MSCs and the mechanisms involved. Rats were injected with 95% ethanol to establish a model of thin endometrium. The rats were randomly divided into normal, sham, model, and UC-MSCs groups. Endometrial morphological alterations were observed by hematoxylin-eosin staining and Masson staining, and functional restoration was assessed by testing embryo implantation. The interaction between UC-MSCs and rat endometrial stromal cells (ESCs) was evaluated using a transwell 3D model and immunocytochemistry. Microarray mRNA and miRNA platforms were used for miRNA-mRNA expression profiling. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses were performed to identify the biological processes, molecular functions, cellular components, and pathways of endometrial injury and UC-MSCs transplantation repair and real-time quantitative reverse transcription PCR (qRT-PCR) was performed to further identify the expression changes of key molecules in the pathways. Endometrium thickness, number of glands, and the embryo implantation numbers were improved, and the degree of fibrosis was significantly alleviated by UC-MSCs treatment in the rat model of thin endometrium. In vitro cell experiments showed that UC-MSCs migrated to injured ESCs and enhanced their proliferation. miRNA microarray chip results showed that expression of 45 miRNAs was downregulated in the injured endometrium and upregulated after UC-MSCs transplantation. Likewise, expression of 39 miRNAs was upregulated in the injured endometrium and downregulated after UC-MSCs transplantation. The miRNA-mRNA interactions showed the changes in the miRNA and mRNA network during the processes of endometrial injury and repair. GO and KEGG analyses showed that the process of endometrial injury was mainly attributed to the decomposition of the extracellular matrix (ECM), protein degradation and absorption, and accompanying inflammation. The process of UC-MSCs transplantation and repair were accompanied by the reconstruction of the ECM, regulation of chemokines and inflammation, and cell proliferation and apoptosis. The key molecules involved in ECM-receptor interaction pathways were further verified by qRT-PCR. Itga1 and Thbs expression decreased in the model group and increased by UC-MSCs transplantation, while Laminin and Collagen expression increased in both the model group and MSCs group, with greater expression observed in the latter. This study showed that UC-MSCs transplantation could promote recovery of thin endometrial morphology and function. Furthermore, it revealed the expression changes of miRNA and mRNA after endometrial injury and UC-MSCs transplantation repair processed, and signaling pathways that may be involved in endometrial injury and repair.
We present a new measurement of the kinetic Sunyaev-Zeldovich effect (kSZ) using Planck cosmic microwave background (CMB) and Baryon Oscillation Spectroscopic Survey (BOSS) data. Using the “LowZ ...North/South” galaxy catalogue from BOSS DR12, and the group catalogue from BOSS DR13, we evaluate the mean pairwise kSZ temperature associated with BOSS galaxies. We construct a “Central Galaxies Catalogue” (CGC) which consists of isolated galaxies from the original BOSS data set, and apply the aperture photometry (AP) filter to suppress the primary CMB contribution. By constructing a halo model to fit the pairwise kSZ function, we constrain the mean optical depth to be τ¯=(0.53±0.32)×10−4(1.65σ) for LowZ North CGC, τ¯=(0.30±0.57)×10−4(0.53σ) for LowZ South CGC, and τ¯=(0.43±0.28)×10−4(1.53σ) for DR13 Group. In addition, we vary the radius of the AP filter and find that the AP size of 7 arcmin gives the maximum detection for τ¯. We also investigate the dependence of the signal with halo mass and find τ¯=(0.32±0.36)×10−4(0.8σ) and τ¯=(0.67±0.46)×10−4(1.4σ) for DR13 Group with halo mass restricted to, respectively, less and greater than its median halo mass, 1012 h−1M⊙. For the LowZ North CGC sample restricted to Mh≳1014 h−1M⊙ there is no detection of the kSZ signal because these high mass halos are associated with the high-redshift galaxies of the LowZ North catalogue, which have limited contribution to the pairwise kSZ signals.
Abstract
Self-assembled architectures of soft matter have fascinated scientists for centuries due to their unique physical properties originated from controllable orientational and/or positional ...orders, and diverse optic and photonic applications. If one could know how to design, fabricate, and manipulate these optical microstructures in soft matter systems, such as liquid crystals (LCs), that would open new opportunities in both scientific research and practical applications, such as the interaction between light and soft matter, the intrinsic assembly of the topological patterns, and the multidimensional control of the light (polarization, phase, spatial distribution, propagation direction). Here, we summarize recent progresses in self-assembled optical architectures in typical thermotropic LCs and bio-based lyotropic LCs. After briefly introducing the basic definitions and properties of the materials, we present the manipulation schemes of various LC microstructures, especially the topological and topographic configurations. This work further illustrates external-stimuli-enabled dynamic controllability of self-assembled optical structures of these soft materials, and demonstrates several emerging applications. Lastly, we discuss the challenges and opportunities of these materials towards soft matter photonics, and envision future perspectives in this field.
Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent ...Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.
Histone lysine specific demethylase 1 (LSD1) was reported to be overexpressed in several human cancers and recognized as a promising anticancer drug target. In the current study, we designed and ...synthesized a novel series of pyrimidine–thiourea hybrids and evaluated their potential LSD1 inhibitory effect. One of the compounds, 6b, containing a terminal alkyne appendage, was shown to be the most potent and selective LSD1 inhibitor in vitro and exhibited strong cytotoxicity against LSD1 overexpressed gastric cancer cells. Compound 6b also showed marked inhibition of cell migration and invasion as well as significant in vivo tumor suppressing and antimetastasis role, without significant side effects by oral administration. Our findings indicate that the pyrimidine–thiourea-based LSD1 inactivator may serve as a leading compound targeting LSD1 overexpressed cancers.
The primordial non-Gaussianity induces scale-dependent bias of the Hi with respect to the underlying dark matter, which exhibits features on the very large scale of the 21-cm power spectrum ...potentially observable with Hi intensity mapping observations. We forecast the prospective constraints on the four fundamental shapes of primordial non-Gaussianity (local, equilateral, orthogonal, and enfolded), with the current and future Hi intensity mapping experiments, BINGO, FAST, and SKA-I. With the current configuration of the experiments and assumed one-year observation time, we find that the SKA-I will provide tighter constraints on the local shape of primoridal non-Gaussianity than Planck. The results are (σfNLlocal,σfNLequil,σfNLorth,σfNLenfold)SKA-I=(0.54,86,25,43), (σfNLlocal,σfNLequil,σfNLorth,σfNLenfold)BINGO=(17,100,128,164), (σfNLlocal,σfNLequil,σfNLorth,σfNLenfold)FAST=(9.5,44,75,94). If the lower frequency band of FAST can be used, the constraint on local-type primordial non-Gaussianity will be σfNL∼1.62 which is better than Planck. In addition, if the observation time for FAST could be extended to two years, the constraint on the equilateral shape of primordial non-Gaussianity would be improved to σfNL∼32. Similarly, if the observational time of SKA-I could be extended to two years, the constraint on local and orthogonal shapes could be improved to 0.43 and 20, respectively, achieving better constraints than Planck.
KDM5B (also known as PLU-1 and JARID1B) is 2-oxoglutarate and Fe2+ dependent oxygenase that acts as a histone H3K4 demethylase, which is a key participant in inhibiting the expression of tumor ...suppressors as a drug target. Here, we present the discovery of pyrazole derivatives compound 5 by structure-based virtual screening and biochemical screening with IC50 of 9.320 μM against KDM5B, and its subsequent optimization to give 1-(4-methoxyphenyl)-N-(2-methyl-2-morpholinopropyl)-3-phenyl-1H-pyrazole-4-carboxamide (27 ab), a potent KDM5B inhibitor with IC50 of 0.0244 μM. In MKN45 cells, compound 27 ab can bind and stabilize KDM5B and induce the accumulation of H3K4me2/3, bona fide substrates of KDM5B, while keep the amount of H3K4me1, H3K9me2/3 and H3K27me2 without change. Further biological study also indicated that compound 27 ab is a potent cellular active KDM5B inhibitor that can inhibit MKN45 cell proliferation, wound healing and migration. In sum, our finding gives a novel structure for the discovery of KDM5B inhibitor and targeting KDM5B may be a new therapeutic strategy for gastric cancer treatment.
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•Pyrazole derivatives were discovered as novel KDM5B inhibitors.•35 compounds were synthesized and studied on their KDM5B inhibitory activities for SARs.•Compound 27 ab is a potent and cellular active KDM5B inhibitor that can inhibit MKN45 cell proliferation and migration.
Tea is the second most widely consumed beverage and contains various bioactive compounds. A simple method to analyze these compounds is of great scientific and commercial interest. In this work, a ...30 min HPLC method was developed using a simple gradient elution system, and the mobile phases and elution gradients were optimized. This method separated 17 polyphenols and three alkaloid compounds in tea extracts, including catechins, alkaloids, phenolic acids, flavonols, and flavone, which are responsible for the bioactivity and flavor of tea. Excellent linearity was observed for all standard calibration curves, and correlation coefficients were above 0.9994. Heatmap analysis demonstrated significant separation between green, black, and pu‐erh tea samples. The method described here is accurate and sensitive enough for the determination of active components in tea and could potentially be applied to other food products for the comprehensive investigation of their quality.
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