Age-related differences in the response of the brain to dietary melatonin

The aged brain is prone to excessive levels of immune activity, not initiated by an acute response to an extrinsic agent. While dietary melatonin is reported to attenuate the extent of expression of proinflammatory genes, little is known about the extent to which these changes can be translated into altered levels of corresponding proteins. The baseline levels of the proinflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-1 alpha, were greater in older (~29 months old) compared to younger (~7 months old) mouse brains. Acute (3 h) exposure to lipopolysaccharide (LPS) induced activation of nuclear factor kappa B (NF-κB), but not inflammatory cytokines in the brain. The serum level of TNF-α was increased after LPS injection, indicating a systemic immune response to the bacterial cell wall component. Dietary melatonin (40 ppm for 9.3 weeks) did not prevent LPS-induced changes in younger animals but caused an increased systemic TNF-α response in older mice. Melatonin did reduce markers of carbonyl formation in brain proteins of young animals and nitrosylative damage to peptide-bound amino acid residues, in the brains of older animals. Acute LPS challenge did not significantly affect these oxidative markers. Thus, despite lack of clear evidence of attenuation of the NF-κB–cytokine inflammatory trajectory within the CNS by melatonin, this agent did show a protective effect against free radical-initiated injury to amino acid residues within proteins. The results illustrate that previously reported changes in gene expression following melatonin treatment need not be closely paralleled by corresponding changes in protein content.     

Genetic polymorphisms for BDNF,COMT, and APOE do not affect gait or ankle motor control in chronic stroke: A preliminary cross-sectional study

ABSTRACT

Background: Motor deficits after stroke are a primary cause of long-term disability. The extent of functional recovery may be influenced by genetic polymorphisms.

Objectives: Determine the effect of genetic polymorphisms for brain-derived neurotrophic factor (BDNF), catechol-O-methyltransferase (COMT), and apolipoprotein E (APOE) on walking speed, walking symmetry, and ankle motor control in individuals with chronic stroke.

Methods: 38 participants with chronic stroke were compared based upon genetic polymorphisms for BDNF (presence [MET group] or absence [VAL group] of a Met allele), COMT (presence [MET group] or absence [VAL group] of a Met allele), and APOE (presence [ε4+ group] of absence [ε4- group] of ε4 allele). Comfortable and maximal walking speed were measured with the 10-m walk test. Gait spatiotemporal symmetry was measured with the GAITRite electronic mat; symmetry ratios were calculated for step length, step time, swing time, and stance time. Ankle motor control was measured as the accuracy of performing an ankle tracking task.

Results: No significant differences were detected (p ≥ 0.11) between the BDNF, COMT, or APOE groups for any variables.

Conclusions: In these preliminary findings, genetic polymorphisms for BDNF, COMT, and APOE do not appear to affect walking speed, walking symmetry, or ankle motor performance in chronic stroke.     

Chromosomal instability triggers cell death via local signalling through the innate immune receptor Toll

Chromosomal instability (CIN) is a hallmark of cancer and has been implicated in cancer initiation, progression and the development of resistance to traditional cancer therapy. Here we identify a new property of CIN cells, showing that inducing CIN in proliferating Drosophila larval tissue leads to the activation of innate immune signalling in CIN cells. Manipulation of this immune pathway strongly affects the survival of CIN cells, primarily via JNK, which responds to both Toll and TNFα/Eiger. This pathway also activates Mmp1, which recruits hemocytes to the CIN tissue to provide local amplification of the immune response that is needed for effective elimination of CIN cells.