Ameliorative Effect of Necrosulfonamide in a Rat Model of Alzheimer's Disease: Targeting Mixed Lineage Kinase Domain-like Protein-Mediated Necroptosis.

Alzheimer's disease (AD) is a progressively debilitating neurodegenerative disorder that has no effective remedy, so far, with available therapeutic modalities being only symptomatic and of modest efficacy. Necroptosis is a form of controlled cell death with a recently emerging link to the pathogenesis of several neurodegenerative diseases. This study investigated the role of necroptosis in the pathogenesis of AD and evaluated the potential beneficial effect of the necroptosis inhibitor, necrosulfonamide (NSA), in a rat model of AD. AD was induced by oral administration of AlCl3 (17 mg/kg/day) for 6 consecutive weeks. Administration of NSA (1.65 mg/kg/day) intraperitoneally for 6 weeks significantly amended AlCl3-induced spatial learning and memory deficits, as demonstrated by enhanced rat performance in Morris water and Y-mazes. NSA alleviated the abnormally high hippocampal expression of tumor necrosis factor-alpha (TNF-α), ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), ß-amyloid, glycogen synthase kinase-3ß (GSK-3ß), phosphorylated tau protein, and acetylcholinesterase with concordant replenishment of acetylcholine. The amendments of AD perturbations achieved by NSA correlated with its inhibitory effect on the phosphorylation of the key necroptotic executioner, mixed lineage kinase domain-like protein (MLKL). Histopathological alterations supported the biochemical findings. In conclusion, NSA treatment represents a promising anti-Alzheimer's approach, mitigating AD neuropathologies via targeting MLKL-dependent necroptosis.

The expression of long non coding RNA genes is associated with expression with polymorphisms of HULC rs7763881 and MALAT1 rs619586 in hepatocellular carcinoma and HBV Egyptian patients.

Long noncoding RNAs (lncRNAs), highly upregulated liver cancer (HULC), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), lncRNA-AF085935, and lncRNA-uc003wbd have been implicated in hepatocellular carcinoma (HCC). Single-nucleotide polymorphism (SNP) in HULC and MALAT1 are associated with HCC susceptibility. However, association between these SNPs and lncRNA-AF085935 and lncRNA-uc003wbd expression and their potential clinical value in differentiating HCC from both hepatitis B virus (HBV)-infected Egyptian patients and the healthy specimens have not been explored yet. In the present study, SNPs rs7763881 in HULC and rs619586 in MALAT1 were genotyped in 70 HBV-positive HCC, 70 HBV patients, and 70 healthy controls in Egyptian population and the level of serum lncRNA-AF085935 and lncRNA-uc003wbd of all the subjects was assayed by quantitative real-time polymerase chain reaction. HULC rs7763881 AC/CC genotype was significantly associated with decreased HCC risk. Similarly, AG/GG of MALAT1 rs619586 was associated with decreased HCC risk with a borderline significance. Serum lncRNA-AF085935 and lncRNA-uc003wbd levels were upregulated in HBV-positive HCC and HBV patients vs controls and discriminated these groups by receiver operating characteristic analysis. Patients carrying AC/CC genotype of rs7763881 and AG/GG of rs619586 had lower serum lncRNA-AF085935 and lncRNA-uc003wbd levels compared with AA genotype. In conclusion, genetic variants of lncRNA HULC and lncRNA MALAT1 are associated with the decreased susceptibility to HCC in HBV-persistent carriers and are correlated with serum lncRNA-AF085935 and lncRNAuc003wbd levels, two potential noninvasive diagnostic biomarkers for HCC.

Significance of Serum Survivin and -31G/C Gene Polymorphism in the Early Diagnosis of Breast Cancer in Egypt.

