Role of long noncoding RNAs; BDNF-AS and 17A and their relation to GABAergic dysfunction in Egyptian epileptic patients.

Epilepsy is a chronic neurological disorder characterized by recurrent unprovoked seizures. Lately, long noncoding RNAs (lncRNAs) have been increasingly appreciated as regulators of epilepsy-related processes, however, their functional role in its pathogenesis is still to be explored. This study investigated the expression levels of lncRNAs; BDNF-AS and 17A in the sera of Egyptian patients with idiopathic generalized and symptomatic focal epilepsy and correlated their levels with brain-derived neurotrophic factor (BDNF), phosphorylated cAMP reaction element -binding protein (p-CREB), gamma- aminobutyric acid (GABA) and glutamate, to underline their related molecular mechanism. A total of 70 epileptic patients were divided into two clinical types, besides 30 healthy controls of matched age and sex. The expression levels of both lncRNAs were markedly upregulated in epileptic groups versus the healthy control group with predominance in the symptomatic focal one. Epileptic patients showed significantly lower levels of BDNF, p-CREB, GABA along with significant increase of glutamate levels and glutamate/ GABA ratio, especially in symptomatic focal versus idiopathic generalized epileptic ones. The obtained data raised the possibility that these lncRNAs might be involved in the pathogenesis of epilepsy via inhibition of GABA/p-CREB/BDNF pathway. The study shed light on the putative role of these lncRNAs in better diagnosis of epilepsy, particularly symptomatic focal epilepsy.

Association of LncRNA-PAX8-AS1 and LAIR-2 polymorphisms along with their expression with clinical and subclinical hypothyroidism.

The genetic and epigenetic architecture of clinical and subclinical hypothyroidism remains unclear. We investigated the impact of long noncoding RNA (LncRNA)-PAX8-AS1 and LAIR-2 genetic variants on the susceptibility to clinical and subclinical hypothyroidism, their influence on LncRNA-PAX8-AS1 and LAIR-2 expression and their potential as hypothyroid biomarkers. Hundred clinical hypothyroid patients, 110 subclinical hypothyroid patients, and 95 healthy controls were enrolled. Gene expression analysis and genotyping were performed by qPCR. LAIR-2 protein, a proinflammatory mediator, was tested by ELISA. Serum LncRNA-PAX8-AS1 was downregulated, whereas LAIR-2 mRNA and protein levels were upregulated in clinical and subclinical hypothyroid patients compared to healthy controls. LncRNA-PAX8-AS1 rs4848320 and rs1110839 were associated with increased risk of clinical hypothyroidism. Interestingly, both SNPs were associated with differential expression of serum LncRNA-PAX8-AS1 among clinical hypothyroid patients. LAIR-2 rs2287828 was associated with elevated risk of both clinical and subclinical hypothyroidism. Harboring the rs2287828 T allele augmented the LAIR-2 mRNA expression among clinical hypothyroid patients, while elevated both LAIR-2 mRNA and protein levels in subclinical hypothyroid patients. The rs4848320-rs1110839-rs2287828 TTT, CTT, and CGT haplotypes were associated with increased hypothyroid risk. Surprisingly, serum LncRNA-PAX8-AS1 and LAIR-2 mRNA expression demonstrated superior diagnostic accuracy for clinical hypothyroidism and turned out as independent predictors in the multivariate analysis. Conclusively, LncRNA-PAX8-AS1 and LAIR-2 genetic variants are novel genetic biomarkers of hypothyroidism that could alter the LncRNA-PAX8-AS1 and LAIR-2 expression. LncRNA-PAX8-AS1 and LAIR-2 expression profiles have the potential as effective diagnostic and prognostic indicators of hypothyroidism.

Circulating lncRNAs HIF1A-AS2 and LINLK-A: Role and Relation to Hypoxia-Inducible Factor-1α in Cerebral Stroke Patients.

