Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer's disease.

Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer's disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.

Mixed bacterial responses to dust exposure in an A549 eukaryotic co-culture.

Recent studies evaluated the impact of dust exposure on pure and mixed cultures of Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae, and Pseudomonas aeruginosa, revealing increased biofilm formation and altered sensitivities to H2O2. In this study, we examined the impact of lead (Pb), house, road, and combined dust on K. pneumoniae and P. aeruginosa in pure, mixed, or eukaryotic co-culture with human alveolar basal epithelial (A549) cells. Although no impact on pure or mixed culture growth was observed when bacteria were exposed to Pb, house, or road dust, increased biofilm was produced by P. aeruginosa in the presence of 0.8 µg/mL of Pb, while P. aeruginosa and K. pneumoniae both exhibited increased biofilm production in the presence of 100 µg/mL of house, road, and combined dust. When co-cultured with eukaryotic A549 cells, both bacteria demonstrated increased proliferation 6 h post-infection when challenged with house, road, or combined dust. However, when mixed bacteria were co-cultured with A549 cells, P. aeruginosa exhibited a significant ~ 1.5-fold increased proliferation in the presence of 100 µg/mL house, road, or combined dust. In sharp contrast, K. pneumoniae exhibited significantly reduced proliferation, when in mixed (with P. aeruginosa) A-549 co-culture, following exposure to 100 µg/mL house, road, or combined dust. To evaluate whether a host cell inflammatory response contributed to this disparity, NF-κB activation was evaluated in each co-culture infection. K. pneumoniae-A-549 co-culture, treated with 100 µg/mL of combined dust, exhibited no alterations in NF-κB translocation to the nucleus. Further, no differences in cytokine production were observed in the K. pneumoniae A-549 co-culture treated with 100 µg/mL of house dust. Taken together, these data suggest that within the lung environment, mixed infections exposed to dust or dust contaminants could benefit one organism at the expense of the other, independent of the activation of inflammatory pathways.

Guggulsterone for Chemoprevention of Cancer.

Guggulsterone [4, 17(20)-pregnadiene-3, 16-dione] is a plant sterol derived from the gum resin of the tree Commiphora wightii. The gum resin of the guggul tree has been used in traditional medicine for centuries to treat obesity, liver disorders, internal tumors, malignant sores, ulcers, urinary complaints, intestinal worms, leucoderma, sinus, edema and sudden paralytic seizures. Guggulsterone has been shown to modulate the nuclear receptors, farnesoid X receptor, pregnane X receptor, CYP 2b10 gene expression, and the bile salt export pump for cholesterol elimination. Recent research indicates that the active components of gum guggul, E- and Zguggulsterone have the potential to both prevent and treat cancers. Guggulsterone inhibits the growth of a wide variety of tumor cells and induces apoptosis through down regulation of antiapoptotic gene products (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), modulation of cell cycle proteins (cyclin D1 and c-Myc), activation of caspases, inhibition of Akt, and activation of JNK. Guggulsterone modulates the expression of gene products involved in metastasis (MMP-9, COX-2, and VEGF) of tumor cells. Guggulsterone mediates gene expression through the modulation of several transcription factors, including NF-κB, STAT3, C/EBPα, androgen receptor, and glucocorticoid receptors. This review describes the anti-cancer properties, molecular targets, and the apoptotic effects of guggulsterone.