Long Term Running Biphasically Improves Methylglyoxal-Related Metabolism, Redox Homeostasis and Neurotrophic Support within Adult Mouse Brain Cortex

Oxidative stress and neurotrophic support decline seem to be crucially involved in brain aging. Emerging evidences indicate the pro-oxidant methylglyoxal (MG) as a key player in the age-related dicarbonyl stress and molecular damage within the central nervous system. Although exercise promotes the overproduction of reactive oxygen species, habitual exercise may retard cellular aging and reduce the age-dependent cognitive decline through hormetic adaptations, yet molecular mechanisms underlying beneficial effects of exercise are still largely unclear. In particular, whereas adaptive responses induced by exercise initiated in youth have been broadly investigated, the effects of chronic and moderate exercise begun in adult age on biochemical hallmarks of very early senescence in mammal brains have not been extensively studied. This research investigated whether a long-term, forced and moderate running initiated in adult age may affect the interplay between the redox-related profile and the oxidative-/MG-dependent molecular damage patterns in CD1 female mice cortices; as well, we investigated possible exercise-induced effects on the activity of the brain derived neurotrophic factor (BDNF)-dependent pathway. Our findings suggested that after a transient imbalance in almost all parameters investigated, the lately-initiated exercise regimen strongly reduced molecular damage profiles in brains of adult mice, by enhancing activities of the main ROS- and MG-targeting scavenging systems, as well as by preserving the BDNF-dependent signaling through the transition from adult to middle age

A Novel Approach to Treat a Rare Case of Interprosthetic Humeral Fracture with Osteosynthesis and Combined Grafting: A Case Report and Review of the Literature

Interprosthetic humeral fractures (IHFs) are severe injury patterns associated with surgical issues and contradictory results. The knowledge and literature on this topic are still lacking. A 76 year-old woman was treated for a fracture occurred between the shoulder and elbow stemmed prosthesis. Severe bone loss was associated with the fracture. Treatment: Open reduction, plate fixation, and bone grafting were considered. A xenograft (used as a mechanical strut medially), a synthetic graft associated with bone growth factors, and scaffolds improved the bone healing process. Satisfactory clinical and radiological outcomes were obtained. A scoping review of the literature was also performed by the authors. Only eight papers reported IHFs with a low level of evidence. In total, eight patients were treated; one paper that reported on biomechanical aspects using finite element analysis is discussed. Conservative treatment leads to non-union, and the surgical approach is the gold standard. The osteosynthesis technique associated with bone grafting leads to the best outcomes. The use of a xenograft mechanical strut, associated with synthetic biological bone grafting, led to complete bone union at 9 months follow-up. Larger cohorts, more standardised results, and multicentric studies are mandatory in order to improve and establish a management and treatment algorithm

Neurotrophic support in brains of mice undergoing a long-term moderate treadmill running.

<p>Western immunoblot against the activated high affinity tyrosinekinase B receptor (p-TrkB) in brain cortices of adult CD1 female mice undergoing a two- or four-month moderate and regular treadmill-based exercise program (E2 or E4, respectively); age-matched sedentary animals (S2, S4) were used as controls (n = 6 per group). Significant age-dependent reductions in the protein amounts of p-TrkB (S4 vs S2) were detected. Two months of exercise caused a conspicuous decrease in the expression levels of p-TrkB, with respect to age-matched unexercised mice (E2 vs S2), whereas protein levels of the activated receptor were significantly elevated after four-month physical activity, when compared to sedentary animals (E4 vs S4). Immunosignals were normalized against the housekeeping β-actin. In the lower sections, representative PVDF-western immunoblots of three independent experiments are reported. Values were given as means ± std. dev. The level of statistical significance was computed by using two-way ANOVA and post-hoc Newman-Keuls test: ** P<0.01; *** P<0.001. Experiments were performed in triplicate.</p

Brain molecular damage of mice undergoing a long-term moderate treadmill running.

<p>Thiobarbituric acid-reactive substances (TBARS, panel a) levels and protein carbonyl content (PCC, panel b) in cortices of mice undergoing a two- or four-month moderate and regular treadmill-based exercise program (E2 or E4, respectively); age-matched sedentary animals (S2, S4) were used as controls (n = 6 per group). No significant age-dependent change was observed in cortical TBARS concentrations (S4 vs S2), while two months of exercise elevated significantly TBARS amounts (E2 vs S2). Four-month exercised and unexercised mice showed similar TBARS levels (E4 vs S4). The PCC increased in an age-dependent manner (S4 vs S2). Two months of exercise elevated PCC, in comparison to sedentary animals (E2 vs S2). Conversely, PCC content was significantly reduced in four-month-exercised mice, when compared to age-matched unexercised animals (E4 vs S4). Values were given as means ± std. dev. The level of statistical significance was computed by using two-way ANOVA and post-hoc Newman-Keuls test: *** P<0.001; ** P<0.01. Experiments were performed in triplicate.</p

Methylglyoxal-related enzymatic removal and molecular damage in brains of mice undergoing a long-term moderate treadmill running.

