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Coffee is among the most commonly consumed beverage all over the world. Studies have increasingly suggested caffeine and coffee as effective therapeutic interventions against Alzheimer's disease (AD). We have therefore utilized the aluminum chloride rat model for AD to compare the influence of moderately caffeinated (Arabian) and decaffeinated (Date palm seed) coffee on cognitive impairment and pathological events in AD. AD rats given Arabian or Date palm seed coffee were protected against memory impairment and had lower serum levels of the abnormal protein (amyloid-beta; Aβ1-42), the central pathogenic contributor to AD, and transforming growth factor-beta (TGF-β). Interestingly, Date palm seed (decaffeinated) coffee seems to provide more pronounced protection against AD than Arabian (moderately caffeinated) coffee as evidenced by the greater decrease in serum Aβ levels. These results suggest a surprising therapeutic potential of moderate caffeine intake in Arabian coffee to ameliorate AD through decreasing serum Aβ levels. However, Date palm seed (decaffeinated) coffee, rich in flavonoids, appears to provide a better AD-modifying ability through a direct reduction of Aβ production. PRACTICAL APPLICATIONS: Consumption of moderately caffeinated Arabian coffee attenuated AD-induced cognitive impairment via its anti-amyloidogenic potential, decreasing Aβ levels. Moreover, intake of decaffeinated Date seed extract, rich in flavonoids, exerted a superior anti-AD potential through a direct reduction of Aβ production. Both of them were also safe and maintained hepatic and renal functions in a rat model of AlCl3 -induced AD. Further clinical studies are warranted to confirm current results and to recommend the regular drinking of Arabian coffee or Date seed extract as a protective approach to delay AD progression in vulnerable individuals or in early disease stages.

Organophosphorus pesticides are widely used as insecticides in agriculture both in developed and developing countries in spite of reported poten­tial toxicity. They induce neurotoxic effects either upon acute or chronic exposure. It was found previously that zinc (Zn) supplementation exerted a neuroprotective effect against organophosphorus pesticide-induced neurodegenerative disorders in experimental animals. This study therefore, aimed to investigate the possible association between serum zinc level and organophosphorus-induced delayed polyneuropathy. Fifty acute organophosphorus poisoned cases admitted to Zagazig University Hospitals from February to August 2016 were enrolled in this study. Another Forty six healthy individuals (age- and sex-matched) served as a control group. Both groups were investigated for serum lipid peroxidation product (malondialdehyde: MDA) and total antioxidant capacity (TAC) levels as well as lymphocytic neuropathy target esterase (NTE) and plasma acetylcholinesterase (AChE). Then, they were followed up for 4 weeks to assess the development of delayed polyneuropathy (diagnosed clinically and confirmed by motor and sensory conduction studies). Serum levels of Zn, MDA and TAC as well as lymphocytic NTE and plasma AChE were measured for those developed organophosphorus delayed polyneuropathy. Organophosphorus intoxication has resulted in a significant elevation in the levels of MDA, suggesting oxidative stress. On the other hand, TAC levels as well as measured lymphocytic NTE and plasma AChE activities were found to be significantly reduced in the intoxicated group. However, at the end of the follow up period, 7 cases developed delayed polyneuropathy; 5 of them were Zn deficient while the rest were with normal Zn level. Cases with delayed polyneuropthy showed also a significant increase in lipid peroxidation along with impairment of estrases activities compared to cases on admission. Furthermore, serum Zn level showed a significant positive correlation with TAC, AChE, NTE and a negative correlation with MDA, where serum zinc level seems to be the strongest determinants for the prediction of delayed polyneuropathy. Thus, we conclude that Zn deficiency has a potential role in organophosphorus -induced delayed polyneuropathy. This may be due to its involvement in the activity of antioxidant enzymes. However, further future large scale studies are needed to clarify the exact mechanism by which Zn deficiency mediated neurotoxicity upon organophosphorus induced polyneuropathy.

