Small Molecules Targeting the RNA-Binding Protein HuR Inhibit Tumor Growth in Xenografts.

The RNA-binding protein Hu antigen R (HuR) is a post-transcriptional regulator critical in several types of diseases, including cancer, making it a promising therapeutic target. We have identified small-molecule inhibitors of HuR through a screening approach used in combination with fragment analysis. A total of 36 new compounds originating from fragment linking or structural optimization were studied to establish structure-activity relationships in the set.

Design, synthesis, and cytotoxic activity of novel 2H-imidazo[1,2-c]pyrazolo[3,4-e]pyrimidine derivatives.

In this study, a series of novel 2H-imidazo [1, 2-c] pyrazolo [3, 4-e] pyrimidine derivatives were designed, synthesized, and evaluated for their cytotoxic activities. The in vitro cell growth inhibition assay of the target compounds indicated their selectivity in inhibiting the proliferation of blood tumor cells (K562, U937) and solid tumor cells (HCT116, HT-29). Compound 9b exhibited the highest antiproliferative activities against K562 (IC = 5.

A near-infrared fluorescent probe that can image endogenous hydrogen polysulfides in vivo in tumour-bearing mice.

Hydrogen polysulfides (HS, n > 1), which are important reactive sulfur species, play crucial roles in HS-related bioactivities, including antioxidation, cytoprotection, activation of ion channels, transcription factor functions and tumour suppression. Monitoring HSin vivo is of significant interest for exploring the physiological roles of HS and the exact mechanisms of HS-related diseases. Herein, we conceive a novel near-infrared fluorescent probe, NIR-CPS, that is used to detect HS in living cells and in vivo.

Design, synthesis and evaluation of calix[4]arene-based carbonyl amide derivatives with antitumor activities.

Calixarenes, with potential functionalization on the upper and lower rim, have been explored in recent years for the design and construction of anticancer agents in the field of drugs and pharmaceuticals. Herein, optimization of bis [N-(2-hydroxyethyl) aminocarbonylmethoxyl substituted calix [4] arene (CLX-4) using structure-based drug design and traditional medicinal chemistry led to the discovery of series of calix [4]arene carbonyl amide derivatives 5a-5t. Evaluation of the cytotoxicity of 5a-5t employing MTT assay in MCF-7, MDA-MB-231 (human breast cancer cells), HT29 (human colon carcinoma cells), HepG2 (human hepatocellular carcinoma cells), A549 (human lung adenocarcinoma cells) and HUVEC (Human Umbilical Vein Endothelial) cells demonstrated that the most promising compound 5h displayed the most superior inhibitory effect against A549 and MDA-MB-231 cells, which were 3.

Design, synthesis, biological activity evaluation of 3-(4-phenyl-1H-imidazol-2-yl)-1H-pyrazole derivatives as potent JAK 2/3 and aurora A/B kinases multi-targeted inhibitors.

In this study, a series of 3-(4-phenyl-1H-imidazol-2-yl)-1H-pyrazole derivatives were designed, synthesized, and evaluated for their biological activities. Upon performing kinase assays, most of the compounds exhibited potent inhibition against JAK2/3 and Aurora A/B with the IC values ranging from 0.008 to 2.

Design, synthesis and biological evaluation of 4-aniline quinazoline derivatives conjugated with hydrogen sulfide (HS) donors as potent EGFR inhibitors against L858R resistance mutation.

In this study, a series of 4-aniline quinazoline derivatives bearing hydrogen sulfide (HS) donors were designed, synthesized and evaluated for biological activities. The synthesized compounds were screened for the enzymatic activities against EGFR and EGFR mutants by kinase target-based cell screening method. The results demonstrate that most compounds exhibit selectively inhibitory activities against TEL-EGFR-L858R-BaF3, especially compound 9h with GI = 0.

Structural Design, Synthesis, and Preliminary Biological Evaluation of Novel Dihomooxacalix[4]arene-Based Anti-tumor Agents.

Calixarene and its derivatives have extensively served as promising anti-tumor agents. Previously, we have synthesized a series of calix[n]arene polyhydroxyamine derivatives ( = 4, 6, 8) and found that 5,11,17,23--butyl-25,27-bis [N-(2-hydroxyethyl)aminocarbonylmethoxyl] calix[4]arene displayed significant effect toward SKOV3, A549, SW1990, HeLa, Raji, and MDA-MB-231 cancer cells. In the present work, we find a replacement of calix[4]arene bone and synthesized 19 novel structurally related dihomooxacalix[4]arene amide derivatives to optimize its efficacy.

Preparation and bioactivity evaluation of N-heterocyclic-linked dihomooxacalix[4]arene derivatives.