Long noncoding RNAs (lncRNAs) have been recently recognized as key players of gene expression in cerebral pathogenesis. Thus, their potential use in stroke diagnosis, prognosis, and therapy is actively pursued. Due to the complexity of the disease, identifying stroke-specific lncRNAs remains a challenge. This study investigated the expression of lncRNAs HIF1A-AS2 and LINK-A, and their target gene hypoxia-inducible factor-1 (HIF-1) in Egyptian stroke patients. It also aimed to determine the molecular mechanism implicated in the disease. A total of 75 stroke patients were divided into three clinical subgroups, besides 25 healthy controls of age-matched and sex-matched. Remarkable upregulation of lncRNA HIF1A-AS2 and HIF1-α along with a downregulation of lncRNA LINK-A was noticed in all stroke groups relative to controls. Serum levels of phosphatidylinositol 3-kinase (PI3K), phosphorylated-Akt (p-Akt), vascular endothelial growth factor (VEGF), and angiopoietin-1 (ANG1) as well as their receptors, malondialdehyde (MDA), and total antioxidant capacity (TAC) were significantly increased, whereas brain-derived neurotrophic factor (BDNF) levels were significantly decreased particularly in hemorrhagic stroke versus ischemic groups. Eventually, these findings support the role of lncRNAs HIF1A-AS2 and LINK-A as well as HIF1-α in activation of angiogenesis, neovascularization, and better prognosis of stroke, especially the hemorrhagic type.

Significance of Some Non-Invasive Biomarkers in the Early Diagnosis and Staging of Egyptian Breast Cancer Patients.

INTRODUCTION: Breast cancer is one of the most relevant malignancies among women. Early diagnosis and accurate staging of breast cancer is important for the selection of an appropriate therapeutic strategy and achieving a better outcome. AIM: This study aimed to explore the significance of some non-invasive biomarkers in the early diagnosis and staging of Egyptian breast cancer patients. SUBJECTS AND METHODS: A total of 135 female patients with physically and pathologically confirmed breast cancer and 40 unrelated controls as well as 40 patients with benign breast mass were enrolled in this study. The malignant breast cancer group was further divided into four groups according to tumor size. Serum levels of carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1), resistin and visfatin were determined by enzyme immunoassay. RESULTS: Elevated levels of CEACAM1, resistin and visfatin were observed in breast cancer patients when compared with normal control and benign groups. The cutoff values, sensitivities and specificities of these biomarkers were appropriate for the discrimination of breast cancer from controls. Additionally, the serum levels of visfatin increased positively with tumor size and consequently with breast cancer stages. CONCLUSION: CEACAM1, resistin and visfatin are valuable in early diagnosis of breast cancer, with visfatin being preferentially used in staging.

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.

miR-26a Potentially Contributes to the Regulation of Fatty Acid and Sterol Metabolism In Vitro Human HepG2 Cell Model of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a metabolic-related disorder ranging from steatosis to steatohepatitis, which may progress to cirrhosis and hepatocellular carcinoma (HCC). This study aimed at assessing the regulatory and protective role of miR-26a on lipid metabolism and progression of NAFLD in human HepG2 cells loaded with free fatty acids (FFA). Lentivirus expressing miR-26a or negative control miR was used to transduce HepG2 cells and to establish stable cell lines. Gain or loss of function using an miR-26a inhibitor was used to compare triglyceride content (TG), total cholesterol level (CL), total antioxidant capacity (TAC), malondialdehyde (MDA) and the level of apoptosis. In addition, quantitative reverse transcription polymerase chain reaction (qPCR) was used to assess the mRNA levels of lipogenesis, TG synthesis, storage genes, inflammatory and fibrogenic markers, and autophagic besides endoplasmic reticulum (ER) stress markers after gaining or losing the function of miR-26a. miR-26a levels decreased in response to FFA in human HepG2 cells. After the establishment of a stable cell line, the upregulation of miR-26a resulted in the downregulation of TG, CL, and MDA levels, through regulating mRNA levels of genes involved in lipid homeostasis, ER stress marker, inflammatory and fibrogenic markers. Nevertheless, there was a marked increment in the mRNA expression of autophagic marker genes. Moreover, miR-26a overexpression protects the cells from apoptosis, whereas inhibition of miR-26a, using an anti-miR-26a oligonucleotide, decreased the expression of miR-26a which potentially contributes to altered lipid metabolism in HepG2 cells loaded with FFA. In conclusion, these findings suggested that miR-26a has a crucial role in regulating fatty acid and cholesterol homeostasis in HepG2 cells, along with the offered protection against the progression of NAFLD in vitro. Hence, miRNAs could receive growing attention as useful noninvasive diagnostic markers to follow the progression of NAFLD and to identify novel therapeutic targets.

