Life-Course Brain Health as a Determinant of Late-Life Mental Health: American Association for Geriatric Psychiatry Expert Panel Recommendations.

This position statement of the Expert Panel on Brain Health of the American Association for Geriatric Psychiatry (AAGP) emphasizes the critical role of life course brain health in shaping mental well-being during the later stages of life. Evidence posits that maintaining optimal brain health earlier in life is crucial for preventing and managing brain aging-related disorders such as dementia/cognitive decline, depression, stroke, and anxiety. We advocate for a holistic approach that integrates medical, psychological, and social frameworks with culturally tailored interventions across the lifespan to promote brain health and overall mental well-being in aging adults across all communities. Furthermore, our statement underscores the significance of prevention, early detection, and intervention in identifying cognitive decline, mood changes, and related mental illness. Action should also be taken to understand and address the needs of communities that traditionally have unequal access to preventive health information and services. By implementing culturally relevant and tailored evidence-based practices and advancing research in geriatric psychiatry, behavioral neurology, and geroscience, we can enhance the quality of life for older adults facing the unique challenges of aging. This position statement emphasizes the intrinsic link between brain health and mental health in aging, urging healthcare professionals, policymakers, and a broader society to prioritize comprehensive strategies that safeguard and promote brain health from birth through later years across all communities. The AAGP Expert Panel has the goal of launching further activities in the coming months and years.

Novel STAT3 small-molecule inhibitors identified by structure-based virtual ligand screening incorporating SH2 domain flexibility.

Efforts to develop STAT3 inhibitors have focused on its SH2 domain starting with short phosphotyrosylated peptides based on STAT3 binding motifs, e.g. pY905LPQTV within gp130. Despite binding to STAT3 with high affinity, issues regarding stability, bioavailability, and membrane permeability of these peptides, as well as peptidomimetics such as CJ-887, have limited their further clinical development and led to interest in small-molecule inhibitors. Some small molecule STAT3 inhibitors, identified using structure-based virtual ligand screening (SB-VLS); while having favorable drug-like properties, suffer from weak binding affinities, possibly due to the high flexibility of the target domain. We conducted molecular dynamic (MD) simulations of the SH2 domain in complex with CJ-887, and used an averaged structure from this MD trajectory as an "induced-active site" receptor model for SB-VLS of 110,000 compounds within the SPEC database. Screening was followed by re-docking and re-scoring of the top 30% of hits, selection for hit compounds that directly interact with pY + 0 binding pocket residues R609 and S613, and testing for STAT3 targeting in vitro, which identified two lead hits with good activity and favorable drug-like properties. Unlike most small-molecule STAT3 inhibitors previously identified, which contain negatively-charged moieties that mediate binding to the pY + 0 binding pocket, these compounds are uncharged and likely will serve as better candidates for anti-STAT3 drug development. IMPLICATIONS: SB-VLS, using an averaged structure from molecular dynamics (MD) simulations of STAT3 SH2 domain in a complex with CJ-887, a known peptidomimetic binder, identify two highly potent, neutral, low-molecular weight STAT3-inhibitors with favorable drug-like properties.

Toward better drug repositioning: prioritizing and integrating existing methods into efficient pipelines.

Recycling old drugs, rescuing shelved drugs and extending patents' lives make drug repositioning an attractive form of drug discovery. Drug repositioning accounts for approximately 30% of the newly US Food and Drug Administration (FDA)-approved drugs and vaccines in recent years. The prevalence of drug-repositioning studies has resulted in a variety of innovative computational methods for the identification of new opportunities for the use of old drugs. Questions often arise from customizing or optimizing these methods into efficient drug-repositioning pipelines for alternative applications. It requires a comprehensive understanding of the available methods gained by evaluating both biological and pharmaceutical knowledge and the elucidated mechanism-of-action of drugs. Here, we provide guidance for prioritizing and integrating drug-repositioning methods for specific drug-repositioning pipelines.

Identification of small molecule inhibitors of neurite loss induced by Aß peptide using high content screening.

Multiple lines of evidence indicate a strong relationship between Αß peptide-induced neurite degeneration and the progressive loss of cognitive functions in Alzheimer disease (AD) patients and in AD animal models. This prompted us to develop a high content screening assay (HCS) and Neurite Image Quantitator (NeuriteIQ) software to quantify the loss of neuronal projections induced by Aß peptide neurons and enable us to identify new classes of neurite-protective small molecules, which may represent new leads for AD drug discovery. We identified thirty-six inhibitors of Aß-induced neurite loss in the 1,040-compound National Institute of Neurological Disorders and Stroke (NINDS) custom collection of known bioactives and FDA approved drugs. Activity clustering showed that non-steroidal anti-inflammatory drugs (NSAIDs) were significantly enriched among the hits. Notably, NSAIDs have previously attracted significant attention as potential drugs for AD; however their mechanism of action remains controversial. Our data revealed that cyclooxygenase-2 (COX-2) expression was increased following Aß treatment. Furthermore, multiple distinct classes of COX inhibitors efficiently blocked neurite loss in primary neurons, suggesting that increased COX activity contributes to Aß peptide-induced neurite loss. Finally, we discovered that the detrimental effect of COX activity on neurite integrity may be mediated through the inhibition of peroxisome proliferator-activated receptor γ (PPARγ) activity. Overall, our work establishes the feasibility of identifying small molecule inhibitors of Aß-induced neurite loss using the NeuriteIQ pipeline and provides novel insights into the mechanisms of neuroprotection by NSAIDs.

