Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer

Mesenchymal stem cells (MSCs) play an important role in chemoresistance. Exosomes have been reported to modify cellular phenotype and function by mediating cell-cell communication. In this study, we aimed to investigate whether exosomes derived from MSCs (MSC-exosomes) are involved in mediating the resistance to chemotherapy in gastric cancer and to explore the underlying molecular mechanism. We found that MSC-exosomes significantly induced the resistance of gastric cancer cells to 5-fluorouracil both in vivo and ex vivo. MSC-exosomes antagonized 5-fluorouracil-induced apoptosis and enhanced the expression of multi-drug resistance associated proteins, including MDR, MRP and LRP. Mechanistically, MSC-exosomes triggered the activation of calcium/calmodulin-dependent protein kinases (CaM-Ks) and Raf/MEK/ERK kinase cascade in gastric cancer cells. Blocking the CaM-Ks/Raf/MEK/ERK pathway inhibited the promoting role of MSC-exosomes in chemoresistance. Collectively, MSC-exosomes could induce drug resistance in gastric cancer cells by activating CaM-Ks/Raf/MEK/ERK pathway. Our findings suggest that MSC-exosomes have profound effects on modifying gastric cancer cells in the development of drug resistance. Targeting the interaction between MSC-exosomes and cancer cells may help improve the efficacy of chemotherapy in gastric cancer.     

ESM-1 silencing decreased cell survival,migration, and invasion and modulated cell cycle progression in hepatocellular carcinoma

Amino Acids - Endothelial cell-specific molecule-1 (ESM-1) is a secretory proteoglycan comprising a mature polypeptide of 165 amino acids and a single dermatan sulfate. The aim of this study was to...     

Controlled synthesis of Pt nanoparticles array through electroreduction of cisplatin bound at nucleobases terminated surface and application into H2O2 sensing

Fabrication of sub-monolayer array of Pt nanoparticles (PtNPs) assembled at nucleobases terminated layers and their application into H(2)O(2) and glucose sensing were reported. To prepare such a PtNPs assembly, 3-mercaptopropionic acid (MPA), Zr(4+), nucleotide-5'-monophosphate (NTMP including guanosine, adenosine, cytidine, uridine-5'-monophosphate, and abbreviations were GMP, AMP, CMP, UMP, respectively) were adsorbed onto Au substrate sequentially to form nucleobases terminated surface and Zr(4+) acted as binder to link carboxylic and phosphoric groups (NTMP/Zr(4+)/MPA/Au). Complexation of cisplatin, cis-Pt(NH(3))(2)Cl(2), with terminated nucleobases and following electrochemical reduction of surface-bound cisplatin gave PtNPs attached surface. Different PtNPs coverage or particle density was obtained depending on the NTMP used and decreased in the order: PtNPs/GMP/Zr(4+)/MPA/Au>PtNPs/AMP/Zr(4+)/MPA/Au>PtNPs/CMP/Zr(4+)/MPA/Au>PtNPs/UMP/Zr(4+)/MPA/Au. The surface loading of Pt was between 160 and 16 ng/cm(2). The as prepared PtNPs can be used as electrocatalysts for H(2)O(2) sensing (detection limit of H(2)O(2)<100 nM) and the sensitivity increased with decreasing PtNPs density. After adsorption of glucose oxidase, the modified electrode can be used as enzymatic electrode for glucose sensing and a detection limit of 38.5 μM was achieved. This study provided an example of fabricating PtNP arrays utilising surface complexation of cisplatin with nucleobases. The advantage of this method is that the NP density can be controlled through changing nucleobases or Pt complexes used to obtain suitable kinetics of the complexation reactions. Additionally, the PtNPs sub-monolayer as prepared has high sensitivity for H(2)O(2) sensing even at a very low loading of Pt.     

The impact of different operating conditions on membrane fouling and EPS production

The main goal of this research was to investigate how different factors influence membrane fouling. The impact of the different concentrations of activated sludge and the amount of extracellular polymer substances (EPS) were monitored. Two pilot plants with submerged membrane modules (hollow fiber and flat sheet) were operated and the raw wastewater was used.Humic substances were identified as the major components of EPS in the activated sludge (more than 34%) in both pilot plants. As the basic constituent in permeate, humic substances were identified as the most dominant components in the effluent (61%) in both pilot plants. Conversely, proteins were mostly analyzed in permeate and supernatant below the detection limit. The total amount of EPS [mg g⁻¹ (VSS)] was similar for concentrations of activated sludge 6, 10 and 14 g L⁻¹. Carbohydrates were identified as the component of EPS which tends most to clog membranes.     