Combinatorial strategy of epigenetic and hormonal therapies: A novel promising approach for treating advanced prostate cancer.

AIMS: Estrogens act as key factors in prostate biology, cellular proliferation and differentiation as well as cancer development and progression. The expression of estrogen receptor (ER)-ß appears to be lost during prostate cancer progression through hypermethylation mechanism. Epigenetic drugs such as 5-aza-2'-deoxycytidine (5-AZAC) and Trichostatin A (TSA) showed efficacy in restoring ERß expression in prostate cancer cells. This study was designed to explore the potential anti-carcinogenic effects resulting from re-expressing ERß1 using 5-AZAC and/or TSA, followed by its stimulation with Diarylpropionitrile (DPN), a selective ERß1 agonist, in prostate cancer cell line PC-3. MAIN METHODS: Cells were treated with 5-AZAC, TSA, DPN and their combination. Subsequently, they were subjected to proliferation assays, determinations of ERß1 expression, protein levels of active caspase-3, cyclin D1, ß-catenin and VEGF. KEY FINDINGS: Treatment with these drugs exhibited an increase in ERß1 expression to different extents as well as active caspase-3 levels. Meanwhile, a significant reduction in cyclin D1, VEGF and ß-catenin levels was achieved as compared to the vehicle control group (p < 0.05). Interestingly, the triple combination regimen led to the most prominent anti-tumor responses in terms of increased apoptosis, reduced proliferation as well as angiogenesis. SIGNIFICANCE: The results support the notion that ERß1 acts as a tumor suppressor protein and suggest that sequential ERß1 expression and activation can offer significant anti-tumor responses. The study highlights that the strategy of merging epigenetic and hormonal therapies may be beneficial in treating advanced prostate cancer.

Coenzyme Q10 and niacin mitigate streptozotocin- induced diabetic encephalopathy in a rat model.

Diabetic encephalopathy is an important complication of diabetes characterized by cognitive impairment, neurochemical and structural abnormalities. This study aimed to investigate the effect of coenzyme Q10 (CoQ10) and niacin as well as their combination in the treatment of encephalopathy associated with streptozotocin (STZ)- induced diabetes in rats. Glibenclamide (reference diabetic drug) and donepezil hydrochloride (acetylcholinesterase inhibitor) were also evaluated. Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg). One month after STZ injection, diabetic rats were treated with the aforementioned drugs for two weeks. The evaluation was done through measuring glucose level, total antioxidant capacity (TAC), interleukin 6 (IL6), DNA degradation as well as serotonin and noradrenaline as neurotransmitters. The present data illustrated that combining CoQ10 and niacin exhibiting the most potent effect in improving the measured parameters and ameliorating some of diabetes complications.

Carbonic anhydrase inhibition boosts the antitumor effects of Imatinib mesylate via potentiating the antiangiogenic and antimetastatic machineries.

