A multivalent engagement of ENL with MOZ.

The epigenetic cofactor ENL (eleven-nineteen-leukemia) and the acetyltransferase MOZ (monocytic leukemia zinc finger) have vital roles in transcriptional regulation and are implicated in aggressive forms of leukemia. Here, we describe the mechanistic basis for the intertwined association of ENL and MOZ. Genomic analysis shows that ENL and MOZ co-occupy active promoters and that MOZ recruits ENL to its gene targets.

Hotspot Cancer Mutation Impairs KAT8-mediated Nucleosomal Histone Acetylation.

KAT8 is an evolutionarily conserved lysine acetyltransferase that catalyzes histone acetylation at H4K16 or H4K5 and H4K8 through distinct protein complexes. It plays a pivotal role in male X chromosome dosage compensation in Drosophila and is implicated in the regulation of diverse cellular processes in mammals. Mutations and dysregulation of KAT8 have been reported in human neurodevelopmental disorders and various cancers.

TAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition.

The histone acetyltransferase p300/CBP is composed of several conserved domains, among which, the TAZ2 domain is known as a protein-protein interaction domain that binds to E1A and various transcription factors. Here we show that TAZ2 has a HAT autoinhibitory function. Truncating p300/CBP at TAZ2 leads to hyperactive HAT and elevated histone H3K27 and H3K18 acetylation in cells.

Hepatic CPT1A Facilitates Liver-Adipose Cross-Talk via Induction of FGF21 in Mice.

Background & Aims: Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and peripheral organs, remain unclear.

Hepatic CPT1A Facilitates Liver-Adipose Cross-Talk Induction of FGF21 in Mice.

Background & Aims: Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and peripheral organs, remain unclear.

New indices system for quantifying the nexus between economic-social development, natural resources consumption, and environmental pollution in China during 1978-2018.

It is meaningful to study how China can maintain the sustainable utilization of natural resources and the continuous improvement of environmental conditions while ensuring the stable development of the economy and society. In this study, a new indices system was proposed for the analysis of nexus among social-economic-natural resource-environment complex systems following the DPSIR (Driving Force - Pressure - State - Impact - Respond) framework, CCD (Coupling Coordination Degree) analysis and VAR (Vector Auto-Regressive) model were applied for quantifying the synergy and trade-off of China in the nexus framework. Results showed that: (1) Although China's rapid development has caused big consumption of natural resources and increasing pollutants discharges during 1978-2018, China has not got into trouble of extreme resource depletion and ecosystem collapse.

Bioinformatics Analysis of the Molecular Mechanism and Potential Treatment Target of Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is an autoimmune disease that mainly affects the spinal joints, sacroiliac joints, and adjacent soft tissues. We conducted bioinformatics analysis to explore the molecular mechanism related to AS pathogenesis and uncover novel potential molecular targets for the treatment of AS. The profiles of GSE25101, containing gene expression data extracted from the blood of 16 AS patients and 16 matched controls, were acquired from the Gene Expression Omnibus (GEO) database.

Discovery of Selective Small-Molecule Inhibitors for the ENL YEATS Domain.

Eleven-nineteen leukemia (ENL) protein is a histone acetylation reader essential for disease maintenance in acute leukemias, in particular, the ()-rearranged leukemia. In this study, we carried out high-throughput screening of a small-molecule library to identify inhibitors for the ENL YEATS domain. Structure-activity relationship studies of the hits and structure-based inhibitor design led to two compounds, and , with IC values below 100 nM in inhibiting the ENL-acetyl-H3 interaction.

Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion.

Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Here, we report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and is inhibited by small molecule compounds, including disulfiram that directly targets the PHD finger of PHF23 (PHF23PHD). Our data support a critical role for the PHD fingers of NUP98-PHF23, and related NUP98-KDM5A and NUP98-BPTF fusions in driving leukemogenesis, and demonstrate that blocking this interaction in NUP98-PHF23 expressing AML cells leads to cell death through necrotic and late apoptosis pathways.