Based on the superior prospects of calixarenes-based agents and N-heterocyclic pharmacophores in biomedical applications, 14 new dihomooxacalix[4]arene N-heterocyclic (pyridine, quinoline, and thiazole) derivatives 4a-4n were efficiently synthesized from the parent compound, namely, -butyldihomooxacalix[4]arene 1; they were further investigated by using their IR, H NMR, C NMR, and HRMS spectra. Among these derivatives, the crystal and molecular structures of 2-aminomethyl-pyridine-substituted dihomooxacalix[4]arene 4f (obtained from methanol) have been determined by X-ray diffraction. In the case of the inhibition assay of cell growth, we evaluated the effects on four select tumor cell lines (MCF-7, HepG2, SKOV3, and HeLa), as well as the normal cell lines of HUVEC, using paclitaxel as the positive control drug.

XueBiJing Injection Versus Placebo for Critically Ill Patients With Severe Community-Acquired Pneumonia: A Randomized Controlled Trial.

Objectives: To investigate whether XueBiJing injection improves clinical outcomes in critically ill patients with severe community-acquired pneumonia.

Design: Prospective, randomized, controlled study.

Setting: Thirty-three hospitals in China.

A reaction-based near-infrared fluorescent probe that can visualize endogenous selenocysteine in vivo in tumor-bearing mice.

Monitoring the fluctuations of endogenous selenocysteine (Sec) in vivo is of significant interest to understand the physiological roles of Sec and the mechanisms of Sec-relevant diseases. Herein, a new near-infrared fluorescent probe, Fsec-1, has been developed for the determination of endogenous Sec in living cells and in vivo. Fsec-1 exhibits large fluorescence enhancement (136-fold) and a remarkably large Stokes shift (195 nm) when reacted with Sec.

Design and synthesis of a novel photoaffinity probe for labelling EGF receptor tyrosine kinases.

The epidermal growth factor receptor (EGFR) and HER2 are two important tyrosine kinases that play crucial roles in signal transduction pathways that regulate numerous cellular functions including proliferation, differentiation, migration, and angiogenesis. In the past 20 years, many proteomic methods have emerged as powerful methods to evaluate proteins in biological processes and human disease states. Among them, activity-based protein profiling (ABPP) is one useful approach for the functional analysis of proteins.

Design, synthesis, and biological evaluation of novel 4-anilinoquinazoline derivatives bearing amino acid moiety as potential EGFR kinase inhibitors.

In this study, a series of 4-anilinoquinazoline derivatives bearing amino acid moiety were designed, synthesized and evaluated for biological activities. The synthesized compounds were screened for anticancer activity against human hepatocellular carcinoma cell HepG2 using SRB assay. In vitro cell growth inhibition assays indicated that compound 6m exhibited moderate inhibitory activities only against human hepatocellular carcinoma cells HepG2 with IC of 8.

Synthesis, X-ray crystal structure and anti-tumor activity of calix[n]arene polyhydroxyamine derivatives.

Calixarene-based compounds are highly effective therapeutic agents against cancer. This study aims to prepare a series of calix [n]arene (n = 4, 6, 8) polyhydroxyamine derivatives (3a-3m) and to study their potential antitumor activities. The single crystal structure of calixs[4]arene derivative 3a was determined through X-ray diffraction.

Structure-Based Drug Design of Small Molecule Peptide Deformylase Inhibitors to Treat Cancer.

Human peptide deformylase (HsPDF) is an important target for anticancer drug discovery. In view of the limited HsPDF, inhibitors were reported, and high-throughput virtual screening (HTVS) studies based on HsPDF for developing new PDF inhibitors remain to be reported. We reported here on diverse small molecule inhibitors with excellent anticancer activities designed based on HTVS and molecular docking studies using the crystal structure of HsPDF.

Down-regulation of microRNA-126 and microRNA-133b acts as novel predictor biomarkers in progression and metastasis of non small cell lung cancer.

Objective: MiRNAs play crucial roles in progression of cancer. However, the underlying mechanisms of miRNAs in non small cell lung cancer are still poorly understood. The aim of this study was to investigate the expression level of microRNA-126 (miR-126) and microRNA-133b (miR-133b) and also their association with clinicopathological features in patients with non small cell lung cancer (NSCLC).

Serum microRNA-365 in combination with its target gene TTF-1 as a non-invasive prognostic marker for non-small cell lung cancer.

Background: MicroRNA (miR)-365 functions as a tumor suppressor in non-small cell lung cancer (NSCLC) cells by targeting thyroid transcription factor 1 (TTF-1).

Aim: To investigate miR-365 and TTF-1 mRNA expression in serum of NSCLC and their associations with patients' prognosis.