Carbonic anhydrase inhibitors have emerged in the past few years as an interesting candidate for the development of novel unconventional strategies. Despite their effect in tumor regression via inhibition of tumor acidification, their potential role is not yet fully elucidated. Herein, we investigated whether acetazolamide (AZ) could modulate imatinib (IM) anticancer activity, both in breast cancer cells (T47D) and in isolated tumor specimens of Ehrlich ascites carcinoma (EAC). The impact of this combination on angiogenesis was evidenced by decreasing PDGF-A expression and enhancing that of TSP-1. In the meantime, AZ significantly suppressed IM-induced attenuation of VEGF secretion in T47D cells, most probably due to NO inhibition. The combination also dramatically decreased the metastatic activity of T47D cells by mitigating the protein levels of MMP-2 and -9 and phosphorylation of p38 MAPK, while increasing the expression of TIMP-1 and -2. In addition, a strong proapoptotic effect was observed in T47D cells after combining AZ and IM in terms of increased caspase-9 and -3 activities. Interestingly, these results were confirmed by the reduction in the isolated tumor volume, MVD, Ki-67 and VEGF expression. Eventually, the study provides a new therapeutic strategy for treating cancer.

A Therapeutic Insight of Niacin and Coenzyme Q10 Against Diabetic Encephalopathy in Rats.

Diabetes mellitus (DM) is characterized by hyperglycemia due to insulin inactivity or insufficiency with increasing risk of developing specific complications, including retinopathy, nephropathy, neuropathy, and atherosclerosis. The aim of the present study is to evaluate the efficacy of coenzyme Q10 (CoQ10), niacin, as well as their combination in ameliorating brain disorders associated with streptozotocin (STZ)-induced diabetes in rats. Glibenclamide, a reference diabetic drug, and donepezil, an acetylcholine inhibitor drug, were also evaluated. Diabetes was induced by single intraperitoneal injection of STZ (60 mg/kg body weight (b.wt)). One-month diabetic rats were treated with the selected drugs daily for another two consecutive weeks. The evaluation was done through the estimation of the levels of blood glucose, serum insulin, and oxidative stress markers: malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH); neurotransmitters: acetylcholinesterase (AchE) and dopamine (DA); vasoconstrictor indices: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1(VCAM-1), and angiotensin II (Ang II); and apoptosis markers: tumor necrosis factor-α (TNF-α) and caspase-3 as well as the histopathological picture of the cerebellum region of the brain. The results revealed that the combination of niacin and CoQ10 improved most of the measured parameters with variable degrees. In conclusion, niacin and CoQ10 are promising dietary supplements in the management of diabetic encephalopathy.

Serum Vitamin D and Vitamin D Receptor Gene Polymorphism in Mycosis Fungoides Patients: A Case Control Study.

BACKGROUND: Vitamin D has been considered a key player in various malignancies including cutaneous cancers. To date, mycosis fungoides (MF) has been the least studied in relation to vitamin D. Furthermore, the vitamin D receptor (VDR) single nucleotide polymorphisms (SNPs) have not been tackled before in the context of MF, despite their incrimination in numerous diseases. AIM OF STUDY: To assess the role of vitamin D in MF by measuring its serum level, and studying VDR SNPs (TaqI, BsmI, FokI) in different stages of MF. PATIENTS AND METHODS: 48 patients with various stages of MF, and 45 healthy controls were included. Complete history, full clinical examination and a five mm punch skin biopsy were performed to all recruited patients. Venous blood samples were withdrawn from both patients and controls to determine the serum vitamin D level and VDR gene polymorphisms. RESULTS: Serum vitamin D level was significantly lower in patients (5.3-33.7 nmol/L)] compared to controls (8.3-90.1 nmol/L)] (P<0.001). A significant difference was observed between patients and controls regarding the FokI polymorphism only, being higher in patients (P = 0.039). Also Vitamin D serum levels differed significantly in patients with FokI genotypes (P = 0.014). No significant correlations were detected between any of the studied parameters and the demographic and clinical data of the included subjects. CONCLUSION: Depressed vitamin D and FokI polymorphism are potentially involved in the context of MF. VDR gene polymorphisms warrant further larger scale investigations to detect the exact genes involved in the pathogenesis of such an enigmatic disease.

Could Caffeic Acid Phenethyl Ester Expand the Antitumor Effect of Tamoxifen in Breast Carcinoma?

