Humans ; Oxidative Stress ; genetics ; Proteasome Endopeptidase Complex ; metabolism ; Protein Modification, Translational ; genetics ; Ubiquitination ; genetics

Erythrocytes ; metabolism ; Humans ; Kidney Diseases ; genetics ; metabolism ; Mitochondria ; genetics ; Mitochondrial Membranes ; metabolism ; Oxidative Stress ; genetics ; physiology

AIMTo investigate the impact of abnormal sperm morphology using the sperm deformity index (SDI) on reactive oxygen species (ROS) production and its correlation with sperm DNA damage.

METHODSSemen samples were collected from men undergoing infertility screening (n = 7) and healthy donors (n = 6). Mature spermatozoa were isolated and incubated with 5 mmol/L beta-nicotinamide adenine dinucleotide phosphate (NADPH) for up to 24 h to induce ROS. Sperm morphology was evaluated using strict Tygerberg's criteria and the SDI. ROS levels and DNA damage were assessed using chemiluminescence and terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick end labeling (TUNEL) assays, respectively.

RESULTSSDI values (median [interquartiles]) were higher in patients than donors (2 [1.8, 2.1] vs. 1.53 [1.52, 1.58], P = 0.008). Aliquots treated with NADPH showed higher ROS levels (1.22 [0.30, 1.87] vs. 0.39 [0.10, 0.57], P = 0.03) and higher incidence of DNA damage than those not treated (10 [4.69, 24.85] vs. 3.85 [2.58, 5.10], P = 0.008). Higher DNA damage was also seen following 24 h of incubation in patients compared to donors. SDI correlated with the percentage increase in sperm DNA damage following incubation for 24 h in samples treated with NADPH (r = 0.7, P = 0.008) and controls (r = 0.58, P = 0.04).

CONCLUSIONSDI may be a useful tool in identifying potential infertile males with abnormal prevalence of oxidative stress (OS)-induced DNA damage. NADPH plays a role in ROS-mediated sperm DNA damage, which appears to be more evident in infertile patients with semen samples containing a high incidence of morphologically abnormal spermatozoa.

DNA Damage ; Humans ; Infertility, Male ; genetics ; pathology ; Male ; Oxidative Stress ; Reactive Oxygen Species ; Spermatozoa ; abnormalities

Animals ; Humans ; Models, Biological ; Oxidative Stress ; genetics ; physiology ; Phosphorylation ; Protein Kinase C ; genetics ; metabolism ; physiology ; Signal Transduction ; genetics ; physiology

The p66Shc gene has emerged as a novel gerontogene affecting health and life during aging. In murine models of aging,a genetic deficiency of the p66Shc gene,which encodes a phosphotyrosine signal adapter protein,extends life span by 30%. p66Shc is a crucial regulator of reactive oxygen species levels and is involved in age-related dysfunctions. UP to now,oxidative stress has been recognized to be involved in human diseases such as high cholesterol,diabetes,and cardiovascular diseases. Further study on the role of p66Shc will facilitate the research of novel disease-targetted drugs and slow down or cure age-related pathologies.
Aging ; genetics ; Animals ; Humans ; Longevity ; genetics ; Mice ; Oxidative Stress ; physiology ; Reactive Oxygen Species ; metabolism ; Shc Signaling Adaptor Proteins ; genetics

Free radical hypothesis of aging emphasized that the age-related accumulation of free radicals results in cell injury. Alzheimer's disease (AD) is the most common form of neurodegenerative disease characterized by impaired cognition and memory of the elderly. Aging is a key risk factor in AD. Substantial evidence suggests that imbalance between free radical formation and clearance promotes AD pathogenesis. The brain overcomes oxidative stress by inducing expression of a set of genes called vitagenes. The protein products of vitagenes include heat shock proteins, heme oxygenases and thioredoxin systems, which serve as endogenous lifeguard of cells. This paper is a review of the expression and function of vitagenes in aging and AD brain, as well as relevant pharmacological study.
Aging ; genetics ; metabolism ; Alzheimer Disease ; genetics ; metabolism ; Brain ; metabolism ; Heat-Shock Proteins ; genetics ; metabolism ; Heme Oxygenase (Decyclizing) ; genetics ; metabolism ; Humans ; Oxidative Stress ; Thioredoxins ; genetics ; metabolism

Mitochondria are important intracellular organelles that produce energy for cellular development, differentiation, and growth. Mitochondrial DNA (mtDNA) presents a 10- to 20-fold higher susceptibility to genetic mutations owing to the lack of introns and histone proteins. The mtDNA repair system is relatively inefficient, rendering it vulnerable to reactive oxygen species (ROS) produced during ATP synthesis within the mitochondria, which can then target the mtDNA. Under conditions of chronic inflammation and excess stress, increased ROS production can overwhelm the antioxidant system, resulting in mtDNA damage. This paper reviews recent literature describing the pathophysiological implications of oxidative stress, mitochondrial dysfunction, and mitochondrial genome aberrations in aging hematopoietic stem cells, bone marrow failure syndromes, hematological malignancies, solid organ cancers, chronic inflammatory diseases, and other diseases caused by exposure to environmental hazards.
DNA, Mitochondrial/*genetics/metabolism ; Hematologic Diseases/genetics/*pathology ; Humans ; *Inflammation ; Mitochondria/genetics ; Mutation ; Neoplasms/genetics/*pathology ; Oxidative Stress ; Reactive Oxygen Species/metabolism

OBJECTIVEThis review examines the evidence that: Diabetes is a state of DNA damage; pathophysiological factors in diabetes can cause DNA damage; DNA damage can cause mutations; and DNA mutation is linked to carcinogenesis.

