Development of Small Molecular Hyper-activators of Human Caseinolytic Peptidase P (hClpP) with a [1,8]-naphthyridinone Scaffold as Novel Anti-cancer Agents.

Based on a clinical staged small molecular hClpP activator ONC201, a class of novel hClpP agonists with a [1,8]naphthyridinone scaffold was designed, synthesized and evaluated in a series of biochemical and biological assays. Mechanism studies for the representative compound F20 indicated that it can potently bind to and activate hClpP, efficiently promote the degradation of hClpP substrates, robustly induce ATF4/CHOP regulated integrated stress responses, strongly inhibit cell growth and effectively induce apoptosis in a subset of cancer cell lines. F20 showed good PK profiles when dosed by intravenous injection and exhibited moderate oral bioavailability in mice.

Development of novel imipridone derivatives with potent anti-cancer activities as human caseinolytic peptidase P (hClpP) activators.

Based on a clinically staged small molecular hClpP activator ONC201, a class of imipridone derivatives was designed and synthesized. These compounds were evaluated in a protease hydrolytic assay, as well as cell growth inhibition assays in three cancer cell lines, MIA PACA-2, HCT116, and MV4-11. A number of compounds that can more potently activate hClpP and more effectively inhibit cell growth in the three cancer cell lines than ONC201 were identified.

Discovery of Dehydrogenated Imipridone Derivatives as Activators of Human Caseinolytic Protease P.

Based on the founding member of imipridones, , a class of dehydrogenated imipridone derivatives was designed, synthesized, and evaluated in a series of biochemical and biological assays as human caseinolytic protease P (hClpP) activators. Mechanism studies for one of the most potent compounds, , indicated that it can potently bind to both recombinant and cellular hClpP, effectively promote the formation of hClpP tetradecamer, efficiently induce the degradation of hClpP substrates, robustly upregulate the expression of ATF4, and strongly inhibit the phosphorylations of AKT and ERK. More importantly, exhibited a promising pharmacokinetic profile in rats and could penetrate the blood brain barrier.

Molecular dynamics simulation of the scratching process of GaAs with different crystal orientations.

Context: In order to further improve the manufacturing technology of resonator facet of GaAs (gallium arsenide)-based laser, the scratching process of GaAs was simulated by molecular dynamics. Models of GaAs crystals with different orientations, including GaAs [100], GaAs [110], and GaAs [111], were generated, followed by scratch simulations on these models. The surface characteristics of scratches, damage width, subsurface damage, stack height, and the distribution and activity characteristics of dislocations were analyzed based on the simulation results.

Design and Research of VR Basketball Teaching System Based on Embedded Intelligent Sensor.

Physical education pedagogy serves as a carrier of physical education theory and practical activities and plays an important role in physical education. The reform and development of education are always related closely to the growth of scientific and technological development, and people's physical education training methods are also undergoing subtle changes. The traditional single and formulaic training methods in the past have gradually turned to modern training methods with better interaction and visibility.

Design, Synthesis, and Biological Evaluations of DOT1L Peptide Mimetics Targeting the Protein-Protein Interactions between DOT1L and MLL-AF9/MLL-ENL.

On the basis of a previously identified DOT1L peptide mimetic (compound ), a series of novel peptide mimetics were designed and synthesized. These compounds can potently bind to AF9 and ENL either in cell-free binding assays or in leukemia cells, and selectively inhibit the growth of leukemia cells containing mixed lineage leukemia (MLL) fusion proteins. The most potent compound exhibited comparable anticancer cellular activities to those of EPZ5676, a clinical stage enzymatic inhibitor of DOT1L in several leukemia cell lines containing MLL fusion proteins.

Nephroprotective Effects of Tetramethylpyrazine Nitrone TBN in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure, but therapeutic options for nephroprotection are limited. Oxidative stress plays a key role in the pathogenesis of DKD. Our previous studies demonstrated that tetramethylpyrazine nitrone (TBN), a novel nitrone derivative of tetramethylpyrazine with potent free radical-scavenging activity, exerted multifunctional neuroprotection in neurological diseases.

Investigation of echocardiographic characteristics and predictors for persistent defects of patent foramen ovale or patent ductus arteriosus in Chinese newborns.

Background: Persistent patent foramen ovale (PFO) and patent ductus arteriosus (PDA) increase the adult risk of cryptogenic embolic stroke and chronic pulmonary hypertension. To understand the characteristics of PFO and PDA in newborns, we investigated the spontaneous closure rate and derived the determinants for residual defects.

Methods: We utilized the database of congenital heart disease (CHD) in Xiamen ChangGung Memorial Hospital from 2015 to 2017 and allocated 2523 eligible newborns into four groups according to PDA, PFO, both or neither at birth.

Chronic stress-induced immune dysregulation in cancer: implications for initiation, progression, metastasis, and treatment.

Psychological stress is a well-accepted risk factor in cancer initiation and progression. The explosive growth of psychoneuroimmunology research in the past decade has yielded an unprecedented wealth of information about the critical role of chronic stress in the immune dysfunction that influences tumor behaviors, which presents insights to mitigate distress and improve prognosis in cancer patients. Chronic stress exacerbates inflammation and causes a metabolism disorder, making it difficult for the organisms to maintain homeostasis and increasing its susceptibility to cancer.

Systemic Analysis of the Prognosis-Related RNA Alternative Splicing Signals in Melanoma.

BACKGROUND Alternative splicing (AS), the mechanism underlying the occurrence of protein diversity, may result in cancer genesis and development when it becomes out of control, as suggested by a growing number of studies. However, systemically analyze of AS events at the genome-wide level for skin cutaneous melanoma (SKCM) is still in a preliminary phase. This study aimed to systemically analyze the bioinformatics of the AS events at a genome-wide level using The Cancer Genome Atlas (TCGA) SKCM data.

The novel N-methyl-d-aspartate receptor antagonist MN-08 ameliorates lipopolysaccharide-induced acute lung injury in mice.

Acute lung injury (ALI) is a clinically severe respiratory disorder, and effective therapy is urgently needed. MN-08, a novel synthetic N-methyl-d-aspartate receptor (NMDAR) antagonist, was investigated for its effect on lipopolysaccharide (LPS)-induced ALI. In vitro, the protective effect of MN-08 on inflammatory response, oxidative stress, and tight junctions (TJs) structure was explored in LPS-induced RAW 264.