Piezo1 suppression reduces demyelination after intracerebral hemorrhage.

Piezo1 is a mechanically-gated calcium channel. Recent studies have shown that Piezo1, a mechanically-gated calcium channel, can attenuate both psychosine- and lipopolysaccharide-induced demyelination. Because oligodendrocyte damage and demyelination occur in intracerebral hemorrhage, in this study, we investigated the role of Piezo1 in intracerebral hemorrhage. We established a mouse model of cerebral hemorrhage by injecting autologous blood into the right basal ganglia and found that Piezo1 was largely expressed soon (within 48 hours) after intracerebral hemorrhage, primarily in oligodendrocytes. Intraperitoneal injection of Dooku1 to inhibit Piezo1 resulted in marked alleviation of brain edema, myelin sheath loss, and degeneration in injured tissue, a substantial reduction in oligodendrocyte apoptosis, and a significant improvement in neurological function. In addition, we found that Dooku1-mediated Piezo1 suppression reduced intracellular endoplasmic reticulum stress and cell apoptosis through the PERK-ATF4-CHOP and inositol-requiring enzyme 1 signaling pathway. These findings suggest that Piezo1 is a potential therapeutic target for intracerebral hemorrhage, as its suppression reduces intracellular endoplasmic reticulum stress and cell apoptosis and protects the myelin sheath, thereby improving neuronal function after intracerebral hemorrhage.

Vitamin E administration erases an enhanced oxidation in multiple sclerosis.

Systemic peroxidation status has been reported as a pathogenic factor for multiple sclerosis (MS). Systemically elevated oxidation levels are associated with serum lipid peroxidation and somatic telomere length (TL) shortening. We investigated whether vitamin E (VE) administration suppresses peroxidation and improves clinical symptoms in 34 MS patients. We analyzed serum lipid peroxidation and degree of TL in circulating leukocytes of MS patients before and after VE treatment. The oxidation level was enhanced and TL was shortened in MS. The MS population treated with VE 400 mg/day for 3 months showed significantly reduced serum lipid oxidation level with maintenance of TL. These findings showed that systemic peroxidation is associated with the development of MS. Antioxidants such as vitamin E can be candidates for supplementary therapeutic agents for MS.

Patients with multiple sclerosis show increased oxidative stress markers and somatic telomere length shortening.

Lipid peroxidation due to oxidative stress (OS) may play an important role in the pathogenesis of chronic systemic inflammatory diseases such as multiple sclerosis (MS). Telomeres, repeated sequences that cap chromosome ends, undergo shortening with each cycle of cell division, resulting in cellular senescence. Research regarding telomere shortening has provided novel insight into the pathogenesis of various diseases. We hypothesized that OS damage leads to inflammatory reactions, which subsequently shortens the telomere length in MS. We enrolled 59 patients with MS, and age- and gender-matched 60 healthy controls. We divided MS subjects into three groups matched for age and gender according to the severity of disability: relatively benign course (BMS), secondary progressive MS, and primary progressive MS (PPMS). We analyzed the telomere length in peripheral blood mononuclear cells and the 8-iso-PGF2α concentration in urine, a reliable and stable marker of lipid peroxidation in vivo. The data showed significant higher levels of urinary 8-iso-PGF2α in MS subjects than in the controls. The lag-time, which represents the direct measurement of the resistance of low-density lipoprotein to oxidation, was shorter in the PPMS subjects than in the groups. Compared to that observed in the controls, the mean telomere length was significantly shorter in the PPMS group, whereas no significant telomere shortening was found between the controls and other subjects. Our data suggest that a decreased telomere length and enhanced lipid peroxidation reflects the severest stage of MS.

[Correlation between lacunar cerebral infarction and serum uric acid level in elderly male hypertension patients].