In breast cancer, there has been evidence of atypical activation of signal transduction and activators of transcription 3 (STAT3). Thymoquinone (TQ) exerts its anti-neoplastic effect through diverse mechanisms, including STAT3 inhibition. The tumor suppressor, microRNA-125a-5p was reported to be downregulated in various breast cancer cells. Therefore, we investigated the influence of TQ and/or doxorubicin on microRNA-125a-5p and its correlation with STAT3 activation as well as tumor growth in mice bearing solid Ehrlich tumors. We found that TQ markedly suppressed inducible and constitutive phosphorylation of STAT3 in tumor tissue without affecting STAT5. Moreover, it attenuated tumor growth, downregulated STAT3 downstream target proteins, and increased the apoptotic activities of caspase-3 and -9. Interestingly, TQ-elicited synergism of doxorubicin anti-neoplastic activity was coupled with upregulation of tumoral microRNA-125a-5p. Taken together, the current findings raise the potential of TQ as a promising chemomodulatory adjuvant to augment mammary carcinoma sensitivity to doxorubicin.

10-Dehydrogingerdione is a novel cholesteryl ester transfer protein (CETP) inhibitor of natural origin. Some synthetic CETP inhibitors have recently been reported to suppress proprotein convertase subtilisin/kexin type 9 (PCSK9). Therefore, the present study aimed mainly to clarify the effect of 10-Dehydrogingerdione on cellular adhesion inflammatory molecules, platelet activation and endothelial dysfunction markers in addition to PCSK9 as compared to atorvastatin in dyslipidemic rabbits. Dyslipidemia was induced in 30 male rabbits, distributed in 3 equal groups through feeding dietary cholesterol (0.5% w/w) for 3 months. Two dyslipidemic groups were concurrently treated with either atorvastatin or 10-Dehydrogingerdione (10 mg/kg/ day, p.o) and dietary cholesterol. One additional group including 10 normal rabbits fed normal diet served as normal control (NC) group. Both 10-Dehydrogingerdione and atorvastatin significantly reduced serum CETP level and activity as well as PCSK9 and low density lipoprotein cholesterol (LDL-C) levels but increased high density lipoprotein cholesterol (HDL-C) levels as compared to dyslipidemic control (DC) rabbits (p

Platelet markers [soluble p selectin (sP-selectin) and soluble CD40 ligand (sCD40L)] are associated with platelet activation and cardiovascular risk. Both policosanol and 10-dehydrogingerdione are natural products with proven CETP inhibitory and antiatherogenic effects. Present work aimed mainly to investigate the levels of platelet activation biomarkers in the serum of dyslipidemic rabbits and the potential of these phytochemicals either alone or in a combination form to protect against atherogenicity. Additionally, this work clarified their effect on PCSK9, a key player in atherosclerosis progression. Daily administration of policosanol and/or 10-dehydrogingerdione at a dose level 10 mg/kg bw resulted in a CETP inhibitory activity, increasing HDL-C level. This protective effect was associated with improvement in lipid profile components and a reduction in PCSK9 level. Interestingly, this combination strengthened the CETP inhibitory activity of these phytochemicals, leading to a greater increase in serum HDL-C level than monotherapy. However, this combination did not enhance the reduction in PCSK9 level. Both drugs also decreased platelet activation and inflammation markers such as sCD40L, sP-selectin, and interferon-gamma (IFN-γ), and their combination showed a synergistic effect. Therefore, such phytochemicals may be regarded as promising agents in the protection against atherothrombosis risk.