BACKGROUND: Breast cancer is one of the most relevant malignancies among women. Molecular abnormalities in promotor region of survivin gene may account for overexpression of survivin and increased breast cancer risk. This study aimed to explore the potential association between survivin promotor gene -31G/C single nucleotide polymorphism (rs9904341) and its serum level alteration on one hand, and the risk of breast cancer in Egyptian patients on the other hand. It also aimed to assess the usefulness of survivin as an early noninvasive diagnostic biomarker and in breast cancer staging. PATIENTS AND METHODS: A total of 135 patients with physically and pathologically confirmed breast cancer and 40 unrelated control subjects as well as 40 patients with benign breast mass were recruited from the early detection unit at National Cancer Institute, Cairo University. Genotyping was performed using allelic discrimination probes by real-time quantitative PCR and serum survivin by enzyme-linked immunosorbent assay. RESULTS: The minor allele C of -31G/C survivin single nucleotide polymorphism was more frequent in breast cancer patients (19.3%) compared to the control group (7.5%). Furthermore, subjects with the GC + CC genotype were at increased risk of breast cancer compared to the GG genotype of the control group and also the benign group. Moreover, those patients exhibited higher serum levels of survivin compared to GG genotype. There was also significant elevation of serum survivin in different breast cancer stages. CONCLUSION: Genetic variation in -31G/C of the survivin gene may contribute to the disposition of breast cancer in the Egyptian population. Serum survivin alteration played a pivotal role in the pathogenesis of breast cancer.

Role of mesenchymal stem cells exosomes derived microRNAs; miR-136, miR-494 and miR-495 in pre-eclampsia diagnosis and evaluation.

BACKGROUND: Pre-eclampsia (PE) is one of the most threatening pregnancy complications. So far neither a secure, competent therapy for PE nor effective biomarkers for a premature discovery has been achieved. However, currently, the use of released microRNAs (miRNAs) as potential biomarkers and therapy targets for various diseases is the dominating area of research. The aim of our study was to identify miRNAs 136, 494 and 495 genes expression in exosomes of peripheral blood compared to umbilical cord mesenchymal stem cells (UCMSCs) conditioned media released exososomes in patients with PE, as valuable markers for PE early prediction. METHODS: Blood samples were collected from 100 patients with PE and 100 control with normal pregnancies. Thirty fresh umbilical cord samples of women with healthy pregnancies (n = 15) and PE patients (n = 15) were retrieved during caesarean deliveries and UCMSCs were isolated from Wharton jelly. The expression of miRNAs 136, 494 and 495 in exosomes of peripheral blood and UCMSCs conditioned media was measured using quantitative real-time PCR method. Unpaired t-test, Pearson correlation test and Receiver operator characteristic (ROC) analysis were used for data analysis. RESULTS: Our study revealed a significantly higher expression levels of miRNAs 136, 494 and 495 in exosomes of peripheral blood and matched with UCMSCs released exosomes from patients with PE compared to normal pregnancies (p = 0.000). In peripheral blood of PE, they were 6.4, 3.9 and 2.1 folds higher, respectively. ROC analysis revealed that the sensitivity and specificity values of miRNA-136 were 95% and 100%, respectively, with a cut-off value of 2.55. The sensitivity and specificity values of miRNA-494 were 86% and 95%, respectively, with a cut-off value of 0.47. The sensitivity and specificity values of miRNA-495 were 90% and 83%, respectively, with a cut-off value of 1.287. CONCLUSION: Our findings suggest that exosomes derived miRNA-136, miRNA-494 and miRNA-495 could be promising circulating biomarkers in early detection of PE. Furthermore, UCMSCs released exosomes miRNA-136, miRNA-494 and miRNA-495 genes expression confirmed peripheral blood results analysis.

Serum levels of chemerin, apelin, vaspin, and omentin-1 in obese type 2 diabetic Egyptian patients with coronary artery stenosis.

Cardiovascular diseases (CVD) are the leading cause of death in the diabetic population. Obesity is a serious problem that has been linked with CVD and diabetes via a variety of adipokines. The aims of this study were to evaluate and correlate circulating chemerin, apelin, vaspin, and omentin-1 levels in obese type 2 diabetic Egyptian patients with coronary artery stenosis (CAS), and to assess their usefulness as noninvasive diagnostic biomarkers. Chemerin, apelin, vaspin, and omentin-1 levels were determined by enzyme immunoassay in coronary artery disease (CAD) I patients (45 non-obese, nondiabetic with CAS), CAD II patients (45 obese, diabetic with CAS), and 30 controls. Patients in CAD I and CAD II groups exhibited higher levels of chemerin and apelin together with lower levels of vaspin and omentin-1 than in controls. These alterations were more significant in CAD II than in CAD I patients. Additionally, adipokine levels were individually correlated with each other and with certain biochemical variables. Moreover, chemerin and vaspin levels could differentiate CAD II patients from CAD I and controls. Alterations of these adipokines may play a crucial role in the pathogenesis of CAS in obese type 2 diabetic Egyptian patients. Chemerin and vaspin could be used as markers to support diagnosis of CAS.

