No abstract

T helper (Th)17 cells, a subset of CD4 T lymphocytes, have strong pro-inflammatory property and appear to be essential in the pathogenesis of many inflammatory diseases. However, the involvement of Th17 cells in Parkinson's disease (PD) that is characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the nigrostriatal system is unclear. Here, we aimed to demonstrate that Th17 cells infiltrate into the brain parenchyma and induce neuroinflammation and DAergic neuronal death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 1-methyl-4-phenylpyridinium (MPP)-induced PD models. Blood-brain barrier (BBB) disruption in the substantia nigra (SN) was assessed by the signal of FITC-labeled albumin that was injected into blood circulation via the ascending aorta. Live cell imaging system was used to observe a direct contact of Th17 cells with neurons by staining these cells using the two adhesion molecules, leukocyte function-associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, respectively. Th17 cells invaded into the SN where BBB was disrupted in MPTP-induced PD mice. Th17 cells exacerbated DAergic neuronal loss and pro-inflammatory/neurotrophic factor disorders in MPP-treated ventral mesencephalic (VM) cell cultures. A direct contact of LFA-1-stained Th17 cells with ICAM-1-stained VM neurons was dynamically captured. Either blocking LFA-1 in Th17 cells or blocking ICAM-1 in VM neurons with neutralizing antibodies abolished Th17-induced DAergic neuronal death. These results establish that Th17 cells infiltrate into the brain parenchyma of PD mice through lesioned BBB and exert neurotoxic property by promoting glial activation and importantly by a direct damage to neurons depending on LFA-1/ICAM-1 interaction.

PI3K/AKT signaling is known to regulate cancer metabolism, but whether metabolic feedback regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal crosstalk between the PI3K/AKT signal and pentose phosphate pathway (PPP) branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of the PPP, by inhibiting the newly identified E3 ligase TIRM21 and promotes the PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of the AKT inhibitor PHLDA3. Knockout of TRIM21 or PHLDA3 promotes crosstalk and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of the PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of this reciprocal crosstalk mechanism may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.

Objective: Gut microbiota-produced trimethylamine Noxide (TMAO) is a risk factor for cardiovascular events. However, conflicting findings regarding the link between plasma TMAO level and prognosis for patients with heart failure have been reported. We examined the association of plasma TMAO concentration with risk of major adverse cardiac events (MACEs) and all-cause mortality in patients with heart failure. Study design: Meta-analysis of prospective clinical studies. Data sources: We searched electronic databases (PubMed, EMBASE) for published prospective studies examining associations between plasma TMAO level and MACEs and all-cause mortality in adults with heart failure. Data synthesis: Hazard ratios (HRs) with 95% confidence intervals for associations between TMAO level and outcomes were estimated in random effects models. In seven eligible studies including a total of 6879 patients (median follow-up, 5.0 years) and adjusted for multiple risk factors, higher plasma TMAO level was associated with greater risks of MACEs (TMAO tertile 3 v tertile 1: