Discovery of Novel Bruton's Tyrosine Kinase PROTACs with Enhanced Selectivity and Cellular Efficacy.

Bruton's tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases, and several BTK inhibitors are already approved for use in humans. Heterobivalent BTK protein degraders are also in development, based on the premise that proteolysis targeting chimeras (PROTACs) may provide additional therapeutic benefits. However, most BTK PROTACs are based on the BTK inhibitor ibrutinib raising concerns about their selectivity profiles, given the known off-target effects of ibrutinib. Here, we disclose the discovery and in vitro characterization of BTK PROTACs based on the selective BTK inhibitor GDC-0853 and the cereblon recruitment ligand pomalidomide. PTD10 is a highly potent BTK degrader (DC50 0.5 nM) that inhibited cell growth and induced apoptosis at lower concentrations than the two parent molecules, as well as three previously reported BTK PROTACs, and had improved selectivity compared to ibrutinib-based BTK PROTACs.

Nickel-catalyzed Enantioselective Hydroarylation and Hydroalkenylation of Styrenes.

We have developed a Ni-catalyzed enantioselective hydroarylation of styrenes with arylboronic acids using MeOH as the hydrogen source, providing an efficient method to access 1,1-diarylalkanes, which are essential structural units in many biologically active compounds. In addition, Ni-catalyzed enantioselective hydrovinylation of styrenes with vinylboronic acids is also realized with good yields and enantioselectivities. The synthetic utility was demonstrated by the efficient synthesis of ( R)-(-)-ibuprofen.

Palladium-catalyzed C-H activation/C-C cross-coupling reactions via electrochemistry.

Palladium-catalyzed C-H activation/C-C cross-coupling reactions typically require stoichiometric chemical oxidants and exogenous ligands. However, there are significant disadvantages associated with the use of traditional stoichiometric oxidants. To overcome these issues, we have developed an electrochemical strategy to achieve methylation and acylation.

A novel non­contact communication between human keratinocytes and T cells: Exosomes derived from keratinocytes support superantigen­induced proliferation of resting T cells.

It is widely accepted that keratinocytes act as non­professional antigen­presenting cells and support superantigen­induced proliferation of resting T cells; however, it remains unknown whether keratinocytes function in situ with T cells via a non­contact mechanism. The current study used a transwell co­culture system and demonstrated, for the first time to the best of the authors' knowledge, that HaCaT cells (the human keratinocyte cell line) did induce T cell proliferation via indirect contact. The data further indicated that exosomes, small membrane vesicles that transfer antigens to recipient cells, are also involved in the superantigen­associated immunity of keratinocytes. The current study provided experimental evidence that HaCaT­exosomes contained MHC I and II, and could interact with T cells. In addition, following interferon γ stimulation, Staphylococcal aureus enterotoxin B­loaded HaCaT cells secreted exosomes to induce the proliferation of CD4+ and CD8+ T cells in vitro. This novel biological function of exosomes reveals a new mechanism of how keratinocytes participate in bacterial superantigen­induced immune responses.

Palladium-Catalyzed C(sp2)-H Acetoxylation via Electrochemical Oxidation.

Palladium-catalyzed arene C(sp2)-H acetoxylation has emerged as a powerful tool to construct a carbon-oxygen (C-O) bond. However, the requirement of stoichiometric chemical oxidants for this transformation possesses a significant disadvantage. To solve this fundamental problem, we now report an anodic oxidation strategy to achieve arene C(sp2)-H acetoxylation.

Palladium-Catalyzed C(sp3)-H Oxygenation via Electrochemical Oxidation.

Palladium-catalyzed C-H activation/C-O bond-forming reactions have emerged as attractive tools for organic synthesis. Typically, these reactions require strong chemical oxidants, which convert organopalladium(II) intermediates into the PdIII or PdIV oxidation state to promote otherwise challenging C-O reductive elimination. However, previously reported oxidants possess significant disadvantages, including poor atom economy, high cost, and the formation of undesired byproducts. To overcome these issues, we report an electrochemical strategy that takes advantage of anodic oxidation of PdII to induce selective C-O reductive elimination with a variety of oxyanion coupling partners.

Excitatory pathways from the vestibular nuclei to the NTS and the PBN and indirect vestibulo-cardiovascular pathway from the vestibular nuclei to the RVLM relayed by the NTS.

Previous studies have confirmed the existence of vestibulo-sympathetic pathways in the central nervous system. However, the exact pathways and neurotransmitters underlying this reflex are unclear. The present study was undertaken to investigate whether the vestibulo-cardiovascular responses are a result of activated glutamate receptors in the caudal vestibular nucleus. We also attempt to verify the indirect excitatory pathways from the vestibular nucleus (VN) to the rostral ventrolateral medulla (RVLM) using a tracing method combined with a vesicular glutamate transporter (VGluTs) immunofluorescence. In anesthetized rats, unilateral injection of l-glutamate (5 nmol) into the medial vestibular nucleus (MVe) and spinal vestibular nucleus (SpVe) slightly increased the mean arterial pressure (MVe: 93.29+/-11.58 to 96.30+/-11.66, SpVe: 91.72+/-15.20 to 95.48+/-17.16). Local pretreatment with the N-methyl-D-aspartate (NMDA)-receptor antagonist MK-801 (2 nmol) significantly attenuated the pressor effect of L-glutamate injected into the MVe compared to the contralateral self-control. After injection of biotinylated dextran amine (BDA) into the MVe and SpVe, and fluorogold (FG) into the RVLM, some BDA-labeled fibres and terminals in the nucleus of solitary tract (NTS) and the parabrachial nucleus (PBN) were immunoreactive for VGluT1 and VGluT2. Several BDA-labeled fibres were closely apposed to FG-labeled neurons in the NTS. These results suggested that activation of caudal vestibular nucleus neurons could induce pressor response and NMDA receptors might contribute to this response in the MVe. The glutamatergic VN-NTS and VN-PBN pathways might exist, and the projections from the VN to the RVLM relayed by the NTS comprise an indirect vestibulo-cardiovascular pathway in the brain stem.

Glutamatergic vestibular neurons express Fos after vestibular stimulation and project to the NTS and the PBN in rats.

In this study, retrograde tracing method combined with phosphate-activated glutaminase (PAG) and Fos immunofluorescence histochemistry was used to identify glutamatergic vestibular nucleus (VN) neurons receiving vestibular inputs and projecting to the nucleus of the solitary tract (NTS) and the parabrachial nucleus (PBN). Conscious animals were subjected to 120 min Ferris-wheel like rotation stimulation. Neuronal activation was assessed by Fos expression in the nucleus of VN neurons. After Fluoro-gold (FG) injection into the caudal NTS, approximately 48% FG-labeled VN neurons were immunoreactive for PAG, and about 14% PAG/FG double-labeled neurons co-existed with Fos. Following FG injection into the PBN, approximately 56% FG-labeled VN neurons were double-labeled with PAG, and about 12% of the PAG/FG double-labeled neurons also expressed Fos. Careful examination of the typology and distribution pattern of these PAG-immunoreactive neurons indicated that the vast majority of these neurons were glutamatergic rather than GABAergic. These results suggest that PAG-immunoreactive VN neurons might constitute excitatory glutamatergic VN-NTS and VN-PBN transmission pathways and these pathways might be involved in vestibulo-autonomic reflexes during vestibular stimulation.