The role of gene polymorphisms and AMH level in prediction of poor ovarian response in Egyptian women undergoing IVF procedure.

OBJECTIVE: The aim of this study is to assess the role of AMH in prediction of poor ovarian response as well as the relation between ESR 2 (+ 1730G>A) (rs4986938) and FSHR p.Thr307Ala (c.919A>G, rs6165) SNPs and the poor ovarian response in Egyptian women undergoing IVF procedure. Discovering the genetic variants associated with ovarian response is an important step towards individualized pharmacogenetic protocols of ovarian stimulation. METHODS: We performed a prospective study on 216 young women with unexplained infertility. Ovarian stimulation was performed according to the GnRH antagonist protocol with a fixed daily morning dose of human menopausal gonadotrophin (HMG). The estrogen receptor (ESR2) (+ 1730G>A) (rs4986938) and FSH receptor p.Thr307Ala (c.919A>G, rs6165) single nucleotide polymorphisms (SNPs) were detected by real-time polymerase chain reaction. Serum FSH, Estradiol (E2) and anti-Müllerian hormone (AMH) levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: This study revealed that the low AMH level was highly significantly related to the poor ovarian response (p < 0.001). Furthermore, the frequency of the ESR2 (AA) genotype and the FSHR (Ala307Ala) genotypes were highly significantly associated with the poor ovarian response (p < 0.001). CONCLUSION: The AMH level in combination with the ESR2 and the FSHR gene polymorphisms predict the poor ovarian response to COH in Egyptian women. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02640976.

Elevated serum microRNA-122/222 levels are potential diagnostic biomarkers in Egyptian patients with chronic hepatitis C but not hepatic cancer.

MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs that regulate gene expression at the post-transcriptional level. Because of their size, specificity, and relative stability in plasma, miRNAs can be used as diagnostic and prognostic biomarkers to monitor liver injury, such as that caused by hepatitis C virus (HCV) and liver cancer. In this study, we investigated miRNA expression patterns from the serum of Egyptian patients with HCV and liver cancer compared with matched healthy controls. Using microarray-based expression profiling followed by real-time quantitative polymerase chain reaction validation, we compared the levels of circulating miRNA-122 and miRNA-222 in serum from patients with hepatitis C virus (n = 40) and liver cancer (n = 60) to matched healthy controls (n = 30). MiRNA SNORD68 was the housekeeping endogenous control. We found that the serum levels of miR-122 and miR-222 were significantly elevated in HCV patients, but not in liver cancer patients, compared with controls. Receiver operating characteristic analysis revealed that miR-122 and miR-222 have a high diagnostic potential in discriminating patients with HCV from controls. Serum miR-222 was significantly higher in HCV patients compared to liver cancer patients. Our results indicate that serum miR-122 and miR-222 are elevated in Egyptian patients with chronic HCV, and these miRNAs have a strong potential to serve as novel biomarkers for liver injury but not specifically for liver cancer.

Genetic polymorphism of estrogen receptor alpha gene in Egyptian women with type II diabetes mellitus.

Estrogen might play an important role in type 2 diabetes mellitus pathogenesis. A number of polymorphisms have been reported in the estrogen receptor alpha gene including the XbaI and PvuII restriction enzyme polymorphisms. The aim of this study was to determine if ESRα gene polymorphisms are associated with type 2 diabetes mellitus and correlated with lipid profile. Ninety diabetic Egyptian patients were compared with forty healthy controls. ESRα genotyping of PvuII and XbaI was performed using restriction fragment length polymorphism analysis. Our study showed that there is more significant difference in the frequency of C and G polymorphic allele between patients and control groups in PvuII and XbaI respectively. Also carriers of minor C and G alleles of PvuII and XbaI gene polymorphisms were associated with increased fasting blood glucose and disturbance in lipid profile as there is an increase in total cholesterol, triglycerides and Low density lipoprotein. So findings of present study suggest the possibility that PvuII and XbaI polymorphisms in ERα are related to T2DM and with increased serum lipids among Egyptian population.

Combination of imatinib and clotrimazole enhances cell growth inhibition in T47D breast cancer cells.

