Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory Impairment.

Brain pathological changes impair cognition early in disease etiology. There is an urgent need to understand aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2 is a mitochondrial-resident protein regulating Ca2+ fluxes to and from mitochondria impacting overall health. We previously reported that Tusc2-/- female mice develop chronic inflammation and age prematurely, causing age- and sex-dependent spatial memory deficits at 5 months old. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in 4-month-old mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2-/- female mice demonstrated a pro-inflammatory increase in astrocytes, expression of IFN-γ in CD4+ T cells and Granzyme-B in CD8+T cells. We also found fewer FOXP3+ T-regulatory cells and Ly49G+ NK and Ly49G+ NKT cells in female Tusc2-/- brains, suggesting a dampened anti-inflammatory response. Moreover, Tusc2-/- hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2+ dynamics. Overall, the data suggest that dysregulation of Ca2+-dependent processes and a heightened pro-inflammatory brain microenvironment in Tusc2-/- mice could underlie cognitive impairment. Thus, strategies to modulate the mitochondrial Tusc2- and Ca2+- signaling pathways in the brain should be explored to improve cognitive health.

Dual STAT­3 and IL­6R inhibition with stattic and tocilizumab decreases migration, invasion and proliferation of prostate cancer cells by targeting the IL­6/IL­6R/STAT­3 axis.

Prostate cancer (PCa) is a key public health problem worldwide; at diagnosis, a high percentage of patients exhibit tumor cell invasion of adjacent tissue. STAT­3, IL­6 receptor (R) and IL­6 serum levels are associated with enhanced PCa migratory, invasive, clonogenic and metastatic ability. Inhibiting the STAT­3 pathway at different levels (cytokines, receptors, and kinases) exhibits relative success in cancer. The present study investigated the effect of Stattic (Stt) + Tocilizumab (Tcz) on proliferative, clonogenic, migratory and invasive ability of human metastatic PCa (assessed by colony formation, wound healing and migration assay). RWPE­1 (epithelial prostate immortalized cells), 22Rv1 (Tumor cells), LNCaP (Metastatic cells) and DU­145 (metastatic, castration­resistant prostate cells) cells were used in vitro to evaluate levels of cytokines, chemokines, growth factors (Cytometric Bead Array), STAT­3, phosphorylated STAT­3 (In­Cell Western), IL­6R, vimentin and epithelial (E­) cadherin (Western Blot). The effect of inhibition of STAT­3 (expressed constitutively in DU­145 cells) with Stt and/or Tcz on expression levels of vimentin, VEGF, and E­cadherin, as well as proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells was assessed. The expression levels of IL­6, C­X­C chemokine ligand 8, VEGF and vimentin, as well as proliferation and migration, were increased in metastatic PCa cells. Treatment with Stt or Tcz decreased vimentin and VEGF and increased E­cadherin expression levels and inhibited proliferative, clonogenic, migratory and invasive capacity of DU­145 cells; addition of IL­6 decreased this inhibitory effect. However, Stt + Tcz maintained inhibition even in the present of high concentrations of IL­6. Stt + Tcz decreased expression of vimentin and VEGF and inhibited the proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells. To the best of our knowledge, the present study is the first to combine Stt, a STAT­3 inhibitor, with Tcz, an antibody against IL­6R, to target tumor cells.

Low-dose endosulfan inhibits proliferation and induces senescence and pro-inflammatory cytokine production in human lymphocytes, preferentially impacting cytotoxic cells.

Endosulfan is a DDT-era organochlorine pesticide. Due to past and current environmental contamination, investigation of endosulfan exposure is of current importance. Acute high dose exposure precipitates neural/endocrine system damage, but the effects on the immune system and of lower doses are not well-characterized. Two relatively low concentrations of endosulfan (i.e. 0.1 and 17 µM ENDO) were investigated in an in vitro study using human peripheral blood mononuclear cells (PBMC) to understand effects of relatively low doses (0.1-25.0 µM [≈0.04-10 ppm/40-10,000 ppb]) of ENDO upon normal human T- and B-lymphocytes and NK cells. The study here found that 17 µM ENDO inhibited phytohemagglutinin-M (PHA)-induced human PBMC proliferation. It was also seen that senescence and apoptosis among non-stimulated cells was increased, specifically within CD8 and NK populations, and that CD4:CD8 ratios also were increased. Treatment of non-stimulated PBMC with ENDO led to overall increases in production of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, -4, and -6, and decreased production of anti-inflammatory IL-10, suggesting an immunosenescence secretory phenotype. Interestingly, when the cells were pre-stimulated with mitogen (PHA), ENDO became inhibitory against the mitogen-induced proliferation and cytokine formation - with the exception of that of TNFα and IL-6, suggesting differential effects of ENDO on activated cells. Thus, at the organismal level, ENDO might also display differential effects during states of autoimmune disease or chronic viral infection in the exposed host.