OBJECTIVE: To study the correlation between lacunar cerebral infarction and level of serum uric acid in elderly male hypertension patients. METHODS: Ninety-eight elderly male hypertension patients were enrolled in this study. They all underwent cerebral magnetic resonance imaging (MRI) scan, and their clinical and laboratory data were collected. The patients were divided into the 1st group (n = 32), the 2nd group (n = 32) and the 3rd group (n = 34) according to the level of serum uric acid. RESULTS: The numbers of lacuner infarction, serum creatinine, urea and high density lipoprotein(HDL) were significantly diferrent from the other groups. The numbers of lacuner infarction were positively related with serum uric acid and urea. Multiple variant analysis showed that serum uric acid was the independent factor of the numbers of lacuner infarction. CONCLUSION: The elevated level of serum uric acid may contribute to the risk factors of lacuner infarction.

Changes in telomere length distribution in low-dose X-ray-irradiated human umbilical vein endothelial cells.

Ionizing radiation (IR) is known to be a cause of telomere dysfunction in tumor cells; however, very few studies have investigated X-ray-related changes in telomere length and the telomerase activity in normal human cells, such as umbilical vein endothelial cells (HUVECs). The loss of a few hundred base pairs from a shortened telomere has been shown to be important with respect to cellular senescence, although it may not be detected according to traditional mean telomere length [assessed as the terminal restriction fragment (TRF)] analyses. In the present study, a continuous time window from irradiation was selected to examine changes in the telomere length, including the mean TRF length, percentage of the telomere length, telomerase activity, apoptotic rate, and survival rate in HUVECs from the first day to the fourth day after the administration of a 0.5-Gy dose of irradiation. The mean TRF length in the irradiated HUVECs showed shorter telomere length in first 3 days, but they were not statistically significant. On the other hand, according to the percentage analysis of the telomere length, a decreasing tendency was noted in the longer telomere lengths (9.4-4.4 kb), with a significant increase in the shortest telomeres (4.4-2.3 kb) among the irradiated cells versus the controls from the first day to the third after irradiation; no significant differences were noted on the fourth day. These results suggest that the shortest telomeres are sensitive to the late stage of radiation damage. The proliferation of irradiated cells was suppressed after IR in contrast to the non-irradiated cells. The apoptotic rate was elevated initially both in IR- and non-IR-cells, but that of IR-cells was maintained at an elevated level thereafter in contrast to that of non-IR-cells decreasing promptly. Therefore, a 0.5-Gy dose of IR induces persistent apoptosis leading to an apparent growth arrest of the normal HUVECs.

Analysis of telomere length and subtelomeric methylation of circulating leukocytes in women with Alzheimer's disease.

BACKGROUNDS AND AIMS: Telomere attrition proceeds with the aging process, and is also associated with aging disease conditions, such as Alzheimer's disease (AD). The aging process also affects subtelomeric methylation status. In the present study, the telomere length and the subtelomeric methylation status in female AD patients were analyzed to see how AD affects telomere structure. METHODS: Terminal restriction fragment length of 23 AD patients' peripheral leukocytes was analyzed with methylation sensitive- and insensitive-isoschizomer by Southern blot. RESULTS: AD patients were found to have normal mean telomere lengths (controls; 6.4 ± 0.9 kb, AD; 6.1 ± 0.8 kb, p = 0.131), a proportionally decreased number of the longest telomeres (>9.4 kb) (controls; 30.3 ± 7.9%, AD; 24.4 ± 8.3%, p = 0.013), increased medium-sized telomeres (controls; 51.7 ± 3.3%, AD 55.5 ± 6.4%, p = 0.015) and unchanged numbers of the shortest telomeres (<4.4 kb) (controls; 18.0 ± 7.8, AD; 20.2 ± 8.9%, p = 0.371) in their peripheral leukocytes. The subtelomeres of telomeres in the shortest range (<4.4 kb) were more methylated in AD subjects than in controls (controls; 0.21 ± 0.23, AD; 0.41 ± 0.26, p = 0.016). CONCLUSIONS: These results may indicate that AD contributes to the loss of cells bearing the shortest telomeres, with hypomethylation of subtelomeres occurring in addition to telomere attrition, resulting in an apparent normal mean telomere length in AD patients. The relatively high subtelomeric methylation status of the shortest telomeres in peripheral blood leukocytes may be a characteristic of AD. This report demonstrates that the epigenetic status of the telomeric region is affected by disease conditions.

