Clinical evaluation of acute necrotizing encephalopathy in children.

Objective: Acute necrotizing encephalopathy (ANE) is a rare but severe encephalopathy and is associated with a high morbidity and mortality. We aimed to analyze and compare the clinical features and predictive indicators of pediatric ANE.

Materials And Methods: This retrospective study included children with ANE diagnosed at Guangzhou Women and Children's Medical Center between November 2018 and January 2020.

[Retracted] miR‑218 suppresses tumor growth and enhances the chemosensitivity of esophageal squamous cell carcinoma to cisplatin.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the western blotting data shown in Fig. 6 and the tumor images shown in Fig. 7A were strikingly similar to data appearing in different form in other articles by different authors.

Dexmedetomidine upregulates microRNA-185 to suppress ovarian cancer growth via inhibiting the SOX9/Wnt/β-catenin signaling pathway.

Dexmedetomidine (DEX) could serve as an adjuvant analgesic during cancer therapies. Abnormal expression of microRNAs (miRNAs) could lead to cancer development. This study was aimed to explore the roles of DEX in ovarian cancer (OC) development.

The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15.

Cardiometabolic syndrome has become a global health issue. Heart failure is a common comorbidity of cardiometabolic syndrome. Successful drug development to prevent cardiometabolic syndrome and associated comorbidities requires preclinical models predictive of human conditions.

Effect of Dexmedetomidine-Mediated Insulin-Like Growth Factor 2 (IGF2) Signal Pathway on Immune Function and Invasion and Migration of Cancer Cells in Rats with Ovarian Cancer.

BACKGROUND The aim of this study was to explore the effect of dexmedetomidine (DEX)-mediated insulin-like growth factor 2 (IGF2) signal pathway on immune function and cancer cell invasion and migration in rats with ovarian cancer. MATERIAL AND METHODS Forty rats with ovarian cancer were divided into 4 groups: model group, and low dose (0.2 μg/kg/hour DEX), medium dose (1.

GDF15 deficiency promotes high fat diet-induced obesity in mice.

Pharmacological treatment of recombinant growth differentiation factor 15 (GDF15) proteins reduces body weight in obese rodents and primates. Paradoxically, circulating GDF15 levels are increased in obesity. To investigate the role of endogenous GDF15 in obesity development, we put GDF15 knockout mice and wildtype controls on high fat diet for the mice to develop diet-induced obesity.

Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys.

In search of metabolically regulated secreted proteins, we conducted a microarray study comparing gene expression in major metabolic tissues of fed and fasted ob/ob mice and C57BL/6 mice. The array used in this study included probes for ~4000 genes annotated as potential secreted proteins. Circulating macrophage inhibitory cytokine 1 (MIC-1)/growth differentiation factor 15 (GDF15) concentrations were increased in obese mice, rats, and humans in comparison to age-matched lean controls.

Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394.

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.

5-Alkyl-2-urea-Substituted Pyridines: Identification of Efficacious Glucokinase Activators with Improved Properties.

Two 1-(4-aryl-5-alkyl-pyridin-2-yl)-3-methylurea glucokinase activators were identified with robust in vivo efficacy. These two compounds possessed higher solubilities than the previously identified triaryl compounds (i.e.

miR-132 targeting E2F5 suppresses cell proliferation, invasion, migration in ovarian cancer cells.

Accumulating evidence showed that microRNA-132 (miR-132) are involved in development and progression of several types of cancers, however, the function and underlying molecular mechanism of miR-132 in ovarian cancer remains unclear. In this study we investigated the biological roles and molecular mechanism of miR-132 in ovarian cancer. Here, we found that that the expression levels of miR-132 were dramatically decreased in ovarian cancer cell lines and clinical ovarian cancer tissue samples.

Trefoil Factor 3 (TFF3) Is Regulated by Food Intake, Improves Glucose Tolerance and Induces Mucinous Metaplasia.

Trefoil factor 3 (TFF3), also called intestinal trefoil factor or Itf, is a 59 amino acid peptide found as a homodimer predominantly along the gastrointestinal tract and in serum. TFF3 expression is elevated during gastrointestinal adenoma progression and has been shown to promote mucosal wound healing. Here we show that in contrast to other trefoil factor family members, TFF1 and TFF2, TFF3 is highly expressed in mouse duodenum, jejunum and ileum and that its expression is regulated by food intake.

C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators.

Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514).

miR-218 suppresses tumor growth and enhances the chemosensitivity of esophageal squamous cell carcinoma to cisplatin.

A growing body of evidence suggests that microRNA-218 (miR-218) acts as a tumor suppressor and is involved in tumor progression, development and metastasis and confers sensitivity to certain chemotherapeutic drugs in several types of cancer. However, our knowledge concerning the exact roles played by miR-218 in esophageal squamous cell carcinoma (ESCC) and the underlying molecular mechanisms remain relatively unclear. Thus, the aims of this study were to detect the expression of miR-218 in human ESCC tissues and explore its effects on the biological features and chemosensitivity to cisplatin (CDDP) in an ESCC cell line (Eca109), so as to provide new insights for ESCC treatment.

Inhibition of secreted frizzled-related protein 5 improves glucose metabolism.