Bioconversion of crude glycerol to glycolipids in Ustilago maydis

Ustilago maydis is known to produce glycolipid-type biosurfactants. Here, we show that U. maydis is able to efficiently convert biodiesel-derived crude glycerol to glycolipids. We have optimized the medium composition and environmental factors for bioconversion of crude glycerol to glycolipids. The synthetic medium (MinCG) contains 50 g L⁻¹ crude glycerol and 20.3 mg L⁻¹ ammonium citrate as the carbon and nitrogen sources, respectively. The supplementation of trace amount of amino acids, Group-B vitamins and precursors of glycolipids, mannose and erythritol, also improved the final yield. At pH 4.0 and 30 °C, 32.1 g L⁻¹ total glycolipids was produced in a 8.2-day fed-batch bioprocess. Methanol at 2% or above severely inhibited cell growth and production of glycolipids. Our results suggest that U. maydis is an excellent host for the bioconversion of crude glycerol to value-added products.     

Role of protein conformational dynamics in the catalysis by 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase

Enzymatic catalysis has conflicting structural requirements of the enzyme. In order for the enzyme to form a Michaelis complex, the enzyme must be in an open conformation so that the substrate can get into its active center. On the other hand, in order to maximize the stabilization of the transition state of the enzymatic reaction, the enzyme must be in a closed conformation to maximize its interactions with the transition state. The conflicting structural requirements can be resolved by a flexible active center that can sample both open and closed conformational states. For a bisubstrate enzyme, the Michaelis complex consists of two substrates in addition to the enzyme. The enzyme must remain flexible upon the binding of the first substrate so that the second substrate can get into the active center. The active center is fully assembled and stabilized only when both substrates bind to the enzyme. However, the side-chain positions of the catalytic residues in the Michaelis complex are still not optimally aligned for the stabilization of the transition state, which lasts only approximately 10(-13) s. The instantaneous and optimal alignment of catalytic groups for the transition state stabilization requires a dynamic enzyme, not an enzyme which undergoes a large scale of movements but an enzyme which permits at least a small scale of adjustment of catalytic group positions. This review will summarize the structure, catalytic mechanism, and dynamic properties of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase and examine the role of protein conformational dynamics in the catalysis of a bisubstrate enzymatic reaction.     

Synthesis and biological activity of desmethoxy analogues of coruscanone A

A series of simple desmethoxy analogues of coruscanone A was prepared via a novel version of Ti(iPrO)(4)-mediated Knoevenagel condensation of cyclopentenedione with substituted benzaldehydes and cinnamic aldehydes, and the compounds were evaluated for antifungal activity and cytotoxicity. The most potent 2-benzylidenecyclopent-4-ene-1,3-dione possessed antifungal effect comparable to coruscanone A and a somewhat broader spectrum of activity against Candida species. The compound was also superior to fluconazole against several non-albicans Candida sp. Evaluation of the ability of the compound to influence cell proliferation using two different assays showed that 2-benzylidenecyclopent-4-ene-1,3-dione has lower cytotoxicity compared to the natural product.     

Efficient synthesis of trisaccharide saponins and their tumor cell killing effects through oncotic necrosis

To investigate the relationship of cytotoxicity and saponins with varied aglycones, based on the structure of indioside E 1, a natural derived anti-tumor active ingredient from Chinese medicinal plant Solanum indicum L., five novel saponins 2-6 bearing the same trisaccharide moiety together with 1 were efficiently synthesized via a transglycosylation strategy. MTT assay revealed the killing effects to tumor cells of the synthesized saponins are varied with the change of aglycones. Furthermore, time-lapse microscopy, LDH release, PI staining, and immunocytochemical investigations demonstrated that the cell death caused by neosaponin 2 was through oncotic necrosis involving plasma membrane perturbation and destruction of cytoskeleton.     

Potent and selective cyclohexyl-derived imidazopyrazine insulin-like growth factor 1 receptor inhibitors with in vivo efficacy

Preclinical and emerging clinical evidence suggests that inhibiting insulin-like growth factor 1 receptor (IGF-1R) signaling may offer a promising therapeutic strategy for the treatment of several types of cancer. This Letter describes the medicinal chemistry effort towards a series of 8-amino-imidazo[1,5-a]pyrazine derived inhibitors of IGF-1R which features a substituted quinoline moiety at the C1 position and a cyclohexyl linking moiety at the C3 position. Lead optimization efforts which included the optimization of structure-activity relationships and drug metabolism and pharmacokinetic properties led to the identification of compound 9m, a potent, selective and orally bioavailable inhibitor of IGF-1R with in vivo efficacy in an IGF-driven mouse xenograft model.