Different levels of hypoxia regulate telomere length and telomerase activity.

This study was designed to identify changes in telomere length and telomerase activity in human umbilical vein endothelial cells (HUVECs) exposed to various levels of hypoxia. Mild hypoxia (10%, 15% oxygen) increased telomere length, which did not appear to change under severe hypoxia (1% oxygen). Telomerase activity in HUVECs correlated inversely with oxygen concentration. Endothelial cell telomere elongation with telomerase activation in conditions of mild hypoxia was demonstrated in this study. High telomerase activity may contribute to hypoxia-related telomere elongation. The best cell growth and longest telomere length were observed at 10% O(2), and this percentage may therefore be the optimal level for maintaining vascular endothelial cells. In addition, elevated telomerase activity maintains telomere length within normal range in conditions of severe hypoxia (1% O(2)). The telomere length distribution in HUVECs under hypoxia seems to be regulated by a balance between telomere attrition by hypoxia and telomere elongation by enhanced telomerase activity acting on telomeres, perhaps in a telomere-length dependent manner.

The Subtelomere of Short Telomeres is Hypermethylated in Alzheimer's Disease.

Telomere shortening has been reported to be related to oxidative stress (OS) associated with the aging process and aging-associated diseases, including Alzheimer's disease (AD). We measured the methylated and non-methylated telomere lengths in the peripheral blood mononuclear cells of 34 AD patients and 49 healthy controls by a Southern blotting analysis, using methylation-sensitive and - insensitive restriction enzyme isoschizomers, MspI and HpaII. AD patients bore normal mean telomere lengths and had an unchanged distribution of the telomere length in peripheral leukocytes. However, the subtelomeres in the shortest telomeres were relatively more methylated in AD patients of both genders, compared with age-matched controls. We observed that the pathogenesis of AD was associated with the epigenetic condition of the subtelomere, but not on the overall telomere length and distribution. The relative elevation of subtelomeric methylation of short telomeres in peripheral blood leukocytes may be a characteristic of AD. This implies that leukocytes containing short telomeres with less methylated subtelomeres tend to be removed faster from the peripheral blood in AD patients.

[Neuropsychological features of elderly patients with mild cognitive impairment susceptible to Alzheimer's disease].

OBJECTIVE: To explore the neuropsychological features of elderly patients with mild cognitive impairment (MCI) susceptible to Alzheimer's disease (AD). METHODS: A total of 47 patients with MCI diagnosed from June to October 2008 and 21 controls with normal cognition at the same convalescent camp were selected and followed up for two years. Montreal cognitive assessment (MoCA), mini mental state examination (MMSE) and clock drawing test (CDT) were performed for all subjects at the onset of study and repeated annually. RESULTS: At Month 12, the visuospatial skill scores of MCI patients decreased significantly versus those of the control (0.6 ± 0.7 vs 0.1 ± 0.6, P = 0.008). No one progressed to AD in neither groups. And at Month 24, both visuospatial skill scores (0.9 ± 0.9 vs 0.4 ± 0.9) and attention scores (1.0 ± 1.0 vs 0.2 ± 0.8) of MCI patients declined significantly versus the control (P = 0.021, 0.001). Among 47 MCI patients, 7 progressed to AD. No obvious difference existed in the score of all items between the AD converters and non-converters at baseline. However, the scores of MMSE (27.6 ± 0.8 vs 28.9 ± 1.0), MoCA (24.3 ± 3.1 vs 27.9 ± 1.6) and such MoCA subitems as visuospatial skill (3.9 ± 0.7 vs 4.5 ± 0.6), language (1.86 ± 0.38 vs 2.65 ± 0.53) and delayed recall (2.1 ± 1.5 vs 3.9 ± 1.0) of the converters were obviously lower than those of the non-converters at Month 12 (P < 0.05). Furthermore, all other scores of the AD converters, except for designation and abstract, were significantly lower than those of the non-converters at Month 24 (P < 0.05). CONCLUSION: The visuospatial skill, executive function, delayed recall and language function of MCI patients progressing to AD tend to have early impairment and significant changes. It may be useful to predict AD among the MCI patients.