Bioluminescence imaging of heme oxygenase-1 upregulation in the Gua Sha procedure.

Gua Sha is a traditional Chinese folk therapy that employs skin scraping to cause subcutaneous microvascular blood extravasation and bruises. The protocol for bioluminescent optical imaging of HO-1-luciferase transgenic mice reported in this manuscript provides a rapid in vivo assay of the upregulation of the heme oxygenase-1 (HO-1) gene expression in response to the Gua Sha procedure. HO-1 has long been known to provide cytoprotection against oxidative stress. The upregulation of HO-1, assessed by the bioluminescence output, is thought to represent an antioxidative response to circulating hemoglobin products released by Gua Sha. Gua Sha was administered by repeated strokes of a smooth spoon edge over lubricated skin on the back or other targeted body part of the transgenic mouse until petechiae (splinter hemorrhages) or ecchymosis (bruises) indicative of extravasation of blood from subcutaneous capillaries was observed. After Gua Sha, bioluminescence imaging sessions were carried out daily for several days to follow the dynamics of HO-1 expression in multiple internal organs.

MeCP2, a key contributor to neurological disease, activates and represses transcription.

Mutations in the gene encoding the transcriptional repressor methyl-CpG binding protein 2 (MeCP2) cause the neurodevelopmental disorder Rett syndrome. Loss of function as well as increased dosage of the MECP2 gene cause a host of neuropsychiatric disorders. To explore the molecular mechanism(s) underlying these disorders, we examined gene expression patterns in the hypothalamus of mice that either lack or overexpress MeCP2. In both models, MeCP2 dysfunction induced changes in the expression levels of thousands of genes, but unexpectedly the majority of genes (approximately 85%) appeared to be activated by MeCP2. We selected six genes and confirmed that MeCP2 binds to their promoters. Furthermore, we showed that MeCP2 associates with the transcriptional activator CREB1 at the promoter of an activated target but not a repressed target. These studies suggest that MeCP2 regulates the expression of a wide range of genes in the hypothalamus and that it can function as both an activator and a repressor of transcription.

Characteristic of hypothalamic kisspeptin expression in the pubertal development of precocious female rats.

To investigate the potential role of kisspeptin in the advance onset of puberty in precocious puberty, model rats induced by danazol were used to study the developmental expression of hypothalamic kisspeptin. Kisspeptin immunoreactive cells were observed in the arcuate nucleus (ARC), periventricular nucleus (PeN) and preoptic area (POA) in model rats on the day of onset-puberty. On the day of post-puberty, however, the number of kisspeptin immunoreactive cells in ARC and PeN decreased while the number of those cells in POA increased. Kisspeptin immunoreactive cells were not detected in hypothalamus in both normal and model rats at their pre-puberty stages. Furthermore, the expression of hypothalamic Kiss-1 mRNA reached top on the day of onset-puberty in both of the normal and model rats, and the expression of Kiss-1 mRNA increased significantly in the model rats compared with those in the normal ones. Our results indicated that kisspeptin might involve in the advance onset of puberty in danazol induced female precocious model rats.

Automated neurite extraction using dynamic programming for high-throughput screening of neuron-based assays.

High-throughput screening (HTS) of cell-based assays has recently emerged as an important tool of drug discovery. The analysis and modeling of HTS microscopy neuron images, however, is particularly challenging. In this paper we present a novel algorithm for extraction and quantification of neurite segments from HTS neuron images. The algorithm is designed to be able to detect and link neurites even with complex neuronal structures and of poor imaging quality. Our proposed algorithm automatically detects initial seed points on a set of grid lines and estimates the ending points of the neurite by iteratively tracing the centerline points along the line path representing the neurite segment. The live-wire method is then applied to link the seed points and the corresponding ending points using dynamic programming techniques, thus enabling the extraction of the centerlines of the neurite segments accurately and robustly against noise, discontinuity, and other image artifacts. A fast implementation of our algorithm using dynamic programming is also provided in the paper. Any thin neurite and its segments with low intensity contrast can be well preserved by detecting the starting and ending points of the neurite. All these properties make the proposed algorithm attractive for high-throughput screening of neuron-based assays.

A computerized cellular imaging system for high content analysis in Monastrol suppressor screens.

In this paper, we describe a new bioimage informatics system developed for high content screening (HCS) applications with the goal to extract and analyze phenotypic features of hundreds of thousands of mitotic cells simultaneously. The system introduces the algorithm of multi-phenotypic mitotic analysis (MMA) and integrates that with algorithms of correlation analysis and compound clustering used in gene microarray studies. The HCS-MMA system combines different phenotypic information of cellular images obtained from three-channel acquisitions to distinguish and label individual cells at various phases of mitosis. The proposed system can also be used to extract and count the number of cells in each phase in cell-based assay experiments and archive the extracted data into a structured database for more sophisticated statistical and data analysis. To recognize different mitotic phases, binary patterns are set up based on a known biological mitotic spindle model to characterize cellular morphology of actin, microtubules, and DNA. To illustrate its utility, the HCS-MMA system has been applied to screen the quantitative response of 320 different drug compounds in suppressing Monastrol. The results are validated and evaluated by comparing the performance of HCS-MMA with visual analysis, as well as clustering of the drug compounds under evaluation.