Autism is a neurodevelopmental disability characterized by deficits in verbal communications, impairments in social interactions, and repetitive behaviors. Several studies have indicated strong involvement of multigenic components in the etiology of autism. Linkage analyses and candidate gene search approaches so far have not identified any reliable susceptibility genes. We are using a proteomic approach to identify protein abnormalities due to aberrant gene expression in autopsied autism brains. In four of eight autism brains, we have found an increase in polarity (more acidic) of glyoxalase I (Glo1) by two-dimensional gel electrophoresis. To identify the molecular change resulting in the shift of Glo1 polarity, we undertook sequencing of GLO1 gene. Direct sequencing of GLO1 gene/mRNA in these brains, has identified a single nucleotide polymorphism (SNP), C419A. The SNP causes an Ala111Glu change in the protein sequence. Population genetics of GLO1 C419A SNP studied in autism (71 samples) and normal and neurological controls (49 samples) showed significantly higher frequency for the A419 (allele frequency 0.6 in autism and 0.4 in controls, one-tailed Fisher's test P < 0.0079). Biochemical measurements have revealed a 38% decrease in Glo1 enzyme activity in autism brains (one-tailed t-test P < 0.026). Western blot analysis has also shown accumulation of advanced glycation end products (AGE's) in autism brains. These data suggest that homozygosity for A419 GLO1 resulting in Glu111 is a predisposing factor in the etiology of autism.
The reduced antioxidative defense in allele epsilon4 carriers is suggested to contribute to beta-amyloidosis in Alzheimer's disease and Down's syndrome. We studied the effect of oxidative stress on accumulation of amyloid-beta peptide (Abeta) in vascular smooth muscle cells (SMCs) that are engaged in production of amyloid-beta in vivo. Previously, we found that oxidative stress caused by ferrous ions induced accumulation of Abeta-apolipoprotein E deposits in lysosomes and was associated with a greater oxidative protein damage in epsilon4 carriers. Here, we demonstrate that ferrous ions induce formation of Abeta deposits also in vascular tunica media in organotypic cultures of whole brain vessels, suggesting the role of oxidative stress in development of vascular beta-amyloidosis. Cellular accumulation of Abeta in SMCs treated with ferrous ions was associated with a greater accumulation of C-terminal amyloid precursor protein (APP) fragments in epsilon4/epsilon4 than in epsilon3/epsilon3 myocytes and reduced the amount of soluble APPalpha in epsilon3/epsilon3, but not epsilon4/epsilon4, cultures. Antioxidant vitamin E prevented these effects, and, when applied alone, diminished the amount of APP C-terminal fragments and increased the amount of secreted APP in epsilon3/epsilon3, but not epsilon4/epsilon4, cells. C-terminal APP-immunoreactive material was accumulated in lysosomes partly with Abeta- and N-terminal APP immunoreactivities. These results suggest that the increased accumulation of APP and its fragments in lysosomes may yield additional amounts of cellular Abeta, particularly in epsilon4 carriers. We hypothesize that the altered processing of APP in SMCs locally exposed to oxidative stress facilitates cellular deposition of Abeta and contribute to the increased risk of development of beta-amyloidosis in epsilon4/epsilon4 carriers.
Telomerase is known to contribute to telomere maintenance and to provide cancer cell immortality. However, numerous reports are showing that the function of the enzyme goes far beyond chromosome ends. The study aimed to explore how telomerase downregulation in MCF7 and MDA-MB-231 breast cancer cells affects their ability to survive. Consequently, sensitivity to drug resistance, proliferation, and adhesion were assessed. The lentiviral-mediated human telomerase reverse transcriptase (hTERT) downregulation efficiency was performed at gene expression and protein level using qPCR and Western blot, respectively. Telomerase activity was evaluated using the Telomeric Repeat Amplification Protocol (TRAP) assay. The study revealed that hTERT downregulation led to an increased sensitivity of breast cancer cells to doxorubicin which was demonstrated in MTT and clonogenic assays. During a long-term doubling time assessment, a decreased population doubling level was observed. Interestingly, it did not dramatically affect cell cycle distribution. hTERT downregulation was accompanied by an alteration in β1-integrin- and by focal adhesion kinase (FAK)-driven pathways together with the reduction of target proteins phosphorylation, i.e., paxillin and c-Src. Additionally, autophagy activation was observed in MDA-MB-231 cells manifested by alternations in Atg5, Beclin 1, LC3II/I ratio, and p62. These results provide new evidence supporting the possible therapeutic potential of telomerase downregulation leading to induction of autophagy and cancer cells elimination.
The epsilon4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease. The reduced antioxidant defense in epsilon4 carriers is suggested to contribute to beta-amyloidosis. We found that oxidative stress induced by treatment with Fe2+ ions raised more protein carbonyls in vascular smooth muscle cells isolated from human brains with apoE genotype epsilon4/epsilon4 than with 3epsilon/epsilon3 and epsilon3/epsilon4. Antioxidant vitamin E prevented formation of carbonyls but not in cells with genotype epsilon4/epsilon4. Treatment with Fe2+ ions induced cellular accumulation of amyloid-beta protein (Abeta)-immunoreactive material that co-localized with heme oxygenase, a marker of oxidative stress, and apoE. We hypothesize that the damage caused by oxidation in epsilon4/epsilon4 carriers facilitates development of beta-amyloidosis.
Due to distressing statistics concerning cardiovascular diseases, remote monitoring of cardiac implantable electronic devices (CIED) has received a priority recommendation in daily patient care. However, most bedside systems available so far are not optimal due to limited patient adherence. We report that smartphone app technology communicating with CIED improved the patient’s engagement and adherence, as well as the accuracy of atrial and ventricular arrhythmias diagnosis, thus offering more efficient treatment and, consequently, better patient clinical outcomes. Our findings are in concordance with previously published results for implantable loop recorders and pacemakers, and provide new insight for heart failure patients with an implanted cardiac resynchronization therapy defibrillator.
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