الفهرس 
Title pageOnly 14 pages are availabe for public view
 |  | from | 118 |  |  |
| | | from | 118 | | |
Abstract
Titanium oxide (TiO2) was mainly used in several applications for years. However, with the discovery of nanotechnology, (TiO2NPs), with its useful characters, are increasingly industry and used. Therefore enhanced environmental and mammalian exposure may be expected, that had put TiO2 nanoparticles under toxicology scope . Toxic influence of MNPs on liver (hepatotoxicity) are now a most concern in nanomedicine, as liver is usually the first organ which comes in contact with MNPs post their ingestion. One of the toxic machinery of nanoparticles (NPs) is the production of reactive oxygen species. It comes from an imbalance between the formation of ROS and a system’s capability to be ready to detoxify the reactive species or repair the resulting insult.
MicroRNAs (miRNAs) are tiny regulatory coding RNAs which repress gene expression at the post-translational level in a sequence-specific manner. They play a crucial role in varying aspects of cell proliferation, differentiation and apoptosis. However, the large number of miRNA genes, those differ expression patterns and the importance of potential miRNA aims revealed that miRNAs are mostly to be included in an extended scope of human pathologies. Changes in their expression have played correspondence with disorder states in pathologic states as Alzheimer’s disease.
The miR-34 family comprises three potential miRNAs (miR-34a, miR-34b, and miR-34c) which are encoded by two kinds of genes. MiR-34a is coded by a certain transcript while miR-34b and miR-34c share a generally first transcript.
MiRNA-93, and miRNA coded by the miR- 106b-25 cluster (analog of the miR-17-92 clusters), has been observed to increase cell life, promote sphere production, and increase tumor size by facilitate angiogenesis
Sirtuins are a family of NAD+ dependent protein deacylases that exert many cellular tasks via reacting with, and deacylating a wide varieties of signaling molecules, translation factors, histones and enzymes. Todays evidence postulated that sirtuin 1 (SIRT-1) expression and/or activity is altered by super physiological levels of oxidative status.
In liver, miR-34a inhibits Sirt-1protein, comprising the farnesyl X receptor and tiny heterodimer partner way. It has been suggested that miR- 93 was decreased in aging mice liver. Both miR-34a and -93 can target several transcription forms and oxidant regulation and denotes gene family trait including Sirt1.
This study aimed to investigate the possible effect of titanium dioxide nanoparticles on oxidative status and the hepatic expression of miR 34-a, miR-93 and anti-aging gene Sirtuin-1 in rats’ liver. The study was conducted on forty male albino rats (150-250 gm body weight). All rats had free access to food and water with 12:12 hour’s light/dark cycle and constant environmental conditions prior to experimentation and then after. The studied rats were divided into four groups group I consists of 10 normal rats that received saline orally and serve as control group. group II consists of 10 normal rats that received titanium dioxide nanoparticles suspension orally in a dose of 50 mg/kg body weight for 14 consecutive days. group II consists of 10 normal rats that received titanium oxide nanoparticles suspension orally in a dose of 75 mg/kg body weight for 14 consecutive days. group IV consists of 10 normal rats that received titanium oxide nanoparticles solution orally in a dose of 100 mg/kg body weight for 14 consecutive days.
On the 15th day, the rats were sacrificed by cervical dislocation. The blood samples were taken immediately from dorsal vein and collected in tubes. Part of the blood was mixed with anticoagulant to separate plasma for assessment of Ferric Reducing Ability of Plasma (FRAP) while the remainder was left for 20 min at 40° C then centrifuged at 3000 xg for 10 minutes to obtain serum for assessment of alanine transaminase (ALT), aspartate transaminase (AST), gamma glutamyl transferase (GGT) activities and bilirubin level.
After sacrificing rats, the livers from all the rats in different groups were removed, rinsed with cold saline. Each liver tissue sample subdivided into four parts for determination of Malondialdehyde (MDA) concentration, total RNA isolation for subsequent determination of hepatic expression of Sirt-1, miR 34-a and miR-93 using Real Time Polymerase Chain Reaction (RT-PCR) and for histopathological investigation.
The results of the present study revealed that aspartate aminotransferase (AST), Alanine aminotransferase (ALT), gamma glultamyltransferase (GGT) activities and total bilirubin (TBIL) level increased significantly in the three different studied groups of rats treated with different doses of TNPs compared to controls. This increase occurred in a dose dependent manner. Moreover the study revealed significant increase in liver Malondialdehyde (MDA) level with simultaneous decrease in ferric reducing antioxidant power in plasma of TiO2NPs treated rats as compared to controls.
Results of the present study showed significant upregulation of hepatic mi RNA 34-a and miRNA-93 and downregulation of SIRT-1 in rats treated with different doses of TiO2NPs when compared to controls. No significant difference in SIRT-1 expression was observed on comparing the group of rats treated with 50 mg/Kg of TiO2NPs with controls.
from the present study it could be concluded that TiO2NPs may accumulate in liver tissue and exert its toxic effect through induction of oxidative stress. Moreover TiO2NPs could affect liver cell integrity predisposing to fibrosis, necrosis and apoptosis. The mechanism behind the nanotoxicity of TiO2NP has not been discussed yet. Our study together with previous ones could attribute it to oxidative stress, thus nanotoxicty is still an important area for further exploration. The present study could shed light on the possible deleterious effect of TiO2NP exposure not only upon oxidant status of cells but also senecence of cells through downregulation of SIRT-1 gene expression and upregulation of two of its regulatory miRNAs 34-a and 93.