Imatinib mesylate (IM), a tyrosine kinase inhibitor, is used as targeted cancer therapy. However, mono-targeting by IM does not always achieve full tumor eradication and thus it is recommended to combine IM with other anticancer agents. Clotrimazole (CLT) is an antifungal azole derivative with promising anticancer effects due to inhibiting the activity of glycolytic enzymes. The present study aimed to evaluate the effect of combining CLT with IM on breast cancer cell line in an attempt to establish effective new combination. T47D human breast cancer cell line was treated with different concentrations of IM and/or CLT for 48 h. IM-CLT interaction was determined by isobologram equation and combination index. Cell viability was confirmed by measuring LDH activity. As indicators of glycolysis inhibition, the expression of hexokinase-2 (HK-2) and 6-phosphofructo-1-kinase (PFK-1) plus the activity of intracellular lactate dehydrogenase (LDH) and pyruvate kinase (PK) were determined. In addition, glucose consumption and adenosine triphosphate (ATP) production were measured. Moreover, nitric oxide (NO), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-α (HIF-α) were also determined as they are modulators for glycolysis. This study demonstrated that IM or CLT synergistically inhibited cell growth in T47D as shown by combination and dose reduction indices. The combination of 15 µM IM and 20 µM CLT significantly decreased glucose consumption, activity of both PK and intracellular LDH, while increased leaked LDH, VEGF and NO in the medium compared to each drug alone. Furthermore the combination decreased gene expression of HK-2, PFK-1 and ATP content compared to the control. In conclusion, the synergistic effect of CLT on IM cytotoxicity in T47D cell line maybe mediated through inhibition of glycolysis and increasing both NO and VEGF. Further studies are required to confirm the efficiency and safety of this combination.

MicroRNAs as predictor markers for response to interferon treatment of chronic hepatitis C genotype-4 in Egyptian patients.

BACKGROUND: Hepatitis C virus genotype 4 (HCV-4) infection is common in the Middle East and Africa, with an extraordinarily high prevalence in Egypt. MicroRNAs (miRNAs) play an important role in various diseases, including HCV infection. The aim of the present study was to assess serum miR-122, miR-221 and miR-21 expression profiles in HCV-4 patients prior to treatment with HCV-4 combination therapy (pegylated alpha interferon and ribavirin) and to determine whether the miRNAs were associated with the drug response. METHODS: RNA was extracted from pretreatment serum samples, and miR-122, miR-221 and miR-21 levels were measured by quantitative PCR. The results were compared among patients with sustained virological responses (SVR) and non-responders (NR). RESULTS: The expression levels of miR-21 and miR-122 were significantly different between the SVR and NR groups. Receiver operator characteristic (ROC) analysis revealed that the sensitivity, specificity and positive predictive values of miR-21 were 82.2%, 77.3% and 88.1%, respectively, with a cut-off value of 1.7. The sensitivity, specificity and positive predictive values of miR-122 were 68.9%, 59.1% and 77.5%, respectively, with a cut-off value of 3.5. CONCLUSION AND SIGNIFICANCE: miR-21 and miR-122 might be useful predictors for SVR in HCV-4 patients prior to the administration of combination therapy. A higher predictive response power was obtained for miR-21 than for miR-122. These results should reduce ineffective treatments.

Visfatin -948G/T and resistin -420C/G polymorphisms in Egyptian type 2 diabetic patients with and without cardiovascular diseases.

Diabetes mellitus is one of the main threats to human health in the 21st century. Visfatin/Nampt and resistin are novel adipokines that have been implicated in the pathogenesis of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) complication. Several genetic studies have shown inconsistent results regarding association of visfatin/Nampt gene (NAMPT) and resistin gene (RETN) polymorphisms with T2DM and CVD complications. Here, we investigate whether NAMPT -948G/T and RETN -420C/G polymorphisms are associated with T2DM, its CVD complications, and serum adipokines levels in 90 Egyptian diabetic patients (44 without CVD and 46 with CVD) along with 60 healthy control subjects. Higher frequencies of NAMPT -948G/G and RETN -420G/G were observed among T2DM patients compared with controls. Furthermore, the frequencies of these genotypes were significantly higher in T2DM patients with CVD than those without CVD. Both NAMPT -948G/G and RETN -420G/G genotypes and G alleles were significantly associated with T2DM and CVD in Egyptian diabetic patients. Moreover, serum visfatin/Nampt and resistin levels were markedly elevated in T2DM patients, with the highest values observed in G/G genotypes among T2DM patients with CVD. In addition, positive correlations were observed between plasma adipokines levels and CVD risk factors. In conclusion, our data suggests that genetic variations in NAMPT -948G/T and RETN -420C/G may contribute to the disposition for T2DM and its CVD complications in Egyptian patients. However, further studies with greater sample size should be performed to verify these results.