Alteration of telomere length and subtelomeric methylation in human endothelial cell under different levels of hypoxia.

BACKGROUND AND AIMS: Hypoxia-associated changes of telomeric structure in cell cultures have been analyzed mainly in cancer cells, stem cells, or cells transduced with vectors containing the telomerase gene, but not in somatic cells. The stability of telomere structure has been reported to be associated with subtelomeric methylation status. However, there are no reports of epigenetic alterations of telomeric regions of human somatic cells under hypoxia. This study aims at detecting and analyzing the subtelomeric methylation status in human somatic cells cultured under hypoxia. METHODS: Mean telomere length and telomerase activity of human umbilical vein endothelial cells (HUVECs) cultured in hypoxic conditions were measured. Subtelomeric methylation status of these cells was assessed by genomic Southern blot with telomere DNA probe using methylation-sensitive and -insensitive isoschizomers, MspI and HpaII. RESULTS: The telomerase activity in HUVECs correlated inversely with the oxygen concentration. Mild hypoxia (10 or 15% oxygen) increased the telomere lengths, whereas the telomere lengths did not appear to change when <1% O(2). The subtelomere of the shortest telomere range was methylated the most at 1% O(2). CONCLUSIONS: Subtelomeric hypermethylation of short telomeres at 1% O(2) compared to milder hypoxia implied that the subtelomeric hypermethylation may yield telomere stability and favor the cell survival of short telomere-bearing cells.

Effect of vitamin E administration on the elevated oxygen stress and the telomeric and subtelomeric status in Alzheimer's disease.

BACKGROUND: Oxidative stress (OS) may be involved in the neurodegenerative process in Alzheimer's disease (AD). Telomeres, the repeated sequences that cap chromosome ends, undergo shortening with each cell division, are sensitive to OS, and serve as markers of a cell's replicative history. Telomere length shortening has been reported to relate to OS with aging process and aging-associated diseases, but the telomeric changes were not always identical, especially in change of telomere length distribution and subtelomeric methylation. The involvement of an OS-associated telomere change in the pathogenesis of AD has been discussed for decades, and the telomere length and telomerase activity were analyzed. However, other telomeric factors, such as the telomere distribution and subtelomeric methylation status, have not yet been analyzed. OBJECTIVE: The subtelomeric methylation status as well as the telomere length were studied in AD with an antioxidant vitamin in terms of OS. METHODS: We measured urinary 8-iso-PGF2α, a lipid-peroxidation product as an OS marker, and methylated and non-methylated telomere lengths in the peripheral blood mononuclear cells by Southern blotting in AD patients before and after vitamin E treatment. RESULTS: The level of urinary 8-iso-PGF2α was found to have increased in AD. Middle-ranged telomeres (4.4-9.4 kb) increased and the shortest telomeres (<4.4 kb) decreased in AD patients. Telomeres were more methylated in both long telomeres and in short telomeres in AD compared with the control. The oral administration of the antioxidant vitamin E in 400 mg/day for 6 months in AD patients partly reversed AD-associated alterations in OS marker levels. CONCLUSIONS: AD patients showed an elevated OS marker level, and vitamin E lowered the OS level. In comparison with controls, AD patients showed shorter telomere lengths. Cells with short and long telomeres bore relatively hypermethylated subtelomeres in AD patients. Aging-associated accumulation of cells bearing short telomeres was not observed in AD. These results imply that long telomeres with hypomethylation tend to shorten faster, and cells bearing short telomeres with hypomethylation tend to more easily enter into a senescent state under elevated OS stress in AD. However, no significant effect on the altered telomeric profiles in AD patients could be detected after a 6-month administration of vitamin E.