Our objective was to figure out whether CYP2D6 gene polymorphisms may account for long term tramadol-induced oxidative stress and hepatotoxicity in 60 patients receiving chronic tramadol treatment in Neurology and Rheumatology Outpatients Clinic, Zagazig University Hospitals, Egypt. As expected, CYP2D6*1 allele (wild type) frequency was significantly greater than CYP2D6*DUP, CYP2D6*4 and CYP2D6*10 alleles in both chronically tramadol-treated and control groups. In tramadol-treated patients, CYP2D6*DUP allele carriers followed by those carrying CYP2D6*1, displayed higher levels of urinary tramadol major active metabolite, O-desmethyltramadol (M1) and serum lipid peroxidation along with lower levels of total antioxidants than those carrying other impaired function alleles (CYP2D6*4&*10), suggesting oxidative stress. There were also significant increases in serum hepatic damage markers including alpha-glutathione transferase (α-GST) levels and liver function enzyme activities in *DUP and *1 carriers compared to carriers of other alleles. Moreover, we reported that in 42 patients with allele *1, tramadol caused mild to moderate hepatotoxicity (grades: 1-2) within 13-16 months while in 7 patients with duplicated allele (*DUP), tramadol caused moderate to severe hepatotoxicity (grades: 2-3) within 10-11 months (moderately longer period but shorter than that observed in allele *1), implying that exposure to tramadol for longer time in extensive and ultra-rapid metabolizers may contribute to hepatotoxicity development. Overall, our results suggest that CYP2D6 gene polymorphisms, particularly enhanced or normal function of CYP2D6, may increase the vulnerability to long term tramadol-induced hepatotoxicity through the enhancement of accumulation of tramadol bioactive metabolite (M1) and hence oxidative stress. Therefore, tramadol doses should be adjusted according to patient's CYP2D6 genotyping analysis to avoid hepatotoxicity.

This study aimed to assess the correlation of serum lactate and creatine phosphokinase (CPK) levels, and their association with severity of organophosphrus poisoning in order to use one of them or both as tools in predicting prognosis. This study was conducted over one year and 68 organophosphate (OP)-poisoned patients were enrolled. Clinical severity of cases was categorized according to Peradeniya organophosphorus poisoning (POP) scale. Levels of serum acetyl choline esterase (AChE), serum CPK and serum lactate were measured on admission (0 h), 6 and 24 h post-ingestion. The results showed a high statistically significant difference between cases and control regarding AChE, CPK and lactate on admission. Also, there was high statistically significant difference regarding AChE, CPK and lactate among different categories of cases on admission, 6 and 24 h post admission. In addition, there was a statistically significant increase among different categories of POP scale regarding the quantity of atropine used in management of cases. Regarding oximes and stay in ICU, there was a statistically significant increase in severe poisoned patients when compared with moderate poisoned ones. A significant negative correlation was observed between AChE and severity of poisoning as well as significant positive correlation between CPK and lactate. It is concluded that serum CPK and serum lactate can be used as predictor of outcomes in OP poisoning and helps in determining cases that need follow up. Serum CPK and serum lactate can be used as predictors of outcomes in OP poisoning and helping in determining the cases that need follow up. Key words: Organophosphrus poisoning, serum lactate, predicting prognosis, serum, admission.

Aims Hypercholesterolemia is a hazard for increasing susceptibility of the heart to myocardial infarction (MI) by inducing platelet hyperaggregability. Clopidogrel and prasugrel have documented cardioprotective effects in clinical studies. Herein, we investigated whether clopidogrel and prasugrel could protect against isoproterenol-induced acute MI (A-MI) under hypercholesterolemic conditions in rats. Main methods Dietary hypercholesterolemic rats were subjected to acute doses of isoproterenol. Serum lipids, inflammatory markers, aortic endothelin1 and endothelial nitric oxide synthase (eNOS) mRNAs expression and immunexpression of BCL2 were determined. Key findings Hypercholesterolemic rats showed infiltration of inflammatory cells and reduction in aortic wall thickness, deposition of fibrous tissue between cardiac muscle fibers. Protective doses of prasugrel or clopidogrel for 28 days before A-MI increased survival, amended the ECG parameters -including ST segment elevation- and improved the histopathological picture in hypercholesterolemic rats. This was coupled with reductions in platelet aggregation, creatine kinase-MB activity, endothelin 1, systemic inflammation and cardiac lipid peroxidation and increment in aortic eNOS expression. Clopidogrel and prasugrel groups showed enhanced BCL2 expression in cardiac fibers and aortic wall. Significance Prasugrel and clopidogrel protected against A-MI via anti-aggregatory and anti-inflammatory effects. These results add to the value of these drugs in correcting cardiovascular dysfunction in patients vulnerable to A-MI after confirmation by appropriate human studies.

