Photo-Induced In Situ Generation of Brønsted Acid for Catalytic Friedel-Crafts Alkylation of Indoles.

A photo-induced indole 2-alkylation reaction was developed with unactivated stereo-congested alkenes used as the Friedel-Crafts alkylation reagent. The neutral, traceless and inexpensive perfluoroalkyl iodide C4 F9 I was used as the radical initiator in catalytic amount under irradiation by a blue LED light. Brønsted acids are in situ generated from the radical transfer reactions between the indole substrates and the perfluoroiodide catalyst. A variety of 2-branched alkylated indole molecules could be obtained from this approach in generally good efficiencies, with a broad scope of functional groups well tolerated. Mechanistic studies via both experimental and computational methods indicate that the reaction was accelerated by the protons generated from the crack of the indole-derived radical cation species.

Fabrication of Host-Guest Complexes between Adamantane-Functionalized 1,3,4-Oxadiazoles and ß-Cyclodextrin with Improved Control Efficiency against Intractable Plant Bacterial Diseases.

Supramolecular chemistry provides huge potentials and opportunities in agricultural pest management. In an attempt to develop highly bioactive, eco-friendly, and biocompatible supramolecular complexes for managing intractable plant bacterial diseases, herein, a type of interesting adamantane-functionalized 1,3,4-oxadiazole was rationally prepared to facilitate the formation of supramolecular complexes via ß-cyclodextrin-adamantane host-guest interactions. Initial antibacterial screening revealed that most of these adamantane-decorated 1,3,4-oxadiazoles were obviously bioactive against three typically destructive phytopathogens. The lowest EC50 values could reach 0.936 (III18), 0.889 (III18), and 2.10 (III19) µg/mL against the corresponding Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas axonopodis pv. citri (Xac), and Pseudomonas syringae pv. actinidiae (Psa). Next, the representative supramolecular binary complex III18@ß-CD (binding mode 1:1) was successfully fabricated and characterized by 1H nuclear magnetic resonance (NMR), isothermal titration calorimetry (ITC), high-resolution mass spectrometry (HRMS), dynamic light scattering (DLS), and transmission electron microscopy (TEM). Eventually, correlative water solubility and foliar surface wettability were significantly improved after the formation of host-guest assemblies. In vivo antibacterial evaluation found that the achieved supramolecular complex could distinctly alleviate the disease symptoms and promote the control efficiencies against rice bacterial blight (from 34.6-35.7% (III18) to 40.3-43.6% (III18@ß-CD)) and kiwi canker diseases (from 41.0-42.3% (III18) to 53.9-68.0% (III18@ß-CD)) at 200 µg/mL (active ingredient). The current study can provide a feasible platform and insight for constructing biocompatible supramolecular assemblies for managing destructive bacterial infections in agriculture.

Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation.

Despite anti-TNF therapy advancements for inflammatory diseases such as rheumatoid arthritis, the burden of diseases remains high. An 11-mer TNF peptide, TNF70-80, is known to stimulate selective functional responses compared to the parent TNF molecule. Here, we show that TNF70-80 binds to the TNF receptor, activating p38 MAP kinase through TNF receptor-associated factor 2. Using truncated TNFR mutants, we identify the sequence in TNFRI which enables p38 activation by TNF70-80. Peptides with this TNFRI sequence, such as TNFRI206-211 bind to TNF and inhibit TNF-induced p38 activation, respiratory burst, cytokine production and adhesion receptor expression but not F-Met-Leu-Phe-induced respiratory burst in neutrophils. TNFRI206-211 does not prevent TNF binding to TNFRI or TNF-induced stimulation of ERK, JNK and NF-κB. TNFRI206-211 inhibits bacterial lipopolysaccharide-induced peritonitis, carrageenan-induced and antigen-induced paw inflammation, and respiratory syncytial virus-induced lung inflammation in mice. Our findings suggest a way of targeting TNF-p38 pathway to treat chronic inflammatory disorders.

A role for the phosphatidylinositol 3-kinase--protein kinase C zeta--Sp1 pathway in the 1,25-dihydroxyvitamin D3 induction of the 25-hydroxyvitamin D3 24-hydroxylase gene in human kidney cells.

The molecular mechanisms that underlie non-genomic induction of the 25-hydroxyvitamin D3 24-hydroxylase (CYP24) gene promoter by the steroid hormone, 1,25-Dihydroxyvitamin D3 (1,25D), are poorly understood. Although we have previously identified a functional inverted GC-box in the early promoter at -113/-105 bp, it is not known whether this site is important for 1,25D induction of the promoter. Using transfected human embryonic kidney (HEK) 293T cells, we now report the functional characterisation of the GC-box and that 1,25D induction of the promoter requires PI3-kinase, PKCzeta and Sp1 but not Sp3. The data show that 1,25D rapidly stimulates PI3-kinase activity which is required for the activation of PKCzeta and the phosphorylation of Sp1. The effects of the PI3-kinase inhibitor, LY294002, and a dominant negative PKCzeta mutant on 1,25D induction of wild-type and a GC-box mutated CYP24 promoter constructs are consistent with the Sp1 site being the target of both kinases. However, these kinases are not required for basal expression of the CYP24 promoter. The data establish a novel non-genomic mechanism which couples 1,25D to the induction of CYP24 gene transcription via the PI3-kinase--PKCzeta--Sp1 pathway acting through the GC-box.

Novel action of n-3 polyunsaturated fatty acids: inhibition of arachidonic acid-induced increase in tumor necrosis factor receptor expression on neutrophils and a role for proteases.

OBJECTIVE: Neutrophils and tumor necrosis factor (TNF) play important roles in the pathogenesis of rheumatoid arthritis (RA). Modulation of TNF receptors (TNFRs) may contribute to the regulation of tissue damage, and n-6 polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA) can increase the expression of TNFRI and TNFRII on neutrophils. Because the n-3 PUFAs are antiinflammatory in RA, we examined whether, as a novel mechanism of action, n-3 PUFAs can antagonize the AA-induced increase in TNFR expression. METHODS: Human neutrophils were treated with PUFAs and examined for changes in surface expression of TNFRs by flow cytometry. Translocation of protein kinase C (PKC) and activation of ERK-1/2 MAPK were determined by Western blotting. Intracellular calcium mobilization was measured in Fura 2-loaded cells by luminescence spectrometry. RESULTS: Pretreatment of neutrophils with nanomolar levels of n-3 PUFAs, eicosapentaenoic acid, or docosahexaenoic acid led to a marked inhibition of the AA-induced up-regulation of TNFRs I and II. Such pretreatment, however, did not prevent AA from stimulating the activities of PKC and ERK-1/2, which is required for the actions of AA or its ability to mobilize Ca(2+). Nevertheless, treatment with n-3 PUFAs caused the stimulation of serine proteases that could cleave the TNFRs. CONCLUSION: These findings suggest a mechanism by which the n-3 PUFAs inhibit the inflammatory response in RA, by regulating the ability of AA to increase TNFR expression. These results help fill the gaps in our knowledge regarding the mechanisms of action of n-3 PUFAs, thus allowing us to make specific recommendations for the use of n-3 PUFAs in the regulation of inflammatory diseases.