Hormetic Effects of Binaphthyl Phosphonothioates as Pro-oxidants and Antioxidants.

Organophosphorous compounds with such a wide variety in structure, application, and biochemical activities include pesticides, herbicides, nerve agents, medicines, reagents in organic chemistry, and additives for polymers. Binaphthyl phosphono-, phosphorothioates, and their derivatives, are useful chiral catalysts for various asymmetric reactions and are expected to act as heavy metal scavengers. In this study, we aimed to evaluate the neurotoxicity and biochemical properties of a new series of binaphthyl phosphonothioates called KK compounds using the mouse hippocampal HT22 cells. Despite negligible structural difference, the compounds exhibited differential general cytotoxic activity which was independent of acetylcholine esterase inhibition; on the other hand, all compounds tested prevented endogenous oxidative stress by suppressing generation of reactive oxygen species. Among them, KK397, KK387, KK410, and KK421 showed hormesis, i.e., biphasic dose responses to endogenous oxidative stress, characterized by beneficial effect at low dose and toxic effect at high dose. At cytotoxic concentrations, these compounds were potent radical generators and activated intracellular signaling molecules such as the p38 mitogen-activated protein kinase, c-Jun NH2-terminal kinase, growth arrest- and DNA damage-inducible gene 153, X-box binding protein 1, and heme oxygenase 1, which are preferentially activated by cell stress-inducing signals, including oxidative and endoplasmic reticulum stress. These findings indicated that novel binaphthyl phosphonothioates can exhibit multiple biochemical properties, functioning as antioxidants and/or pro-oxidants, depending on the concentration, and chemical modification of binaphthyl organophosphorus compounds endowed them with unique characteristics and multiple beneficial functions.

CAR-expressing NK cells for cancer therapy: a new hope.

Since the approval in 2017 and the amazing achievement of Kymriah and Yescarta, the number of basic researchers and clinical trials investigating the safety and efficacy of chimeric antigen receptor-expressing T cells (CAR-T cells) has been relentlessly increasing. Up to now, more than 200 clinical trials are listed on clinical trial database of NIH and the basic research is countless. However, the production of allogeneic CAR-T cells products is still expensive and has toxicity. Thus, more effort is needed to develop reliable off-the-shelf cellular therapeutic methods with safety and efficiency for the treatment of patients with cancer. As a kind of innate effector lymphocyte with potent antitumor activity, natural killer cells (NK cells) have attracted much attention. Until now, basic and clinical research has shown that chimeric antigen receptor-expressing NK cell (CAR-NK) therapy may play a significant anti-tumor role and its safety is higher than CAR-T cell therapy. In this review, we discuss advantages and shortages of employing CAR-NK cells as a novel cellular therapy against cancer.

Chemoselective and Stereoselective Alcoholysis of Binaphthyl Phosphonothioates: Straightforward Access to Both Stereoisomers of Biologically Relevant P-Stereogenic Phosphonothioates.

P-Stereogenic phosphonothioates have attracted great attention due to their potent biological activities as analogues of phosphoric acids and phosphorothioates. We demonstrate here straightforward access to P-stereogenic phosphonothioates through the use of binaphthyl phosphonothioates as a chiral template. The first-step alcoholysis of binaphthyl phosphonothioates proceeded via a transfer of the axial chirality of a binaphthyl group to the central chirality of a phosphorus atom to give only monoalcohol adducts with moderate to excellent diastereoselectivities. Further alcoholysis of the obtained products in the presence of a small excess of alcohol and base proceeded with complete elimination of a binaphthyl group to give the corresponding P-stereogenic phosphonothioates with high enantiomeric excess. A DFT study of the reaction mechanisms in first-step alcoholysis indicated that the coordination of a sulfur atom to a sodium cation is the key factor in controlling the diastereoselectivities. This method can be applied to prepare both stereoisomers of a G6P analogue with high diastereomeric purity.

Stem cell secretome as a new booster for regenerative medicine.

Stem cells are an undifferentiated cell population that has the ability to develop into many different cell types and also has the ability to repair damaged tissues in some cases. For a long time, the stem cell regenerative paradigm has been based on the assumption that progenitor cells play a critical role in tissue repair by means of their plasticity and differentiation potential. However, recent works suggest that the mechanism underlying the benefits of stem cell transplantation might relate to a paracrine modulatory effect rather than the replacement of affected cells at the site of injury. This paracrine modulatory effect derives from secretome which comprises a diverse host of growth factors, cytokines, chemokines, angiogenic factors, and exosomes which are extracellular vesicles that are produced in the endosomal compartment of most eukaryotic cells and are from about 30 to several hundred nanometers in diameter. The role of these factors is being increasingly recognized as key to the regulation of many physiological processes including leading endogenous and progenitor cells to sites of injury as well as mediating apoptosis, proliferation, migration, and angiogenesis. In reality, the immunomodulatory and paracrine role of these factors may mainly account for the therapeutic effects of stem cells and a number of in vitro and in vivo researches have proved limited stem cell engraftment at the site of injury. As a cell-free way for regenerative medicine therapies, stem cell secretome has shown great potential in a variety of clinical applications including prevention of cardiac disfunction, neurodegenerative disease, type 1 diabetes, hair loss, tumors, and joint osteoarthritis.

Hydrolysis of Phosphonothioates with a Binaphthyl Group: P-Stereogenic O-Binaphthyl Phosphonothioic Acids and Their Use as Optically Active Ligands and Chiral Discriminating Agents.

The hydrolysis of phosphonothioates with a binaphthyl group afforded the first example of O-(2'-hydroxy)binaphthyl phosphonothioic acids in good to high yields and >95:5 diastereoselectivity. The reaction proceeds via an axis-to-center chirality-transfer reaction. The ability of these acids to act as chiral molecular auxiliaries was demonstrated by using them as optically active ligands for the asymmetric ethylation of benzaldehyde and as a chiral discriminating agent for chiral aliphatic amines.

Evidence for species-dependent biosynthetic pathways for converting carlactone to strigolactones in plants.

Strigolactones (SLs), comprising compounds with diverse but related chemical structures, are determinant signals in elicitation of germination in root parasitic Orobanchaceae and in mycorrhization in plants. Further, SLs are a novel class of plant hormones that regulate root and shoot architecture. Dissecting common and divergent biosynthetic pathways of SLs may provide avenues for modulating their production in planta. Biosynthesis of SLs in various SL-producing plant species was inhibited by fluridone, a phytoene desaturase inhibitor. The plausible biosynthetic precursors of SLs were exogenously applied to plants, and their conversion to canonical and non-canonical SLs was analysed using liquid chromatography-tandem mass spectrometry. The conversion of carlactone (CL) to carlactonoic acid (CLA) was a common reaction in all investigated plants. Sorghum converted CLA to 5-deoxystrigol (5-DS) and sorgomol, and 5-DS to sorgomol. One sorgomol-producing cotton cultivar had the same SL profile as sorghum in the feeding experiments. Another cotton cultivar converted CLA to 5-DS, strigol, and strigyl acetate. Further, 5-DS was converted to strigol and strigyl acetate. Moonseed converted CLA to strigol, but not to 5-DS. The plant did not convert 5-DS to strigol, suggesting that 5-DS is not a precursor of strigol in moonseed. Similarly, 4-deoxyorobanchol was not a precursor of orobanchol in cowpea. Further, sunflower converted CLA to methyl carlactonoate and heliolactone. These results indicated that the biosynthetic pathways of hydroxy SLs do not necessarily involve their respective deoxy SL precursors.