Cisplatin is a widely used chemotherapeutic agent in treating various types of cancers. However, it can induce neurotoxicity and nephrotoxicity, limiting its dose and clinical use. Although previous studies indicated the direct link between cisplatin-induced central neurotoxicity and oxidative stress, the exact mechanism is not completely understood. Therefore, herein we investigated the effects of prophylactic and concurrent treatment with (−)-epigallocatechin-3-gallate (EGCG), a natural polyphenolic neuroprotective antioxidant, on cisplatin-induced brain toxicity in rats to delineate its molecular mechanism of action. We found that cisplatin initiated a cascade of genetic, biological, and histopathological changes in the brain cortex, inducing inflammatory cytokines, appearance of scattered inflammatory cells, nitro-oxidative stress, and apoptotic proteins in the cerebral cortex. However, EGCG not only protected against cisplatin-induced inflammatory burden but also ameliorated the induction of nitro-oxidative stress and apoptotic proteins triggered by cisplatin in the cerebral cortex of pre- and co-treated rats with respect to their unprotected counterparts. EGCG anti-inflammatory effect here may be attributed to the downregulation of nuclear factor kappa B (NF-κB). Additionally, this natural polyphenol significantly ameliorated cisplatin-elicited reduction in cerebral cortex brain-derived neurotrophic factor and acetylcholine esterase. Upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream heme oxygenase-1 (HO-1) by EGCG prophylactic and concurrent administration here seems also to play a key role in the protective impact of EGCG against cisplatin toxicity through enhancing total antioxidant capacity. Thus, EGCG can be used as a promising prophylactic adjuvant for preventing the development of brain inflammation and oxidative damage associated with cisplatin chemotherapy.

Insulin-degrading enzyme (IDE, insulysin) is a rate-limiting enzyme in the insulin degradation process. It is an intracellular 110-kDa thiol zinc-metalloendopeptidase located in the cytosol, peroxisomes, endosomes and cell surface. IDE catalyzes degradation of several small proteins including insulin, amylin and β-amyloid protein. In addition, insulin clearance was expressed as a target in the treatment of type 2 diabetes given the role of hyperinsulinemia in the pathogenesis of insulin resistance. In this study, fourtyadult male Wistar albino rats were used, thirty rats received 20% fructose in drinking water (HFW) for six weeks to induce diabetes. Subsequently, these rats developed significantly higher body weights, dyslipidemia, hyperglycemia and insulin resistance compared to their controls. Significant increase in the levels of serum glucagon, IDE in liver tissue along with an inhibition of insulin receptor phosphorylation were also observed. Concurrent oral administration of vitamin D3 along with HFW resulted in significant decrease of serum glucose, total cholesterol, triacylglycerol and LDL-C levels. Vitamin D alleviated also insulin resistance, where both IDE, glucagon levels showed significant decrease along with activation of insulin receptor phosphorylation. Normal rats, received vitamin D3 only demonstrated non significant changes of the studied biomarkers. We concluded that vitamin D3 ameliorated insulin resistance and hyperinsulinemia in diabetic rat model received HFW through reduction of IDE and activation of insulin receptor phosphorylation.

Tacrolimus is a powerful immunosuppressive agent with hepatotoxic and nephrotoxic effects. It has a protective role against many toxicants. This study was conducted to evaluate the possible protective role of spirulina against tacrolimus induced hepatotoxicity and nephrotoxicity. Forty adult male albino rats divided into 4 groups. Group I, control group, Group II, spirulina group (received spirulina 500 mg/Kg body weight (bw)/day orally), Group III, tacrolimus group (received tacrolimus 12 mg/kg bw/day orally); and Group VI, prophylactic group (orally administered spirulina for 3 days before and 28 days concurrently with tacrolimus in the same previous doses). Tacrolimus induced adverse effects on both liver and kidney functions and structure that was manifested by elevated hepatic transaminases, total and direct bilirubin, albumin, blood urea nitrogen, serum creatinine and creatinine clearance. There was a significant decrease in serum total antioxidant capacity (TAC) and hepatic and renal total thiol molecules (TTM), with a significant increase in serum malondialdehyde in tacrolimus group. Histopathologically, tacrolimus induced swelling and granulation of hepatocytes, congestion of blood sinusoids and degeneration of bile ductiles, glomerular hypertrophy and segmentation, swelling, degeneration and hyalinosis of renal tubules. Spirulina pre- and co-treatment significantly improved these deleterious effects. This was accompanied by partial restoration of the expression of PCNA near to the normal level observed in control rats. Moreover, spirulina treatment did not alter the trough blood tacrolimus levels or tacrolimus-induced immunosuppression. Further studies are warranted to evaluate whether transplant patients on tacrolimus treatment may benefit from the protective effects of spirulina. Key words: Antioxidant, malondialdehyde (MDA), total antioxidant capacity (TAC), tacrolimus, total thiol molecules (TTM), proliferating cell nuclear antigen (PCNA), spirulina.