Elucidating the role of secreted frizzled-related protein 5 (SFRP5) in metabolism and obesity has been complicated by contradictory findings when knockout mice were used to determine metabolic phenotypes. By overexpressing SFRP5 in obese, prediabetic mice we consistently observed elevated hyperglycemia and glucose intolerance, supporting SFRP5 as a negative regulator of glucose metabolism. Accordingly, Sfrp5 mRNA expression analysis of both epididymal and subcutaneous adipose depots of mice indicated a correlation with obesity.

Advancing therapeutic discovery through phenotypic screening of the extracellular proteome using hydrodynamic intravascular injection.

Objective: Although the human genome encodes ∼ 20,000 protein-coding genes, only a very small fraction of these have been explored as potential targets for therapeutic development. The challenge of identifying and validating new protein targets has contributed to the significant reduction in the productivity of the pharmaceutical industry in the recent decade, highlighting the continued need to find new therapeutic targets.

Research Design And Methods: The traditional methods to discover new targets are expensive, low throughput and time consuming, usually taking years to validate or invalidate a target.

A ThPOK-LRF transcriptional node maintains the integrity and effector potential of post-thymic CD4+ T cells.

The transcription factor ThPOK promotes CD4(+) T cell differentiation in the thymus. Here, using a mouse strain that allows post-thymic gene deletion, we show that ThPOK maintains CD4(+) T lineage integrity and couples effector differentiation to environmental cues after antigenic stimulation. ThPOK preserved the integrity and amplitude of effector responses and was required for proper differentiation of types 1 and 2 helper T cells in vivo by restraining the expression and function of Runx3, a nuclear factor crucial for cytotoxic T cell differentiation.

Aminopyrazole-Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies.

Herein, we report the lead optimization of amrinone-phenylalanine based GPR142 agonists. Structure-activity relationship studies led to the discovery of aminopyrazole-phenylalanine carboxylic acid 22, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound 22, together with its orally bioavailable ethyl ester prodrug 23, were found to be suitable for in vivo proof-of-concept studies.

Potent and Orally Bioavailable GPR142 Agonists as Novel Insulin Secretagogues for the Treatment of Type 2 Diabetes.

GPR142 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR142 agonists stimulate insulin secretion in the presence of high glucose concentration, so that they could be novel insulin secretagogues with reduced or no risk of hypoglycemia. We report here the optimization of HTS hit compound 1 toward a proof of concept compound 33, which showed potent glucose lowering effects during an oral glucose tolerance test in mice and monkeys.

Activation of FFA1 mediates GLP-1 secretion in mice. Evidence for allosterism at FFA1.

FFA1 (GPR40) and GPR120 are G-protein-coupled receptors activated by long-chain fatty acids. FFA1 is expressed in pancreatic β-cells, where it regulates glucose-dependent insulin secretion, and GPR120 has been implicated in mediating GLP-1 secretion. We show here that FFA1 co-localizes with GLP-1 in enteroendocrine cells and plays a critical role in glucose management by mediating GLP-1 secretion in vivo.

Thpok-independent repression of Runx3 by Gata3 during CD4+ T-cell differentiation in the thymus.

CD4(+) helper T cells are essential for immune responses and differentiate in the thymus from CD4(+) CD8(+) "double-positive" (DP) thymocytes. The transcription factor Runx3 inhibits CD4(+) T-cell differentiation by repressing Cd4 gene expression; accordingly, Runx3 is not expressed in DP thymocytes or developing CD4(+) T cells. The transcription factor Thpok is upregulated in CD4-differentiating thymocytes and required to repress Runx3.

An inhibitory antibody against dipeptidyl peptidase IV improves glucose tolerance in vivo.

Dipeptidyl peptidase IV (DPP-IV) degrades the incretin hormone glucagon-like peptide 1 (GLP-1). Small molecule DPP-IV inhibitors have been used as treatments for type 2 diabetes to improve glucose tolerance. However, each of the marketed small molecule drugs has its own limitation in terms of efficacy and side effects.

The transcription factors Thpok and LRF are necessary and partly redundant for T helper cell differentiation.

T helper (Th) cells are critical for defenses against infection and recognize peptides bound to class II major histocompatibility complex (MHC II) molecules. Although transcription factors have been identified that direct Th cells into specific effector fates, whether a "master" regulator controls the developmental program common to all Th cells remains unclear. Here, we showed that the two transcription factors Thpok and LRF share this function.

Phenylalanine derivatives as GPR142 agonists for the treatment of type II diabetes.

GPR142 is a novel GPCR that is predominantly expressed in pancreatic β-cells. GPR142 agonists potentiate glucose-dependent insulin secretion, and therefore can reduce the risk of hypoglycemia. Optimization of our lead pyridinone-phenylalanine series led to a proof-of-concept compound 22, which showed in vivo efficacy in mice with dose-dependent increase in insulin secretion and a decrease in glucose levels.

CD4-CD8 differentiation in the thymus: connecting circuits and building memories.

The proper choice of the CD4-helper or CD8-cytotoxic lineages by developing T cells is crucial for the generation of an antigen-responsive and functionally fit T cell repertoire. Here we present a brief overview of the transcriptional control of this process, with emphasis on two issues. The study of Cd4 expression, that had previously generated important paradigms for transcriptional regulation in eukaryotic cells, now brings new twists to the concept of 'epigenetic memory'.