Evaluation of naproxen and cromolyn activities against cancer cells viability, proliferation, apoptosis, p53 and gene expression of survivin and caspase-3.

We previously reported the inhibitory profiles of naproxen and cromolyn against glycogen synthase kinase-3ß, which partly explain the molecular mechanisms of their anti-cancer properties. In this study, we performed a detailed biochemical evaluation of the two drugs against colorectal adenocarcinoma (Caco2), hepatocellular carcinoma (HepG2), mammary gland carcinoma (MCF7), epitheloid cervix carcinoma (Hela), lung carcinoma (A5W9) and epidermoid larynx carcinoma (Hep2) cell lines. Additionally, we performed cellular viability tests using trypan blue, proliferation MTT assay, apoptosis, p53 and real-time polymerase chain reaction for gene expression of survivin and caspase-3. Not only the two drugs were found to significantly reduce the viability of different cell lines, but they also were shown to have potent dose-dependent reduction of cellular proliferation. They exhibited cytotoxicity IC50 values of 3.69 and 4.16 µM for naproxen and cromolyn, respectively. Viability and proliferation results clearly correlated with apoptosis and p53 experiments in showing that both drugs significantly raised apoptotic percentages. Furthermore, we observed a significant reduction in survivin and elevation of caspase-3 gene expression upon exposure to the two drugs. It can be concluded that both naproxen and cromolyn have significant anti-cancer properties.

The therapeutic effects of bone marrow-derived mesenchymal stem cells and simvastatin in a rat model of liver fibrosis.

Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) proteins including collagen that occurs in most types of chronic liver diseases. Studies concerning the capacity of mesenchymal stem cells (MSCs) and simvasatain (SIMV) to repair fibrotic tissues through reducing inflammation, collagen deposition, are still controversial. This study aimed to investigate the therapeutic efficacy of bone marrow (BM)-derived MSCs and SIMV on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Rats were divided into: normal, CCl4, CCl4/MSCs, CCl4/SIMV, CCl4/MSCs/SIMV, and SIMV groups. BM-derived MSCs were detected by RT-PCR of CD29 and were then infused into the tail vein of female rats that received CCl4 injection to induce liver fibrosis. Sex-determining region Y (SRY) gene on Y-chromosome gene was assessed by PCR to confirm homing of the male stem cells in liver tissue of the female recipients. Serum liver function tests, liver procollagens I and III, tissue inhibitors of metalloproteinase-1 (TIMP-1), endoglin, matrix metalloproteinase-1 (MMP-1) gene expressions, transforming growth factor-beta (TGF-ß1) immunostaining, and histopathologicl examination were performed. MSCs and SIMV decreased liver procollagens I and III, TIMP-1 and endoglin gene expressions, TGF-ß1 immunostaining, and serum liver function tests compared with the CCl4 group. MMP-1 expression was increased in the CCl4/MSCs group. Histopathological examination as well as fibrosis score supports the biochemical and molecular findings. It can be concluded that MSCs and SIMV were effective in the treatment of hepatic CCl4-induced fibrosis-rat model. Treatment with MSCs was superior to SIMV. This antifibrotic effect can be attributed to their effect on the MMPs/TIMPs balance which is central in fibrogenesis.

Naproxen and cromolyn as new glycogen synthase kinase 3ß inhibitors for amelioration of diabetes and obesity: an investigation by docking simulation and subsequent in vitro/in vivo biochemical evaluation.

Naproxen and cromolyn were investigated as new inhibitors of glycogen synthase kinase-3ß (GSK-3ß) in an attempt to explain their hypoglycemic properties. Study included simulated docking experiments, in vitro enzyme inhibition assay, and in vivo validations. Both drugs not only were optimally fitted within a GSK-3ß binding pocket via several attractive interactions with key amino acids but also exhibited potent in vitro enzymatic inhibitory activities of IC50 1.5 and 2.0 µM for naproxen and cromolyn, respectively. In vivo experiments illustrated that both drugs significantly reduced serum glucose and increased hepatic glycogen- and serum insulin levels in normal and type II diabetic Balb/c mice models. In obese animal model, both drugs exhibited significant reduction in mice weights, serum glucose, and resistin levels along with significant elevation in serum insulin, C-peptide, and adiponectin values. It can be concluded that naproxen and cromolyn are novel GSK-3ß inhibitors and can help in management of diabetes and obesity.

