NeuroImmune pharmacology and therapeutics最新文献

SARS-CoV-2 has, since its emergence in 2019, become a global pandemic. Disease outcomes are worsened in older patients who are infected. The causes for this is multifactorial, but one potential cause for this disparity is increased rates of cellular senescence in older individuals, particularly in immune cells. Cellular senescence, the accumulation of factors resulting in cell growth arrest and apoptosis resistance, increases as individuals age. In immune cells, senescence is associated with increased inflammation, and alterations in immune response. We utilized a co-culture system consisting of senescent or non-senescent macrophages directly cultured with fibroblasts, and infected with SARS-CoV-2. We assessed the expression of collagen and fibronectin, important molecules in the extracellular matrix, as well as a number of fibrogenic factors. We observed that infection with SARS-CoV-2 induced collagen production in co-cultures with senescent, but not non-senescent macrophages. Fibronectin expression was decreased in both co-culture conditions. While significant results were not observed, concentrations of other fibrogenic molecules were consistent with the collagen results. These data demonstrate that senescence in macrophages alters the production of fibrotic molecules from fibroblasts in a SARS-CoV-2 infection model. As collagen and fibronectin expression are generally directly correlated, this suggests that senescence dysregulates fibrogenesis in response to infection with SARS-CoV-2. There is a need to further investigate the mechanisms for these changes.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and this study underlines the significance of a small molecule glyceryl tribenzoate (GTB), a FDA approved food additive, in preventing parkinsonian pathologies in MPTP-induced animal models. The study conducted in MPTP-induced mice demonstrated dose-dependent protection of nigral tyrosine hydroxylase (TH) and striatal dopamine level by GTB oral treatment and the optimum dose was found to be 50 mg/kg/d. In the next phase, the study was carried out in MPTP-injected hemiparkinsonian monkeys, which recapitulate better clinical parkinsonian syndromes. GTB inhibited MPTP-driven induction of glial inflammation, which was evidenced by reduced level of GTP-p21^Ras and phospho-p65 in SN of monkeys. It led to decreased expression of inflammatory markers such as IL-1β and iNOS. Simultaneously, GTB oral treatment protected nigral TH cells, striatal dopamine, and improved motor behaviour of hemiparkinsonian monkeys. Presence of sodium benzoate, a GTB metabolite and a FDA-approved drug for urea cycle disorders and glycine encephalopathy, in the brain suggests that the neuroprotective effect imparted by GTB might be mediated by sodium benzoate. Although the mechanism of action of GTB is poorly understood, the study sheds light on the therapeutic possibility of a food additive GTB in PD.

Objectives: Interferon Regulatory Factors (IRFs) regulate transcription of type-I interferons (IFNs) and IFN-stimulated genes. We previously reported that IFN-regulatory factor 7 (IRF7) is significantly upregulated in the brain of HIV-1 transgenic (HIV-1Tg) rats compared to F344 control rats in a region dependent manner [Li MD, Cao J, Wang S, Wang J, Sarkar S, Vigorito M, et al. Transcriptome sequencing of gene expression in the brain of the HIV-1 transgenic rat. PLoS One 2013]. The RNA deep-sequencing data were deposited in the NCBI SRA database with Gene Expression Omnibus (GEO) number GSE47474. Our current study utilized QIAGEN CLC Genomics Workbench and Ingenuity Pathway Analysis (IPA) to identify molecular pathways underlying the involvement of IRF7 in the HIV antiviral response.

Methods: The differential RNA expression data between HIV-1Tg and F344 rats as well as HAND+ and HIV+ cognitively normal patients was collected from GSE47474 and GSE152416, respectively. The "Core Expression Data Analysis" function identified the significant canonical pathways in the datasets with or without IRF7 and its 455 associated molecules.

Results: It was found that IRF7 and its 455 associated molecules altered the expression of pathways involving neurotransmission, neuronal survival, and immune function.

Conclusions: This in-silico study reveals that IRF7 is involved in the promotion of macrophage activity, neuronal differentiation, the modulation of the Th-1/Th-2 ratio, and the suppression of HIV-1 translation. Furthermore, we demonstrate that bioinformatics tools such as IPA can be employed to simulate the complete knockout of a target molecule such as IRF7 to study its involvement in biological pathways.