Insulin-degrading enzyme (IDE) is the major zinc-metalloprotease involved in the cleavage of insulin, β-amyloid protein and mainly contributes to the pathophysiology of type 2 diabetes and Alzheimer’s disease. Therefore, this enzyme is expressed as candidate target for drugs used in the management of diabetes and peptide hydroxamates have been reported recently as inhibitors for IDE. Novel synthesized peptide hydroxamic acid II containing tryptophan and a sulfonamide bond has been prepared in our laboratory. The aim of this study was to determine whether this drug could be of value in modulating diabetic states in rats. In this study, forty adult male Wistar albino rats received 20% fructose in drinking water (HFW) for six weeks to induce diabetes. Administration of the prepared compound at two dose level (5 and 10 mg/kg body weight, p.o) to diabetic rats significantly reduced IDE protein, glucagon levels, improved insulin receptor signaling (phosphorylation), insulin sensitivity and lipid profile. However, it induced certain up-regulation of IDE mRNA expression. These findings may confirm its role in the modulation of glucose homeostasis through IDE and insulin receptor signaling. Key words: Insulin degrading enzyme, insulin receptors phosphorylation, insulin resistance, glucagon, hyperlipidemia.

Atrazine (ATZ) is one of the most commonly used herbicides contaminating plants, soil and water resources. Several strategies have been used to counteract ATZ toxicity. Here, we tested the hypothesis that lycopene could ameliorate ATZ-induced toxicity in the adrenal cortex. For this purpose, 35 adult male albino rats were randomized into five equal groups: untreated control, vehicle control (received 0.5 mL corn oil/day), lycopene (treated with lycopene dissolved in 0.5 mL corn oil, 10 mg/kg b.w./day), ATZ (received ATZ dissolved in 0.5 mL corn oil 300 mg/kg b.w./day), and ATZ + lycopene (treated with ATZ and lycopene at the same previously mentioned doses). All treatments were given by oral gavage for 4 weeks. We found that ATZ exposure significantly increased relative adrenal weight, plasma ACTH levels, and adrenal oxidative stress as manifested by elevated malondialdehyde levels, decreased reduced glutathione content and depressed antioxidant enzyme activities in adrenal cortex tissues with respect to control groups. Furthermore, the transcription of adrenal cortex nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear factor kappa B, and caspase-3 genes was increased significantly compared with the control groups. This was accompanied with DNA fragmentation and structural and ultrastructural changes in zona glomerulosa and zona fasiculata of the adrenal cortex. Notably, all these changes were partially ameliorated in rats treated concomitantly with ATZ and lycopene. Our results showed that lycopene exerts protective effects against ATZ-induced toxicity in rat adrenal cortex. These effects may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO-1 pathway.

