Autologous organoid co-culture model reveals T cell-driven epithelial cell death in Crohn's Disease.

Lympho-epithelial interactions between intestinal T resident memory cells (Trm) and the epithelium have been associated with inflammatory bowel disease (IBD) activity. We developed ex vivo autologous organoid-mucosal T cell cocultures to functionally assess lymphoepithelial interactions in Crohn's Disease (CD) patients compared to controls. We demonstrate the direct epithelial cell death induced by autologous mucosal T cells in CD patients but not in controls.

Thiol-Based Potent and Selective HDAC6 Inhibitors Promote Tubulin Acetylation and T-Regulatory Cell Suppressive Function.

Several new mercaptoacetamides were synthesized and studied as HDAC6 inhibitors. One compound, 2b, bearing an aminoquinoline cap group, was found to show 1.3 nM potency at HDAC6, with >3000-fold selectivity over HDAC1.

Poly(ADP-ribose) polymerase 1 is a novel target to promote axonal regeneration.

Therapeutic options for the restoration of neurological functions after acute axonal injury are severely limited. In addition to limiting neuronal loss, effective treatments face the challenge of restoring axonal growth within an injury environment where inhibitory molecules from damaged myelin and activated astrocytes act as molecular and physical barriers. Overcoming these barriers to permit axon growth is critical for the development of any repair strategy in the central nervous system.

Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin.

Aims: Pharmacological activation of the adaptive response to hypoxia is a therapeutic strategy of growing interest for neurological conditions, including stroke, Huntington's disease, and Parkinson's disease. We screened a drug library with known safety in humans using a hippocampal neuroblast line expressing a reporter of hypoxia-inducible factor (HIF)-dependent transcription.

Results: Our screen identified more than 40 compounds with the ability to induce hypoxia response element-driven luciferase activity as well or better than deferoxamine, a canonical activator of hypoxic adaptation.

Chromatin modifications associated with DNA double-strand breaks repair as potential targets for neurological diseases.

The integrity of the genome is continuously challenged by both endogenous and exogenous DNA damaging agents. Neurons, due to their post-mitotic state, high metabolism, and longevity are particularly prone to the accumulation of DNA lesions. Indeed, DNA damage has been suggested as a major contributor to both age-associated neurodegenerative diseases and acute neurological injury.

Specific acetylation of p53 by HDAC inhibition prevents DNA damage-induced apoptosis in neurons.

Histone deacetylase (HDAC) inhibitors have been used to promote neuronal survival and ameliorate neurological dysfunction in a host of neurodegenerative disease models. The precise molecular mechanisms whereby HDAC inhibitors prevent neuronal death are currently the focus of intensive research. Here we demonstrate that HDAC inhibition prevents DNA damage-induced neurodegeneration by modifying the acetylation pattern of the tumor suppressor p53, which decreases its DNA-binding and transcriptional activation of target genes.

Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A.

Structure-based drug design combined with homology modeling techniques were used to develop potent inhibitors of HDAC6 that display superior selectivity for the HDAC6 isozyme compared to other inhibitors. These inhibitors can be assembled in a few synthetic steps, and thus are readily scaled up for in vivo studies. An optimized compound from this series, designated Tubastatin A, was tested in primary cortical neuron cultures in which it was found to induce elevated levels of acetylated alpha-tubulin, but not histone, consistent with its HDAC6 selectivity.

HDAC6 is a target for protection and regeneration following injury in the nervous system.

Central nervous system (CNS) trauma can result in tissue disruption, neuronal and axonal degeneration, and neurological dysfunction. The limited spontaneous CNS repair in adulthood and aging is often insufficient to overcome disability. Several investigations have demonstrated that targeting HDAC activity can protect neurons and glia and improve outcomes in CNS injury and disease models.

Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke.

Achieving therapeutic efficacy in ischemic stroke represents one of the biggest challenges in translational neurobiology. Despite extensive efforts, tissue plasminogen activator remains the only available intervention for enhancing functional recovery in humans once a stroke has occurred. To expand the repertoire of therapeutic options in stroke, one must consider and target its diverse pathophysiologies that trigger cell loss in a manner that also permits and enhances neuronal plasticity and repair.

Quantitative gene expression profiling of mouse brain regions reveals differential transcripts conserved in human and affected in disease models.

Using serial analysis of gene expression, we collected quantitative transcriptome data in 11 regions of the adult wild-type mouse brain: the orbital, prelimbic, cingulate, motor, somatosensory, and entorhinal cortices, the caudate-putamen, the nucleus accumbens, the thalamus, the substantia nigra, and the ventral tegmental area. With >1.2 million cDNA tags sequenced, this database is a powerful resource to explore brain functions and disorders.