Apolipoprotein E-Mimetic Peptide COG1410 Enhances Retinal Ganglion Cell Survival by Attenuating Inflammation and Apoptosis Following TONI.

Vision loss after traumatic optic nerve injury (TONI) is considered irreversible because of the retrograde loss of retinal ganglion cells (RGCs), which undergo inflammation and apoptosis. Previous studies have shown that COG1410, a mimic peptide derived from the apolipoprotein E (apoE) receptor binding region, shows neuroprotective activity in acute brain injury. However, the detailed role and mechanisms of COG1410 in RGC survival and vision restoration after TONI are poorly understood.

Few-view CT image reconstruction using improved total variation regularization.

X-ray radiation is harmful to human health. Thus, obtaining a better reconstructed image with few projection view constraints is a major challenge in the computed tomography (CT) field to reduce radiation dose. In this study, we proposed and tested a new algorithm that combines penalized weighted least-squares using total generalized variation (PWLS-TGV) and dictionary learning (DL), named PWLS-TGV-DL to address this challenge.

Linifanib exerts dual anti-obesity effect by regulating adipocyte browning and formation.

Obesity is caused by energy imbalance and accompanied by adipocyte hypertrophy and hyperplasia. Therefore, both enhancement of adipocyte energy expenditure and inhibition of adipogenesis are viable ways to combat obesity. Using the Ucp1-2A-luciferase reporter animal model previously reported by us as a screening platform, a chemical compound Linifanib was identified as a potent inducer of UCP1 expression in primary inguinal adipocytes in vitro and in vivo.

Production of a novel Poria cocos immunomodulatory protein in Pichia pastoris: cloning, expression, purification and activities assays.

In this study, the cDNA of immunomodulatory protein from Poria cocos (PCP) was amplified by reverse transcription polymerase chain reaction and used to transform P. Pastoris cells, resulting in rPCP expression as a secreted protein to a concentration of ~ 38 mg/L following methanol induction in shake flasks. Approximately 1.

White Matter Injury in Early Brain Injury after Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a major cause of high morbidity, disability, and mortality in the field of neurovascular disease. Most previous SAH studies have focused on improving cerebral blood flow, reducing cerebral vasospasm, reducing neuronal calcium overload, and other treatments. While these studies showed exciting findings in basic science, therapeutic strategies based on the findings have not significantly improved neurological outcomes in patients with SAH.

Apolipoprotein E Exerts a Whole-Brain Protective Property by Promoting M1? Microglia Quiescence After Experimental Subarachnoid Hemorrhage in Mice.

Subarachnoid hemorrhage (SAH) is a neurologically destructive stroke in which early brain injury (EBI) plays a pivotal role in poor patient outcomes. Expanding upon our previous work, multiple techniques and methods were used in this preclinical study to further elucidate the mechanisms underlying the beneficial effects of apolipoprotein E (ApoE) against EBI after SAH in murine apolipoprotein E gene-knockout mice (Apoe, KO) and wild-type mice (WT) on a C57BL/6J background. We reported that Apoe deficiency resulted in a more extensive EBI at 48 h after SAH in mice demonstrated by MRI scanning and immunohistochemical staining and exhibited more extensive white matter injury and neuronal apoptosis than WT mice.

Discovery and optimization of 1-(1H-indol-1-yl)ethanone derivatives as CBP/EP300 bromodomain inhibitors for the treatment of castration-resistant prostate cancer.

The CREB (cAMP responsive element binding protein) binding protein (CBP) and its homolog EP300 have emerged as new therapeutic targets for the treatment of cancer and inflammatory diseases. Here we report the identification, optimization and evaluation of 1-(1H-indol-1-yl)ethanone derivatives as CBP/EP300 inhibitors starting from fragment-based virtual screening (FBVS). A cocrystal structure of the inhibitor (22e) in complex with CBP provides a solid structural basis for further optimization.

The natural compound, formononetin, extracted from Astragalus membranaceus increases adipocyte thermogenesis by modulating PPARγ activity.