Despite tamoxifen (TAM) is beneficial in treating a significant proportion of patients with breast cancer, many women still relapse after long-term therapy. Caffeic acid phenethyl ester (CAPE) is a component of honeybee propolis, with a plethora of important biological actions including anticancer activity. This study aimed to explore the cytotoxicity, the type of drugs interaction as well as the apoptotic and autophagic pathways of the combined treatment of TAM and CAPE in MCF-7 cells. Their antitumor activity and effect on survival of mice bearing Ehrlich tumor were also analyzed. The results showed synergistic cytotoxic effects, manifested by significant activation of apoptotic machinery, along with downregulation of protein levels of Bcl-2 and beclin-1, upon using the combination regimen. However, the ratio between microtubule-associated protein light chain 3-II and -I was not altered. Moreover, a decrease in vascular endothelial growth factor level was detected. Similarly, TAM + CAPE increased the life span of tumor-bearing animals and caused a marked regression in their tumor size and weight compared with those treated with either TAM or CAPE alone. In conclusion, CAPE relatively improved the anticancer activity of TAM in both in vitro and in vivo models via its apoptotic and angiostatic potentials.

Role of Rho Kinase Inhibition in the Protective Effect of Fasudil and Simvastatin Against 3-Nitropropionic Acid-Induced Striatal Neurodegeneration and Mitochondrial Dysfunction in Rats.

3-Nitropropionic acid (3-NP)-induced neurotoxicity is an experimental model which mimics the pathology and motor abnormalities seen in Huntington's disease (HD) in human. The present investigation was directed to estimate the role of rho kinase (ROCK) inhibition in the possible protective effect of fasudil and simvastatin in 3-NP-induced striatal neurodegeneration in rats. Animals were injected s.c. with 3-NP (20 mg/kg/day) for 1 week with or without administration of fasudil (10 mg/kg/day, p.o.) or simvastatin (20 mg/kg/day, p.o.). At the end of experiment, motor and behavioral abnormalities were evaluated. Animals were then sacrificed for measurement of mitochondrial membrane potential as well as succinate dehydrogenase (SDH) and caspase-3 activities in striatum. Moreover, tumor necrosis factor-alpha (TNF-α) level and protein expressions of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), ROCK, phosphorylated-Akt (p-Akt), endothelial and inducible nitric oxide synthase (eNOS and iNOS), Bax, and Bcl-2 were estimated. Finally, histological changes as demonstrated by striatum injury score, glial activation, and percentage of altered mitochondria were assessed. Both fasudil and simvastatin effectively inhibited 3-NP-induced behavioral, biochemical, and histological changes through inhibition of ROCK activity. However, fasudil provided more amelioration in histological changes, mitochondrial membrane potential and SDH activity in addition to p-Akt and PGC-1α protein expressions. The present study highlights a significant role of ROCK/p-Akt/eNOS pathway in the protective effects of fasudil and simvastatin on neurotoxicity and mitochondrial dysfunction induced by 3-NP in rats. Thus, specific inhibition of ROCK may be considered a promising new approach in the management of HD.

Curcumin, Silybin Phytosome(®) and α-R-Lipoic Acid Mitigate Chronic Hepatitis in Rat by Inhibiting Oxidative Stress and Inflammatory Cytokines Production.

Chronic hepatitis is recognized as a worldwide health problem that gradually progresses towards cirrhosis and hepatocellular carcinoma. Despite the large number of experiments using animal models for allergic hepatitis, it is still difficult to produce a picture of chronic hepatitis. Therefore, this study was conducted to introduce an animal model approximating to the mechanism of chronicity in human hepatitis. The study also aimed to examine the hepatoprotective effects of curcumin, silybin phytosome(®) and α-R-lipoic acid against thioacetamide (TAA)-induced chronic hepatitis in rat model. TAA was administered intraperitoneally at a dose of 200 mg/kg three times weekly for 4 weeks. At the end of this period, a group of rats was killed to assess the development of chronic hepatitis in comparison with their respective control group. TAA administration was then discontinued, and the remaining animals were subsequently allocated into four groups. Group 1 was left untreated, whereas groups 2-4 were allowed to receive daily oral doses of curcumin, silybin phytosome(®) or α-R-lipoic acid, respectively, for 7 weeks. Increases in hepatic levels of malondialdehyde associated with TAA administration were inhibited in groups receiving supplements. Furthermore, glutathione depletion, collagen deposition, macrophage activation and nuclear factor κappa-B expression as well as tumour necrosis factor-α and interleukin-6 levels were significantly decreased in response to supplements administration. Serological analysis of liver function and liver histopathological examination reinforced the results. The above evidence collectively indicates that the antioxidant and anti-inflammatory activities of curcumin, silybin phytosome(®) and α-R-lipoic acid may confer therapeutic efficacy against chronic hepatitis.