Serum human leukocyte antigen-G and soluble interleukin 2 receptor levels in acute lymphoblastic leukemic pediatric patients.

AIMS AND BACKGROUND: Human leukocyte antigen-G and interleukin-2 receptor play pivotal roles in the proliferation of lymphocytes, and thus generation of immune responses. Their overexpression has been evidenced in different malignant hematopoietic diseases. This study aimed to validate serum soluble human leukocyte antigen-G (sHLA-G) and serum soluble interleukin-2 receptor (sIL-2R) as an additional tool for the diagnosis and follow up of acute lymphoblastic leukemia (ALL). SUBJECTS AND METHODS: Both markers were determined by ELISA in the serum of 33 ALL pediatric patients before treatment and after intensification phase of chemotherapy as well as in the serum of 14 healthy donors that were selected as a control group. RESULTS: ALL patients showed abnormal CBC and high serum lactate dehydrogenase, which were improved after chemotherapy. Also, there was a non-significant increase in serum sHLA-G in ALL patients compared with the control group. However, after chemotherapy, sHLA-G was increased significantly compared with before treatment. On the other hand, serum sIL-2R in ALL patients was increased significantly compared with the control group. After chemotherapy, sIL-2R decreased significantly compared with before treatment. CONCLUSIONS: From these results it could be suggested that measurement of serum sHLA-G might be helpful in diagnosis of ALL, while sIL-2R might be useful in diagnosis and follow-up of ALL in pediatric patients.

Cytoprotective effects of DL-alpha-lipoic acid or squalene on cyclophosphamide-induced oxidative injury: an experimental study on rat myocardium, testicles and urinary bladder.

The present study aimed to evaluate the role of DL-alpha-lipoic acid (LA) and squalene (SQ) on oxidative cardiac, testicular and urotoxic damage induced by cyclophosphamide (CP). Male Wistar rats were divided into four groups; three groups received a single intraperitoneal injection of CP (200mg/kg BW) to induce toxicity, and two of these groups received either LA (35 mg/kg BW) or SQ (0.4 ml/rat) orally 7 days before and 7 days after CP injection. A vehicle-treated control group was also included. Oxidative damage was observed by decreased serum total antioxidant capacity (TAC) level and abnormal alterations in glutathione peroxidase (GPx) and glutathione reductase (GR) activities, levels of glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO) and calcium (Ca(+2)) in the heart, testes and urinary bladder of CP-administered rats. Cardiac marker enzyme activities; creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and aspartate transaminase (AST) showed severe declines whereas testicular markers; sorbitol dehydrogenase (SDH), gamma-glutamyl transferase (gamma-GT), acid and alkaline phosphatases (ACP and ALP), serum testosterone (T) level and haemoglobin (Hb) absorbance were abnormal. Histopathological observations were also altered. These CP-induced pathological alterations were attenuated by treatment with LA or SQ. These findings highlight the efficacy of LA and SQ as cytoprotectants in CP-induced toxicity.

Age-associated changes in protein oxidation and proteasome activities in rat brain: modulation by antioxidants.

The free radical theory of ageing postulates that age-associated neurodegeneration is caused by an imbalance between pro-oxidants and antioxidants resulting in oxidative stress. The current study showed regional variation in brain susceptibility to age-associated oxidative stress as shown by increased lipofuscin deposition and protein carbonyl levels in male rats of age 15-16 months compared to control ones (3-5 months). The hippocampus is the area most vulnerable to change compared to the cortex and cerebellum. However, proteasomal enzyme activity was not affected by age in any of the brain regions studied. Treatment with melatonin or coenzyme Q10 for 4 weeks reduced the lipofuscin content of the hippocampus and carbonyl level. However, both melatonin and coenzyme Q10 treatments inhibited beta-glutamyl peptide hydrolase activity. This suggests that these molecules can alter proteasome function independently of their antioxidant actions.