Methods: MiR-365 and TTF-1 mRNA expression in 100 NSCLCs and 100 healthy control sera were detected by quantitative real-time PCR (qRT-PCR).

Effect of Avastin on the number and structure of tumor blood vessels of nude mice with A549 lung adenocarcinoma.

The aim of the present study was to investigate the effect of Avastin on the number and structure of tumor blood vessels of nude mice with A549 lung adenocarcinoma. A total of 30 nude mice were randomly divided into three groups, namely the control, the Avastin I (Avastin 3 mg/kg) and the Avastin II (Avastin 6 mg/kg) groups. Following treatment, ELISA was used to detect the expression level of vascular endothelial growth factor (VEGF) in tumor tissues.

Theoretical study on the structural and antioxidant properties of some recently synthesised 2,4,5-trimethoxy chalcones.

The free radical scavenging activity of a series of 2,4,5-trimethoxy chalcones has been computationally explored using the density functional theory (DFT) method. Three potential working mechanisms, hydrogen atom transfer (HAT), stepwise electron transfer proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) have been investigated. The physiochemical parameters including O-H bond dissociation enthalpy (BDE), ionisation potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA) and electron transfer enthalpy (ETE) have been calculated in gas phase and solvents.

Prognostic potential of microRNA-138 and its target mRNA PDK1 in sera for patients with non-small cell lung cancer.

microRNA (miR)-138 has been recognized as a potential tumor suppressor via regulating 3-phosphoinositide-dependent protein kinase-1 (PDK1) expression in non-small cell lung cancer (NSCLC) cells. The aim of this study was to investigate miR-138 and PDK1 mRNA expression in serum of NSCLC and their associations with patients' prognosis. miR-138 and PDK1 mRNA expressions in 100 NSCLCs and 100 healthy control sera were detected by quantitative real-time PCR.

Density functional theory study of the structure-antioxidant activity of polyphenolic deoxybenzoins.

Quantum chemical calculations based on the density functional theory (DFT) have been employed to study the relationship between the structure and the antioxidant activity of four polyphenolic deoxybenzoins (DOBs) in solvents and the gas phase. The three main working mechanisms, H-atom transfer (HAT), single electron transfer-proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) have been investigated. The calculated results closely matched experimental values.

Theoretical study on the antioxidant properties of 2'-hydroxychalcones: H-atom vs. electron transfer mechanism.

The free radical scavenging activity of six 2'-hydroxychalcones has been studied in gas phase and solvents using the density functional theory (DFT) method. The three main working mechanisms, hydrogen atom transfer (HAT), stepwise electron-transfer-proton-transfer (ET-PT) and sequential-proton-loss-electron-transfer (SPLET) have been considered. The O-H bond dissociation enthalpy (BDE), ionization potential (IP), proton affinity (PA) and electron transfer energy (ETE) parameters have been computed in gas phase and solvents.

Design, synthesis, quantum chemical studies and biological activity evaluation of pyrazole-benzimidazole derivatives as potent Aurora A/B kinase inhibitors.

Novel pyrazole-benzimidazole derivatives have been designed and synthesized. The entire target compounds were determined against cancer cell lines U937, K562, A549, LoVo and HT29 and were screened for Aurora A/B kinase inhibitory activity in vitro. The compounds 7a, 7b, 7i, 7k and 7l demonstrated significant cancer cell lines and Aurora A/B kinase inhibitory activities.

L-citrulline protects against glycerol-induced acute renal failure in rats.

There is an increasing evidence that oxidative stress plays an important role in the pathogenesis of rhabdomyolysis-induced acute renal failure (ARF). In this study, protective effects of L-citrulline on glycerol-induced ARF in rats were investigated. Six groups of rats were employed in this study: group 1 served as a control; group 2 was only given glycerol (50%, 10 mL/kg, i.

Synthesis and quantum chemical studies of new 4-aminoquinazoline derivatives as Aurora A/B kinase inhibitors.

Nine novel 4-aminoquinazoline derivatives were designed and synthesized. Biochemical and cellular analyses demonstrated that most of the derivatives exhibited a strong activity to inhibit Aurora A and B kinases and to suppress the proliferation of a panel of human tumor cell lines (U937, K562, A549, LoVo, and HT29). Quantum chemical studies were also carried out to determine the structural features of these compounds engaged in the inhibition of Aurora kinases.

Protective effects of nizofenone administration on the cognitive impairments induced by chronic restraint stress in mice.

The present study was aimed to investigate the effects of nizofenone administration on the chronic restraint stress-induced cognitive impairments in mice. Adult male mice were randomized into five groups: control group, nizofenone control group, chronic restraint stress group, and nizofenone treatment groups (3.0mg/kg and 9.