Modulation of Tamoxifen Cytotoxicity by Caffeic Acid Phenethyl Ester in MCF-7 Breast Cancer Cells.

Although Tamoxifen (TAM) is one of the most widely used drugs in managing breast cancer, many women still relapse after long-term therapy. Caffeic acid phenethyl ester (CAPE) is a polyphenolic compound present in many medicinal plants and in propolis. The present study examined the effect of CAPE on TAM cytotoxicity in MCF-7 cells. MCF-7 cells were treated with different concentrations of TAM and/or CAPE for 48 h. This novel combination exerted synergistic cytotoxic effects against MCF-7 cells via induction of apoptotic machinery with activation of caspases and DNA fragmentation, along with downregulation of Bcl-2 and Beclin 1 expression levels. However, the mammalian microtubule-associated protein light chain LC 3-II level was unchanged. Vascular endothelial growth factor level was also decreased, whereas levels of glutathione and nitric oxide were increased. In conclusion, CAPE augmented TAM cytotoxicity via multiple mechanisms, providing a novel therapeutic approach for breast cancer treatment that can overcome resistance and lower toxicity. This effect provides a rationale for further investigation of this combination.

Potential antifibrotic and angiostatic impact of idebenone, carnosine and vitamin E in nano-sized titanium dioxide-induced liver injury.

BACKGROUND/AIM: The present study investigated the in vitro and in vivo effects of individual and combined doses of idebenone, carnosine and vitamin E on ameliorating some of the biochemical indices of nano-sized titanium dioxide (n-TiO2) in mice liver. METHODS: The in vitro cytotoxic effect of nano-sized anatase TiO2 (21 nm) on hepatic cell lines (HepG 2) was investigated. Additionally, n-TiO2 was orally administered (150 mg/kg/day) for 2 weeks, followed by a daily intragastric gavage of the aforementioned antioxidants for 1 month. RESULTS: n-TiO2 induced significant cytotoxicity in hepatic cell lines and elevated the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic total antioxidant capacity (TAC) and nitrite/nitrate (NOx) levels. Meanwhile, glutathione-S-transferase (GST) activity was significantly reduced. Moreover, RT-PCR and western blot analysis showed that n-TiO2 significantly altered the mRNA and protein expressions of transforming growth factor-beta (TGF-ß1) and Smad-2, as well as vascular endothelium growth factor (VEGF). Histopathological examination of hepatic tissue reinforced these results. CONCLUSION: Idebenone, carnosine and vitamin E ameliorated the deviated parameters with the combination regimen demonstrating the most pronounced effect. Oxidative stress, liver fibrosis and angiogenesis may be implicated in n-TiO2-induced liver toxicity.

Amelioration of titanium dioxide nanoparticles-induced liver injury in mice: possible role of some antioxidants.