DATA SOURCESWe retrieved information from the PubMed database up to January, 2014, using various search terms and their combinations including DNA damage, diabetes, cancer, high glucose, hyperglycemia, free fatty acids, palmitic acid, advanced glycation end products, mutation and carcinogenesis.

STUDY SELECTIONWe included data from peer-reviewed journals and a textbook printed in English on relationships between DNA damage and diabetes as well as pathophysiological factors in diabetes. Publications on relationships among DNA damage, mutagenesis, and carcinogenesis, were also reviewed. We organized this information into a conceptual framework to explain the possible causal relationship between DNA damage and carcinogenesis in diabetes.

RESULTSThere are a large amount of data supporting the view that DNA mutation is a typical feature in carcinogenesis. Patients with type 2 diabetes have increased production of reactive oxygen species, reduced levels of antioxidant capacity, and increased levels of DNA damage. The pathophysiological factors and metabolic milieu in diabetes can cause DNA damage such as DNA strand break and base modification (i.e., oxidation). Emerging experimental data suggest that signal pathways (i.e., Akt/tuberin) link diabetes to DNA damage. This collective evidence indicates that diabetes is a pathophysiological state of oxidative stress and DNA damage which can lead to various types of mutation to cause aberration in cells and thereby increased cancer risk.

CONCLUSIONSThis review highlights the interrelationships amongst diabetes, DNA damage, DNA mutation and carcinogenesis, which suggests that DNA damage can be a biological link between diabetes and cancer.

Animals ; DNA Damage ; genetics ; Diabetes Mellitus, Type 2 ; genetics ; metabolism ; Humans ; Neoplasms ; genetics ; metabolism ; Oxidative Stress ; genetics ; physiology ; Reactive Oxygen Species ; metabolism

OBJECTIVETo design and synthesize ribozymes targeting 138 and 218 sites of the mRNA nucleotide of mouse caspase-12, a key intermedium of ER stress mediated apoptosis, and to identify their activities through in vitro transcription and cleavage.

METHODSThe mouse caspase-12 gene fragment was obtained by RT-PCR and cloned into the PGEM-T vector under the control of T7 RNA polymerase promoter. The transcription product of the target was labeled with a-32P UTP, while ribozymes were not labeled. Ribozyme and target RNA were incubated for 90 min at 37 degree C in a reaction buffer to perform the cleavage reaction.

RESULTSIt was found that under a condition of 37 degree C, pH 7.5 and with Mg2+ in a concentration of 10 mmol/L, Rz138 and Rz218 both cleaved targets at predicted sites, and the cleavage efficiency of Rz138 was 100%.

CONCLUSIONRz138 and Rz218 prepared in vitro possess the perfect specific catalytic cleavage activity. Rz138 has excellent cleavage efficiency. It may be a promising tool to prevent ER stress induced apoptosis through catalytic cleavage of caspase-12 mRNA in vivo. It also can be used to verify whether caspase-12 is necessary in ER stress induced apoptosis.

Animals ; Base Sequence ; Caspase 12 ; genetics ; Endoplasmic Reticulum ; metabolism ; Mice ; Mice, Inbred BALB C ; Molecular Sequence Data ; Oxidative Stress ; genetics ; RNA, Catalytic ; chemistry ; genetics ; RNA, Messenger ; genetics

OBJECTIVETo investigate the potential substitution effect of hOGG1 and hMTH1 on oxidative DNA damage, based on gene-deficient cell strains models.

METHODShOGG1 and hMTH1 gene deficient cell strains models were established by Human embryonic lung fibroblasts (HFL) cells. After HFL cells being exposed to 100 µmol/L H₂O₂ for 12 h, HPLC-EC detecting technique and RT-PCR method were adopted to analyze the genetic expression level of 8-oxo-dG (7, 8-dihydro-8-oxoguanine).

RESULTSThe gene-deficient cell strains models of hOGG1 and hMTH1 were obtained by infecting target cells with high titer of lentivirus. The mRNA expression level of hOGG1 was 0.09 ± 0.02, 91% lower than it in normal HFL cells, which was 1.00 ± 0.04. As the same, the mRNA expression level of hMTH1 (0.41 ± 0.04) also decreased by 60% compared with it in normal HFL cells (1.02 ± 0.06). After induced by 100 µmol/L H₂O₂ for 12 h, the genetic expression level of hMTH1 in hOGG1 gene-deficient cells (1.26 ± 0.18) increased 25% compared with it in control group (1.01 ± 0.07). Meanwhile, the genetic expression level of hOGG1 in hMTH1 gene-deficient cells (1.54 ± 0.25) also increased by 52%. The DNA 8-oxo-dG levels in hOGG1 gene-deficient cells (2.48 ± 0.54) was 3.1 times compared with it in the control group (0.80 ± 0.16), the difference showed statistical significance (P < 0.01). Whereas the 8-oxo-dG levels in hMTH1 gene-deficient cells (1.84 ± 0.46) was 2.3 times of it in the control group, the difference also showed statistical significance (P < 0.01).

CONCLUSIONBased on gene-deficient HFL cells models, a synergetic substitution effect on DNA damage and repair activity by both hOGG1 and hMTH1 were firstly discovered when induced by oxidation. The substitution effect of hOGG1 were stronger than that of hMTH1.

Cell Line ; DNA Damage ; DNA Glycosylases ; genetics ; DNA Repair ; DNA Repair Enzymes ; genetics ; Fibroblasts ; metabolism ; Humans ; Oxidative Stress ; genetics ; Phosphoric Monoester Hydrolases ; genetics