Discovery of Novel Imidazo[4,5-c]quinoline Derivatives to Treat Inflammatory Bowel Disease (IBD) by Inhibiting Multiple Proinflammatory Signaling Pathways and Restoring Intestinal Homeostasis.

As a complex pathogenesis driven by immune inflammatory factors and intestinal microbiota, the treatment of inflammatory bowel disease (IBD) may rely on the comprehensive regulation of these important pathogenic factors to reach a favorable therapeutic effect. In the current study, we discovered a series of imidazo[4,5-c]quinoline derivatives that potently and simultaneously inhibited two primary proinflammatory signaling pathways JAK/STAT and NF-κB. Especially, lead compound 8l showed potent inhibitory activities against interferon-stimulated genes (IC50: 3.3 nM) and NF-κB pathways (IC50: 150.7 nM) and decreased the release of various proinflammatory factors at the nanomolar level, including IL-6, IL-8, IL-1ß, TNF-α, IL-12, and IFN-γ. In vivo, 8l produced a strong anti-inflammatory activity in both dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute enteritis models and restored the structural composition of gut microbiota. Collectively, this study provided valuable lead compounds for the treatment of IBD and revealed the great anti-inflammatory potential of the simultaneous suppression of JAK/STAT and NF-κB signals.

Effect of continuous hemofiltration on severe acute pancreatitis with different intra-abdominal pressure: A cohort study.

BACKGROUND: The clinical efficacy and timing of continuous veno-venous hemofiltration (CVVH) in the treatment of severe acute pancreatitis (SAP) remain uncertain. In this prospective cohort study, patients with SAP were classified according to intra-abdominal pressure (IAP). METHODS: Seventy-four patients with SAP admitted to the intensive care unit were randomly divided into group A (IAP ≥20 mm Hg) and group B (with IAP ≤20 mm Hg). Then, according to whether CVVH was administered or not, groups A and B were divided into 4 subgroups: group A1 and B1 (non-CVVH treatment), group A2 and B2 (CVVH treatment). Changes in clinical and laboratory indicators were recorded before and on the seventh day after treatment, and clinical outcomes were analyzed. RESULTS: Before treatment, there was no significant difference in general conditions between subgroups A1 and A2, and between subgroups B1 and B2. After CVVH treatment, the indicators recorded in group A2 were significantly improved compared to those in group A1 (P < .05). In group A2, the 28 day operation rate was lower (P < .05), as mechanical ventilation, gastric decompression, and intensive care unit treatment time were shorter (P < .05). However, there was no statistically significant difference in any of the above indicators between subgroups B (P > .05). Groups A2 and B2 had more days of negative fluid balance within 1 week of admission than groups A1 and B1 (P < .05). CONCLUSIONS: For SAP, patients with IAP ≥20 mm Hg can benefit from treatment with CVVH, but for patients with IAP ≤20 mm Hg, the efficacy is not clear, and monitoring IAP may be an indicator to decide whether or when to initiate CVVH. Negative fluid balance caused by CVVH treatment may be one of the reasons for the benefit of this group of patients.

Pinning multisynchronization of delayed fractional-order memristor-based neural networks with nonlinear coupling and almost-periodic perturbations.

This paper concerns the multisynchronization issue for delayed fractional-order memristor-based neural networks with nonlinear coupling and almost-periodic perturbations. First, the coexistence of multiple equilibrium states for isolated subnetwork is analyzed. By means of state-space decomposition, fractional-order Halanay inequality and Caputo derivative properties, the novel algebraic sufficient conditions are derived to ensure that the addressed networks with arbitrary activation functions have multiple locally stable almost periodic orbits or equilibrium points. Then, based on the obtained multistability results, a pinning control strategy is designed to realize the multisynchronization of the N coupled networks. By the aid of graph theory, depth first search method and pinning control law, some sufficient conditions are formulated such that the considered neural networks can possess multiple synchronization manifolds. Finally, the multistability and multisynchronization performance of the considered neural networks with different activation functions are illustrated by numerical examples.

Design and one-pot synthesis of 2-thiazolylhydrazone derivatives as influenza neuraminidase inhibitors.

Two series of novel 2-thiazolylhydrazone derivatives were designed and synthesized via one-pot reaction of benzaldehyde derivatives, [Formula: see text]-haloketones and thiosemicarbazide. The structures of compounds 1 and 2 were characterized by [Formula: see text] NMR and [Formula: see text] NMR, and compound 1g was further confirmed by X-ray crystallography. All of the target compounds were evaluated for their NA inhibitory activity against influenza viral neuraminidase (H1N1) in vitro, and the results showed that many compounds exhibited moderate to strong inhibitory activities against influenza viral neuraminidase (H1N1). Among them, compounds 1p, 1q and 2c showed the most potent inhibitory activities with [Formula: see text] values ranging from 10.50 to [Formula: see text]. Our structure-activity relationship analysis indicated that 2-thiazolylhydrazone is an effective scaffold for NA inhibitors and that introducing an ethoxycarbonyl group to the 5-position of thiazole ring could enhance inhibitory potency. Molecular docking was performed on the most active compounds 1p and 2c to provide more insight into their mechanism of interaction.

Apoptosis of human gastric cancer SGC-7901 cells induced by mitomycin combined with sulindac.

AIM: To investigate the effects of mitomycin (MMC) combined with sulindac on cell viability, apoptotic induction and expression of apoptosis-related gene Bcl-2 and cyclooxygenase-2 (COX-2) in gastric cancer SGC-7901 cells. METHODS: Human gastric cancer SGC-7901 cells were divided into three treatment groups,namely sulindac treatment group, MMC treatment group and combined sulindac with MMC treatment group. After being treated with drugs, cell viability was examined by MTT assay. Flow cytometry was used to evaluate the cell cycle distribution and apoptotic rates. Morphology of the cells was observed under light microscope and interactive laser microscope. Expression of COX-2 and Bcl-2 was determined by immunocytochemical method. RESULTS: After exposure for 12 h to three kinds of drugs, gastric cancer SGC-7901 cells presented some morphological features of apoptosis, including cell shrinkage, nuclear condensation, DNA fragmentation and formation of apoptotic bodies. Growth inhibition was more obvious in combined sulindac with MMC treatment group and sulindac treatment group than in MMC treatment group. The apoptotic rates in co-treated cells and MMC-treated cells 24 h after treatment were 12.0% and 7.2%, respectively. After exposure for 24 h to MMC, the expression of COX-2 and Bcl-2 protein was up-regulated, COX-2 levels were down-regulated but Bcl-2 gene expression was not changed significantly in combined treatment group. CONCLUSION: MMC-induced apoptosis is reduced by up-regulating the expression of COX-2 and Bcl-2 genes. MMC combined with sulindac can suppress the growth of gastric cancer cells through induction of apoptosis mediated by down-regulation of apoptosis-related Bcl-2 and COX-2 gene.