This study investigates the efficacy of idebenone, carnosine and vitamin E in ameliorating some of the biochemical indices induced in the liver of titanium dioxide nanoparticles (TiO2 NPs) intoxicated mice. Nano-anatase TiO2 (21 nm) was administered (150 mg/kg/day) for 2 weeks followed by the aforementioned antioxidants either alone or in combination for 1 month. TiO2 NPs significantly increased serum liver function enzyme activities, liver coefficient and malondialdehyde levels in hepatic tissue. They also suppressed hepatic glutathione level and triggered an inflammatory response via the activation of macrophages and the enhancement of tumor necrosis factor-α and interleukin-6 levels. Moreover, the mRNA expression of nuclear factor-erythroid-2-related factor 2, nuclear factor kappa B and Bax was up-regulated whereas that of Bcl-2 was down-regulated following TiO2 NPs. Additionally, these NPs effectively activated caspase-3 and caused liver DNA damage. Oral administration of idebenone (200mg/kg), carnosine (200mg/kg) and vitamin E (100mg/kg) alleviated the hazards of TiO2 NPs with the combination regimen showing a relatively higher effect. The histopathological examination reinforced these findings. In conclusion, oxidative stress could be regarded as a key player in TiO2 NPs-induced liver injury. The study also highlights the anti-inflammatory and the anti-apoptotic potentials of these antioxidants against the detrimental effects of TiO2 NPs.

Analysis of oxidative stress status, catalase and catechol-O-methyltransferase polymorphisms in Egyptian vitiligo patients.

Vitiligo is the most common depigmentation disorder of the skin. Oxidative stress is implicated as one of the probable events involved in vitiligo pathogenesis possibly contributing to melanocyte destruction. Evidence indicates that certain genes including those involved in oxidative stress and melanin synthesis are crucial for development of vitiligo. This study evaluates the oxidative stress status, the role of catalase (CAT) and catechol-O-Methyltransferase (COMT) gene polymorphisms in the etiology of generalized vitiligo in Egyptians. Total antioxidant capacity (TAC) and malondialdehyde (MDA) levels as well as CAT exon 9 T/C and COMT 158 G/A polymorphisms were determined in 89 patients and 90 age and sex-matched controls. Our results showed significantly lower TAC along with higher MDA levels in vitiligo patients compared with controls. Meanwhile, genotype and allele distributions of CAT and COMT polymorphisms in cases were not significantly different from those of controls. Moreover, we found no association between both polymorphisms and vitiligo susceptibility. In conclusion, the enhanced oxidative stress with the lack of association between CAT and COMT polymorphisms and susceptibility to vitiligo in our patients suggest that mutations in other genes related to the oxidative pathway might contribute to the etiology of generalized vitiligo in Egyptian population.

Chrysin alleviates testicular dysfunction in adjuvant arthritic rats via suppression of inflammation and apoptosis: comparison with celecoxib.

Long standing rheumatoid arthritis (RA) is associated with testicular dysfunction and subfertility. Few studies have addressed the pathogenesis of testicular injury in RA and its modulation by effective agents. Thus, the current study aimed at evaluating the effects of two testosterone boosting agents; chrysin, a natural flavone and celecoxib, a selective COX-2 inhibitor, in testicular impairment in rats with adjuvant arthritis, an experimental model of RA. Chrysin (25 and 50mg/kg) and celecoxib (5mg/kg) were orally administered to Wistar rats once daily for 21days starting 1h before arthritis induction. Chrysin suppressed paw edema with comparable efficacy to celecoxib. More important, chrysin, dose-dependently and celecoxib attenuated the testicular injury via reversing lowered gonadosomatic index and histopathologic alterations with preservation of spermatogenesis. Both agents upregulated steroidogenic acute regulatory (StAR) mRNA expression and serum testosterone with concomitant restoration of LH and FSH. Furthermore, they suppressed inflammation via abrogation of myeloperoxidase, TNF-α and protein expression of COX-2 and iNOS besides elevation of IL-10. Alleviation of the testicular impairment was accompanied with suppression of oxidative stress via lowering testicular lipid peroxides and nitric oxide. With respect to apoptosis, both agents downregulated FasL mRNA expression and caspase-3 activity in favor of cell survival. For the first time, these findings highlight the protective effects of chrysin and celecoxib against testicular dysfunction in experimental RA which were mediated via boosting testosterone in addition to attenuation of testicular inflammation, oxidative stress and apoptosis. Generally, the 50mg/kg dose of chrysin exerted comparable protective actions to celecoxib.