<p>Immunoreactivity levels against arg-pyrimidine (arg-pyr, panel a) and specific activities of glyoxalase 1 (GLO1, panel b) and glyoxalase 2 (GLO2, panel c) in brain cortices of adult CD1 female mice undergoing a two- or four-month moderate and regular treadmill-based exercise program (E2 or E4, respectively); age-matched sedentary animals (S2, S4) were used as controls (n = 6 per group). Dot blot assays revelead an age-dependent increase in the levels of MG-damaged proteins (S4 vs S2). No significant variation of MG-damaged polypeptides was detected after two months of exercise (E2 vs S2), while immunoreactivity against MG-modified arginine residues decreased markedly after four-month physical activity, with respect to age-matched unexercised mice (E4 vs S4). Immunosignals were normalized against the Coomassie Brilliant Blue (CBB)-based total protein staining. In the panel a, right section, representative PVDF-dot immunoblots of three independent experiments are reported, together with analyses for total protein loading performed by the ImageJ software. Both GLO1 and GLO2 specific activities increased in an age-dependent manner (S4 vs S2). The exercise program elevated GLO2 activity exclusively after two months of regular exercise (E2 vs S2), whereas GLO1 specific activity was increased only after four months of physical activity (E4 vs S4). Values were given as means ± std. dev. The level of statistical significance was computed by using two-way ANOVA and post-hoc Newman-Keuls test: * P<0.05; *** P<0.001. Experiments were performed in triplicate.</p

Antioxidant enzymatic defense in brains of mice undergoing a long-term moderate treadmill running.

<p>Specific activities of superoxide dismutase (SOD) (panel a), catalase (CAT) (panel b) and glutathione peroxidase (GPX) (panel c) in brain cortices of adult CD1 female mice undergoing a two- or four-month moderate and regular treadmill-based exercise program (E2 or E4, respectively); age-matched sedentary animals (S2, S4) were used as controls (n = 6 per group). No major age-dependent variation of tSOD and CAT specific activities was revealed; however, a significant increase in GPX activity was detected when comparing S4 and S2. Two-month physical activity reduced specific activities of tSOD, CAT and GPX catalytic capacities (E2 vs S2), whereas four-month exercise triggered a significant elevation of tSOD and CAT (E4 vs S4). Values were given as means ± std. dev. The level of statistical significance was computed by using two-way ANOVA and post-hoc Newman-Keuls test: * P<0.05; ** P<0.01; *** P<0.001. Experiments were performed in triplicate.</p

Neurotrophic support in brains of mice undergoing a long-term moderate treadmill running.

<p>Western immunoblot against the brain derived neurotrophic factor (BDNF) (panel a) and the phosphorilated cAMP response element binding (p-CREB) transcriptional activator (panel b) in brain cortices of adult CD1 female mice undergoing a two- or four-month moderate and regular treadmill-based exercise program (E2 or E4, respectively); age-matched sedentary animals (S2, S4) were used as controls (n = 6 per group). A significant age-dependent variation in BDNF protein expression was detected (S4 vs S2). BDNF levels were also significantly reduced in two-month exercised mice (E2 vs S2), yet strongly enhanced in four-month exercised mice (E4 vs S4), with respect to age-matched counterparts. Significant age-dependent reductions in the protein levels of p-CREB (S4 vs S2). Two months of exercise caused a conspicuous decrease in p-CREB protein levels (E2 vs S2), whereas p-CREB protein amounts increased after four months of regular running (E4 vs S4), with respect to age-matched unexercised mice. Immunosignals were normalized against the housekeeping β-actin. Representative PVDF-western immunoblots of three independent experiments are reported. Values were given as means ± std. dev. The level of statistical significance was computed by using two-way ANOVA and post-hoc Newman-Keuls test: * P<0.05; ** P<0.01; *** P<0.001. Experiments were performed in triplicate.</p

Glutathione-related status in brains of mice undergoing a long-term moderate treadmill running.

<p>Specific activity of glutathione reductase (GR) (panel a) and balance of the glutathione redox couple (panel b) in brain cortices of adult CD1 female mice undergoing a two- or four-month moderate and regular treadmill-based exercise program (E2 or E4, respectively); age-matched sedentary animals (S2, S4) were used as controls (n = 6 per group). No significant age-dependent change in GR activity could be observed (S4 vs S2). Two-month physical activity caused a marked increase in GR activity (E2 vs S2), while no statistical differences were found when comparing GR specific activities between E4 and S4 groups. No significant age-dependent change was observed in the total vs oxidized GSH ratio (S4 vs S2). Both two and four months of exercise caused a marked decrease of the total vs disulfide glutathione ratio (E2 vs S2 and E4 vs S4). Values were given as means ± std. dev. The level of statistical significance was computed by using two-way ANOVA and post-hoc Newman-Keuls test: *** P<0.001. Experiments were performed in triplicate.</p