Roflupram alleviates autophagy defects and reduces mutant hSOD1-induced motor neuron damage in cell and mouse models of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease involving motor neuron (MN) degeneration and is characterized by ongoing myasthenia and amyotrophia in adults. Most ALS patients die of respiratory muscle paralysis after an average of 3-5 years. Defective autophagy in MNs is considered an important trigger of ALS pathogenesis. Roflupram (ROF) was demonstrated to activate autophagy in microglial cells and exert protective effects against Parkinson's disease (PD) and Alzheimer's disease (AD). Therefore, our research aimed to investigate the efficacy and mechanism of ROF in treating ALS both in vivo and in vitro. We found that ROF could delay disease onset and prolong the survival of hSOD1-G93A transgenic mice. Moreover, ROF protected MNs in the anterior horn of the spinal cord, activated the AMPK/ULK1 signaling pathway, increased autophagic flow, and reduced SOD1 aggregation. In an NSC34 cell line stably transfected with hSOD1-G93A, ROF protected against cellular damage caused by hSOD1-G93A. Moreover, we have demonstrated that ROF inhibited gliosis in ALS model mice. Collectively, our study suggested that ROF is neuroprotective in ALS models and the AMPK/ULK1 signaling pathway is a potential therapeutic target in ALS, which increases autophagic flow and reduces SOD1 aggregation.

Renewable UV-curable polyester methacrylate/cellulose nanocrystals composite resin for wood waterproof coating.

Low-viscosity UV-curable resins are widely used in industry as they allow for UV curing materials with reduced amounts of reactive diluents to adjust the viscosity. But their mechanical properties and waterproof performance after curing as UV coatings still need to be improved. Here, a series of low-viscosity bio-based UV-curable polyester methacrylates were synthesized through L-lactide (LA) andε-caprolactone (CL) monomers. The results show that the introduction of star-shaped structure and random copolymerization of LA and CL can effectively reduce the viscosity of the resin to 313 mPa · s and at the same time increase the double bond conversion rate and maintain good mechanical properties. The composite resin was prepared by blending the star-shaped low-viscosity polyester methacrylate resin with cellulose nanocrystals (CNCs), and the microstructure was characterized by XRD and TEM. The curing kinetics, mechanical properties, thermal properties and waterproof properties of the composite resin were further tested. When the mass fraction of CNCs is 2.5 wt%, the water absorption rate of the pine samples coated with UV-cured composite resin is reduced to 17%, which is 65% lower than that of the uncoated samples and 20% lower than that of the samples coated with resin without CNC. This article provides a feasible and effective method for improving the mechanical properties and waterproof performance of low-viscosity UV-curing resins.

Brucine inhibits proliferation of glioblastoma cells by targeting the G-quadruplexes in the c-Myb promoter.

The proto-oncogene c-Myb plays an important role in cell proliferation, and its upregulation affects the development of glioblastomas. G-quadruplexes are secondary DNA or RNA structures that usually form in the promoter region of oncogenes, including c-Myb, and regulate the expression of these genes. The traditional Chinese medicine, brucine, is a ligand of the G-quadruplexes located in the promoter region of c-Myb. The present study investigated the therapeutic effects and mechanism of action of brucine in U87, LN18, and LN229 cells in vitro and in vivo. Our results showed that brucine suppressed the growth of these cells in vitro by arresting the cell cycle and reducing c-Myb expression. Dual-luciferase reporter assays showed that brucine inhibited c-Myb expression by targeting the guanine-rich sequence that forms G-quadruplexes in the c-Myb promoter. Moreover, U87 tumors were suppressed by brucine in a tumor xenograft nude mouse model. Therefore, brucine is potentially effective for treating glioblastomas.

Gut microbiota is involved in the alleviation of loperamide-induced constipation by honey supplementation in mice.

Constipation is one of the most common functional gastrointestinal disorders accompanied with intestinal dysbiosis. Laxatives for constipation usually have side effects. Bee honey is a natural food with unique composition, antimicrobial properties, and bifidogenic effect. In order to assess whether honey can ameliorate loperamide-induced constipation in BALB/c mice through the alteration of the gut microbiota, the present study was undertaken. Mice were given Jarrah honey (7.5 g/kg body weight) by gavage once per day for 5 days. Fecal water content, intestinal transit rate together with the colon concentrations of substance P (SP), vasoactive intestinal peptide (VIP), and serotonin (5-hydroxytryptamine; 5-HT) were evaluated. Furthermore, we determined the effect of honey treatment on gut microbiota in mice using stool genomic 16S rRNA sequencing. As a result, honey showed an obvious improvement in fecal water content and alleviated constipation by modulating the microbial composition of the microbiota, and this was highly associated with a proportional decrease in gut Desulfovibrio. In addition, we found that the colon level of neurotransmitters SP and VIP was significantly related to microbial variations. Our results indicate that gut microbiota is involved in the alleviation of loperamide-induced constipation by honey supplementation in mice, and it could be considered as an evaluating parameter in constipation therapy strategies.

ß-catenin contributes to cordycepin-induced MGMT inhibition and reduction of temozolomide resistance in glioma cells by increasing intracellular reactive oxygen species.

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors, and it has a poor prognosis. Temozolomide (TMZ) is the primary alkylating agent used to treat GBM. Nevertheless, a number of GBM patients are resistant to TMZ. Therefore, there is an urgent need for more effective therapeutic options. Cordycepin (COR) is a natural chemical with anti-tumor effects, although its mechanism of action is poorly understood. Several lines of evidence suggest that O6-methylguanine DNA methyltransferase (MGMT) repairs damaged DNA and contributes to drug resistance to TMZ in gliomas. The Wnt/ß-catenin pathway regulates MGMT gene expression. However, whether cordycepin inhibits MGMT expression by downregulating the ß catenin pathway and augmenting chemosensitivity to TMZ in glioma cells remains unclear. In the present study, we found that cordycepin inhibited the viability of glioma cells and induced apoptosis, cell cycle arrest, overproduction of reactive oxygen species (ROS) and reduction of glutathione (GSH) in vitro. Moreover, cordycepin significantly reduced tumor volume and prolonged median survival of tumor-bearing rats in vivo. We also found that cordycepin inhibited MGMT expression and augmented chemosensitivity to TMZ in glioma cells in vitro and in vivo, accompanied by downregulation of p-GSK-3ß and ß-catenin. Moreover, overexpression of MGMT reversed the synergistic effect of cordycepin and TMZ. Pharmacological inhibition of GSK-3ß with CHIR-99021 or overexpression of ß-catenin reversed cordycepin-induced reduction of cell viability, downregulation of ß-catenin and MGMT, increase of apoptosis and reduction of TMZ resistance. Furthermore, we found that ß-catenin regulated cordycepin-induced overproduction of ROS by decreasing GSH. Inhibition of ROS production with N-acetyl-l-cysteine (NAC) not only rescued the reduction of cell viability but also eliminated ß-catenin and MGMT inhibition, prevented glioma cells apoptosis and reversed the synergistic effect of cordycepin and TMZ. Taken together, we demonstrated that ß-catenin contributed to cordycepin-induced MGMT inhibition and reduction of TMZ resistance in glioma cells via increasing intracellular ROS. These results indicate that cordycepin may be a novel agent to improve GBM treatment, especially in TMZ-resistant GBM with high MGMT expression.