Circulating microRNAs in Huntington's disease: Emerging mediators in metabolic impairment.

Huntington's disease (HD) is a hereditary neurodegenerative disease, with peripheral consequences that negatively contribute to quality of life. Circulating microRNAs (cmiRNAs) are being explored for their roles in intercellular communication and gene expression regulation, which allows gaining insight into the regulation of crosstalk between neuronal and peripheral tissues. Here, we explore the cmiRNA profile of plasma samples from fifteen symptomatic patients, with 40-45 CAG repeats in the HTT gene, and seven healthy matched controls. Isolated miRNAs from plasma samples were run against human miRNome panels, which have sequences for 752 human mature miRNAs. We found that 168 cmiRNAs are altered in symptomatic patients. Considering Bonferroni's correction, miR-877-5p, miR-223-3p, miR-223-5p, miR-30d-5p, miR-128, miR-22-5p, miR-222-3p, miR-338-3p, miR-130b-3p, miR-425-5p, miR-628-3p, miR-361-5p, miR-942 are significantly increased in HD patients as compared with controls. Moreover, after patient's organization according to approved HD scales, miR-122-5p is significantly decreased in HD patients with Unified Huntington's Disease Rating Scale >24, whereas an increase in miR-100-5p levels and a decrease in miR-641 and miR-330-3p levels were recorded when patients were rearranged by Total Functional Capacity. These results suggest that cmiRNA profile could be further modified by disease progression, making cmiRNAs useful as monitoring biomarkers. Analysis of target genes indicated a general overexpression of cmiRNAs implicated in metabolism regulation. Profiling cmiRNA of HD subjects opens the possibility of personalized therapies for different groups of HD patients, based on disease modifiers: regulation of altered pathways might contribute to not only alleviate disease symptoms, but also influence HD progression.

Physical Activity as Healthy Intervention Against Severe Oxidative Stress in Elderly Population.

Severe oxidative stress is a relevant risk factor for major deleterious health-related events in older people and is thought to be an important contributor to age-related disease. Literature has suggested oxidative stress as a therapeutic target for mitigating the biological decline and attenuating the occurrence of adverse clinical events in aged individuals. However, definitive treatments are not known. Regular and moderate physical activity has been proposed as possible intervention for slowing age-related decline. This healthy strategy presents a wide range of beneficial aspects for elderly, from the reduction of morbidity, disability, frailty and mortality rates to treatment of many age-related disorders. Importantly, the global benefits on health are not shared by any other strategies. Nevertheless, the physiological basis by which exercise produces its benefits to the organism is not fully understood. This review summarizes the evidence for the role of physical activity as potential healthy intervention for mitigating the negative aspects of aging through the modulation of the oxidative mechanisms.

Effects of the circadian mutation 'tau' on the Harderian glands of Syrian hamsters.

The Syrian hamster Harderian gland (HG) is an organ continually exposed to oxidative stress caused by high concentrations of porphyric metabolites. According to previous studies, melatonin, which is rhythmically secreted by the pineal gland and tonically produced by the HG, antagonizes the oxidative damage. HGs exhibit a strong gender-dependent correlation between porphyrins, melatonin, and histological appearance. In HGs of both sexes, we have investigated effects of a single gene defect in the circadian clock system (tau mutation) causing a shortened free-running period and an advanced maximum of circulating melatonin. Comparisons were made with wild-type animals, one group of which received daily pharmacological injections of melatonin in late photophase. Changes were observed in histological characteristics, porphyrin content, antioxidant enzyme activities, and damage of proteins and lipids. HGs of tau hamsters showed morphological changes which can be partially interpreted in terms of increased damage. Additionally, tau females exhibited a many-fold augmentation in the percentage of so-called type II cells, which are otherwise typical for the male glands. In tau hamsters of both sexes, major antioxidative enzyme activities (superoxide dismutase, glutathione reductase, and catalase) were markedly enhanced, a presumably compensatory response to increased oxidative stress. Higher oxidative damage in tau HGs was directly demonstrable by a many-fold increase in protein carbonyl. Rises in antioxidative enzymes were also observed upon injections of melatonin; this was, however, not accompanied by changes in protein carbonyl, so that enzyme inductions by the hormone should be understood as protective actions. Our data are not only in accordance with findings on protective effects by melatonin, but also with our earlier observation made in Drosophila that perturbations in the circadian system lead to increased oxidative stress.

Porphyric enzymes in hamster Harderian gland, a model of damage by porphyrins and their precursors. A chronobiological study on the role of sex differences.

The Syrian hamster Harderian gland (HG), representing a highly porphyrogenic organ, was used as a model system for studying physiologically occurring damage of biomolecules by porphyrins and their precursors, phenomena associated with from the pathological situation of porphyrias. The species used exhibits the peculiarity of much higher porphyrogenesis in females than in males, offering possibilities for comparison of effects by different porphyrin levels in one species. Since concentrations of free, and therefore, radical-generating porphyric metabolites are difficult to determine in the presence of high amounts of secreted and crystallizing porphyrins, which are, moreover, mainly surface-reactive, and since indications existed for temporal changes in the oxidative stress caused by these molecules, the following approach was chosen: in HGs of both females and males, activities of the relevant porphyric enzymes, delta-aminolevulinate synthase (ALA-S), delta-aminolevulinate dehydratase (ALA-D) and porphobilinogen deaminase (PBG-D), were determined throughout the circadian cycle. Results were compared with the temporal patterns of lipid peroxidation and protein damage in the same glands. In females, a strong correspondence was observed between protein carbonyl and lipid peroxidation, peaking at the end of both photophase and scotophase; maximal activities of the three porphyric enzymes ALA-S, ALA-D, and PBG-D either coincided or slightly preceded the peaks of oxidative damage. In males, lower enzyme activities, especially in PBG-D, were associated with weakly expressed rhythmicity. Correspondingly, lipid peroxidation was lower and exhibited a smaller rhythm amplitude; protein carbonyl of males showed a temporal pattern differing from that of females, with regard to amplitude and phasing. These data are in agreement with morphological observations demonstrating particularly severe cell damage in the female HG under normal conditions.

Physiological oxidative stress model: Syrian hamster Harderian gland-sex differences in antioxidant enzymes.

The Syrian hamster Harderian gland, a juxtaorbital organ exhibiting marked gender-associated differences in contents of porphyrins and melatonin, was used as a model system for comparing strong (in females) and moderate (in males) physiological oxidative stress. Histological differences showing much higher cell damage in females were studied in conjunction with lipid peroxidation and activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. Lipid peroxidation and enzyme activities were measured throughout the circadian cycle, revealing the importance of dynamical processes in oxidative stress. Especially in lipid peroxidation and in catalase, short-lasting rises exhibited strongest gender differences. Peaks of lipid peroxidation were about three times higher in females, compared to males. Catalase peaks of females exceeded those in males by several hundred-fold. Average levels of superoxide dismutase and glutathione peroxidase were about three or two times higher in females, respectively. A clear-cut diurnally peaking rhythm was found in glutathione peroxidase of females, which was not apparent in males. Glutathione reductase showed differences in time patterns, but less in average activities. The time courses of lipid peroxidation and of protective enzymes are not explained by circulating melatonin, whereas melatonin formed in the Harderian gland should contribute to differences in average levels. Neither damage nor antioxidative defense simply reflect the illumination cycle and are, therefore, not only a consequence of photoreactions.