Design, Synthesis, and Biological Evaluation of Thioglucoside Analogues of Gliflozin as Potent New Gliflozin Drugs.

In this study, we have investigated the potential of two classes of thioglucoside analogues of gliflozins as antidiabetic drugs, one with substitutions of S-atoms in meta-positions (similar to C-glucoside SGLT2 inhibitors, TAGs A, B, and C) and the other with substitutions of S-atoms in ortho-positions (similar to O-glucoside SGLT2 inhibitors, TAGs D, E, F, and G). These TAGs were confirmed to show good stability against ß-glucosidase and to have no acute toxicity to cultured cells. Most importantly, TAGs D, E, F, and G all showed high inhibitory activity against SGLT2 (IC50: 2.0-5.9 nM) and thus have great potential to be developed as new gliflozin drugs. Compared with the synthesis of C-glucoside gliflozins, the synthesis of TAGs is simple, efficient, and associated with low costs, high yields, and very mild reaction conditions.

Efficient Synthesis of 2-OH Thioglycosides from Glycals Based on the Reduction of Aryl Disulfides by NaBH4.

An improved method to efficiently synthesize 2-OH thioaryl glycosides starting from corresponding per-protected glycals was developed, where 1,2-anhydro sugars were prepared by the oxidation of glycals with oxone, followed by reaction of crude crystalline 1,2-anhydro sugars with NaBH4 and aryl disulfides. This method has been further used in a one-pot reaction to synthesize glycosyl donors having both "armed" and "NGP (neighboring group participation)" effects.

Concise Synthesis of 1-Thioalkyl Glycoside Donors by Reaction of Per-O-acetylated Sugars with Sodium Alkanethiolates under Solvent-Free Conditions.

A relatively green method for synthesizing 1-thioalkyl glycosides has been developed, where sodium alkanethiolates were used to react with per-O-acetylated sugars instead of odorous alkyl mercaptans in the presence of BF3·Et2O without the use of solvents under mild conditions. Furthermore, we found that 1,2-trans-ß-thioglycosides can be converted into corresponding 1,2-cis-α-thioglycosides in the presence of trifluoromethanesulfonic acid in nonpolar solvents under mild conditions. This provides a simple and efficient new approach for synthesizing challenging 1,2-cis-α-thioglycosides.

Efficient oxygen evolution reaction on RuO2nanoparticles decorated onion-like carbon (OLC).

Oxygen evolution reaction (OER) is an important half-cell reaction of the electrical water splitting, for its high overpotential associated with sluggish OER kinetics. Therefore, it is critical to develop highly active and durable electrocatalysts to reduce the overpotential. Herein, ultra-small RuO2nanoparticles (NPs) supported on onion-like carbon (OLC) and carbon nanotube (CNT) are successfully synthesized by means of wet impregnation combined with annealing treatment, respectively. The microstructure characterization results showed OLC perfect graphitic carbon layer structure, and the RuO2NPs supported on the OLC possess larger particle size compared with the RuO2NPs supported on the CNT. Moreover, the electronic structure of Ru in RuO2/OLC was also optimized by the OLC support to be beneficial for the OER. The OER performance of the catalysts were investigated in 1 M KOH solution. The results show RuO2/OLC has a comparable OER activity to the commercial RuO2, but a significantly higher mass activity than the commercial RuO2. When compared with the RuO2/CNT, RuO2/OLC not only exhibits lower overpotential and Tafel slop, but also owns more active sites and higher TOF value, indicating the OLC support improved the OER activity of RuO2/OLC. Moreover, RuO2/OLC showed a superior stability compared with RuO2/CNT, which can be attributed to the excellent electrochemical oxidation-resistance of the OLC.

Knockdown of Bcl-2-Associated Athanogene-3 Can Enhance the Efficacy of BGJ398 via Suppressing Migration and Inducing Apoptosis in Gastric Cancer.

BACKGROUND: Gastric cancer (GC) is one of the most common malignancies of the digestive tract worldwide, and cancer cell resistance against anticancer drugs remains a major challenge for GC treatment. Nvp-BGJ398 (BGJ398) is considered as a common drug for cancer treatment; however, Bcl-2-associated athanogene-3 (BAG3) plays an important role in drug resistance. AIMS: To investigate the function of BAG3 on the sensitivity of GC cells to BGJ398. METHODS: The expression of BAG3 in GC cells and GC resistance cells was examined by qRT-PCR and western blot. The resistance to BGJ398 was detected by viability assay, and a half-maximal inhibitory concentration (IC50) was calculated. The cell migration and apoptosis were determined by wound-healing assay and flow cytometry assay. RESULTS: BAG3 was highly expressed in drug-resistant cells Fu97R and Snu16R. BAG3 was also associated with sensitivity of Snu16 cells to BGJ398, promoting migration but inhibiting apoptosis. However, knockdown of heat shock transcription factor 1 (HSF1) suppressed BAG3 expression and lowered the sensitivity to BGJ398 in Snu16R cells. Knockdown of BAG3 inhibited tumor growth and cell apoptosis but induced cell apoptosis and amplified the sensitivity to BGJ398 in Snu16R cells, followed by enhancing BGJ398-induced antitumor function in a Snu16R-derived xenograft mouse model. CONCLUSION: The mechanism of resistance to BGJ398 in GC is mediated by BAG3/HSF1, and combined treatment with shBAG3 could improve the efficacy of BGJ398 in GC. Thus, BAG3-targeted therapy improves the antitumor efficacy of BGJ398, which might provide a novel therapeutic strategy for GC.

Helicobacter pylori promote inflammation and host defense through the cagA-dependent activation of mTORC1.

Mechanistic target of rapamycin complex 1 (mTORC1) functions as regulating different cellular processes, including cell growth, proliferation, motility, survival, metabolism, autophagy, and protein transcription. Recently, it also found to be associated with many infections and inflammatory diseases, playing complex roles in pathogens growth and inflammation regulation. However, the regulation mechanism of mTORC1 in gastric epithelial cells and its role in Helicobacter pylori (H. pylori) infection and related gastritis remain unclear. Here, we identified that the phosphorylation of mechanistic target of rapamycin (mTOR) and the expression of DEP domain-containing mTOR-interacting protein (DEPTOR) was increased in gastric mucosa of H. pylori-infected patients and mice, as well as in H. pylori-infected gastric epithelial cells, which were largely depended on H. pylori cagA. The expression of DEPTOR was regulated via mTORC1, but, in turn, inhibited mTORC1. Knockdown mTOR significantly decreased expression and secretion of cytokines tumor necrosis factor-α, interleukin-1ß, and interleukin-6, chemokines CCL7 and CXCL16, and antimicrobial peptide LL37 in vitro, while knockdown DEPTOR had the opposite effect. Similar observations were made using mTOR knockout (KO) mice in vivo, moreover. The gastric inflammation was attenuated, while the bacterial burden was increased in mTOR KO mice during H. pylori infection. These findings supported H. pylori promote gastritis and inhibit bacterial colonization through the cagA-dependent activation of mTORC1.