Publications by authors named "Shalonda M Ingram"

Historically, animal models have been routinely used in the characterization of novel chemical entities (NCEs) for various psychiatric disorders. Animal models have been essential in the in vivo validation of novel drug targets, establishment of lead compound pharmacokinetic to pharmacodynamic relationships, optimization of lead compounds through preclinical candidate selection, and development of translational measures of target occupancy and functional target engagement. Yet, with decades of multiple NCE failures in Phase II and III efficacy trials for different psychiatric disorders, the utility and value of animal models in the drug discovery process have come under intense scrutiny along with the widespread withdrawal of the pharmaceutical industry from psychiatric drug discovery.

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Article Synopsis
  • The degeneration of cholinergic neurons in the basal forebrain is linked to cognitive deficits and sleep disturbances in mild cognitive impairment (MCI) and Alzheimer's disease (AD).
  • Currently, acetylcholinesterase inhibitors (AChEIs) are the only FDA-approved treatments targeting these cognitive issues but show limited effects on sleep architecture.
  • A study found that the direct-acting muscarinic receptor agonist xanomeline significantly improved wakefulness and arousal in nonpathologically aged mice, outperforming donepezil, particularly during the active phase of their circadian cycle.
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The dopamine transporter (DAT) is essential for the reuptake of the released neurotransmitter dopamine (DA) in the brain. Psychostimulants, methamphetamine and cocaine, have been reported to induce the formation of DAT multimeric complexes in vivo and in vitro. The interpretation of DAT multimer function has been primarily in the context of compounds that induce structural and functional modifications of the DAT, complicating the understanding of the significance of DAT multimers.

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Background/aims: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that binds to the antioxidant response element(s) (ARE) in target gene promoters, enabling oxidatively stressed cells to respond in order to restore redox homeostasis. Post-translational modifications (PTMs) that mediate activation of Nrf2, in the cytosol and its release from Keap1, have been extensively studied but PTMs that impact its biology after activation are beginning to emerge. In this regard, PTMs like acetylation, phosphorylation, ubiquitination and sumoylation contribute towards the Nrf2 subcellular localization, and its transactivation function.

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Activation of the Hedgehog (Hh) pathway effector GLI1 is linked to tumorigenesis and invasiveness in a number of cancers, with targeting of GLI1 by small molecule antagonists shown to be effective. We profiled a collection of GLI antagonists possessing distinct mechanisms of action for efficacy in phenotypic models of inflammatory and non-inflammatory breast cancer (IBC and non-IBC) that we showed expressed varying levels of Hh pathway mediators. Compounds GANT61, HPI-1, and JK184 decreased cell proliferation, inhibited GLI1 mRNA expression and decreased the number of colonies formed in TN-IBC (SUM149) and TNBC (MDA-MB-231 and SUM159) cell lines.

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Although there is no standard treatment protocol for inflammatory breast cancer (IBC), multi-modality treatment has improved survival. In this study we profiled the NCI approved oncology drug set in a qHTS format to identify those that are efficacious in basal type and ErbB2 overexpressing IBC models. Further, we characterized the sensitivity of an acquired therapeutic resistance model to the oncology drugs.

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