Background And Purpose: Increasing energy expenditure through adipocyte thermogenesis is generally accepted as a promising strategy to mitigate obesity and its related diseases. However, few clinically effective and safe agents are known to promote adipocyte thermogenesis. In this study, 20 traditional Chinese herbal medicines were screened to examine whether they induced adipocyte thermogenesis.

High-Throughput Sequencing and Co-Expression Network Analysis of lncRNAs and mRNAs in Early Brain Injury Following Experimental Subarachnoid Haemorrhage.

Subarachnoid haemorrhage (SAH) is a fatal neurovascular disease following cerebral aneurysm rupture with high morbidity and mortality rates. Long non-coding RNAs (lncRNAs) are a type of mammalian genome transcript, are abundantly expressed in the brain and are involved in many nervous system diseases. However, little is currently known regarding the influence of lncRNAs in early brain injury (EBI) after SAH.

Adipocyte SIRT1 controls systemic insulin sensitivity by modulating macrophages in adipose tissue.

Adipose tissue inflammation, characterized by augmented infiltration and altered polarization of macrophages, contributes to insulin resistance and its associated metabolic diseases. The NAD-dependent deacetylase SIRT1 serves as a guardian against metabolic disorders in multiple tissues. To dissect the roles of SIRT1 in adipose tissues, metabolic phenotypes of mice with selective ablation of SIRT1 in adipocytes and myeloid cells were monitored.

Visualization and Quantification of Browning Using a Ucp1-2A-Luciferase Knock-in Mouse Model.

Both mammals and adult humans possess classic brown adipocytes and beige adipocytes, and the amount and activity of these adipocytes are considered key factors in combating obesity and its associated metabolic diseases. Uncoupling protein 1 (Ucp1) is the functional marker of both brown and beige adipocytes. To facilitate a reliable, easy, and sensitive measurement of Ucp1 expression both in vivo and in vitro, we generated a Ucp1-2A-luciferase knock-in mouse by deleting the stop codon for the mouse Ucp1 gene and replacing it with a 2A peptide.

Brown Adipogenic Reprogramming Induced by a Small Molecule.

Brown adipose tissue (BAT) has attracted considerable research interest because of its therapeutic potential to treat obesity and associated metabolic diseases. Augmentation of brown fat mass and/or its function may represent an attractive strategy to enhance energy expenditure. Using high-throughput phenotypic screening to induce brown adipocyte reprogramming in committed myoblasts, we identified a retinoid X receptor (RXR) agonist, bexarotene (Bex), that efficiently converted myoblasts into brown adipocyte-like cells.

Harmine Induces Adipocyte Thermogenesis through RAC1-MEK-ERK-CHD4 Axis.

Harmine is a natural compound possessing insulin-sensitizing effect in db/db diabetic mice. However its effect on adipose tissue browning is unknown. Here we reveal that harmine antagonizes high fat diet-induced adiposity.

Inhibition of Blood-Brain Barrier Disruption by an Apolipoprotein E-Mimetic Peptide Ameliorates Early Brain Injury in Experimental Subarachnoid Hemorrhage.

Apolipoprotein E (ApoE)-mimetic peptides have been demonstrated to be beneficial in secondary brain injury following experimental subarachnoid hemorrhage (SAH). However, the molecular mechanisms underlying these benefits in SAH models have not been clearly identified. This study investigated whether an ApoE-mimetic peptide affords neuroprotection in early brain injury (EBI) following SAH by attenuating BBB disruption.

Potential implications of Apolipoprotein E in early brain injury after experimental subarachnoid hemorrhage: Involvement in the modulation of blood-brain barrier integrity.

Apolipoprotein E (Apoe) genetic polymorphisms have been implicated in the long term outcome of subarachnoid haemorrhage (SAH), but little is known about the effect of Apoe on the early brain injury (EBI) after SAH. This study investigated the potential role of APOE in EBI post-SAH. Multiple techniques were used to determine the early BBB disruption in EBI post-SAH in a murine model using wild-type (WT) and Apoe-/- (KO) mice.