Aims Bisphenol A (BPA) has been shown to induce liver fibrosis in rodents. Therefore, this study examined the protective effect of a triple combination of curcumin (Cur), N-acetyl cysteine (NAC) and propolis (Prp) extract against BPA-induced hepatic fibrosis. Methods 100 Wistar male rats were equally assigned into 10 groups; one group was designated as control. 10 rats were gavaged with BPA (50 mg/kg/day) for 8 wk and left un-treated (BPA group). The remaining 80 rats were divided into 8 groups, distributed in 2 models. Protective model: rats were daily co-treated with BPA and Cur (100 mg/kg, p.o) or NAC (150 mg/kg, p.o) or Prp (200 mg/kg, p.o) or their combination for 8 wk. Preventive model: rats were daily treated with Cur or NAC or Prp or their combination for 4 wk before BPA administration and then in the same manner as protective model. Key findings Current treatment interventions significantly alleviated BPA-induced hepatic damage and fibrosis. They also restored pro-oxidant/antioxidant balance, shifted cytokine balance towards the anti-inflammatory side, decreasing interleukin-1β/interleukin-10 ratio. Moreover, these compounds seem to exert anti-apoptotic effects by increasing the immunoexpression of B-cell lymphoma 2 in hepatocytes and decreasing hepatic caspase-3 content. Finally, they ameliorated extracellular matrix turn over through down-regulation of matrix metalloproteinase-9 and up-regulation of tissue inhibitor of matrix metalloproteinase-2 genetic expression. Significance Current treatments guarded against BPA-induced hepatic fibrosis due to their antioxidant, anti-inflammatory and anti-apoptotic properties, decreasing extracellular matrix turnover. Interestingly, the triple therapy provided hepatoprotection superior to monotherapy. Besides, prophylactic and concurrent treatments seem to be more effective than concurrent treatments.

Aims Although chloroquine and diclofenac are not cardiovascular drugs, their chronic administration may trigger cardiotoxicity. We, therefore, evaluated the cardiotoxic impact of diclofenac in chloroquine-treated adjuvant arthritic rats and the protective role of Rho-kinase inhibitors. Methods 90 male rats were equally distributed into 9 groups including control. Arthritis was induced by S.C injection of Complete Freund's adjuvant in hind paw plantar surface. Arthritic rats were subdivided into 8 groups, orally treated with: no drug, chloroquine (50 mg/kg), diclofenac sodium (1 mg/kg) and chloroquine + diclofenac. To study the role of Rho-kinase in chloroquine/diclofenac-triggered cardiotoxicity, four arthritic groups were also co-treated with Rho-kinase inhibitors (fasudil or atorvastatin) along with diclofenac and chloroquine + diclofenac. Key findings All treatments significantly elevated serum cardiac injury and dysfunction markers as well as left ventricular malondialdehyde but depleted antioxidants with the greatest effect in the combination group. Chloroquine and/or diclofenac; in particular, their combination shifted the balance between left ventricular pro- and anti-apoptotic proteins towards myocardial apoptosis. Surprisingly, treatment with diclofenac or chloroquine/diclofenac markedly up-regulated cardiac RhoA and Rho-kinase1. Such up-regulation was coupled with a greater increase in cardiac oxidative damage biomarkers in the combination group than in individually-treated ones. However, Rho-kinase inhibition protected against diclofenac-induced increase in myocardial oxidative damage markers. Significance Diclofenac greatly amplified cardiac oxidative damage in chloroquine-treated arthritic rats via up-regulation of Rho-kinase1. However, Rho-kinase inhibitors provided cardioprotection against diclofenac toxicity. Overall, they could be used as safer adjuvants to diclofenac during the treatment of rheumatoid arthritis with chloroquine.

The rational of the current study was to assess whether Tribulus terrestris extract (TTE) could alleviate long-term copper (Cu) overload-induced testicular dysfunction compared to enalapril and losartan. Rats were administered either vehicle (control group, n = 10) or copper sulfate pentahydrate (CuSO4·5H2O, 200 mg/kg, p.o) for 90 days (n = 40). Cu-treated rats were randomized into four equal groups. One group was left untreated (Cu group) while the remaining three groups were daily co-treated with one of the following treatments along with CuSO4: TTE (10 mg/kg, p.o); enalapril (30 mg/kg, p.o); losartan (10 mg/kg, p.o). Excess Cu intake resulted in Cu overload coupled with a significant elevation in systolic blood pressure and serum angiotensin II levels along with a reduction in serum nitric oxide level. All concomitant treatments led to an alleviation of such deleterious effects. However, only losartan failed to ameliorate angiotensin II elevation. Additionally, all treatments protected the testes against Cu-overload-elicited zinc depletion and oxidative stress. Regarding reproductive function, the relative weights of testes, serum levels of testosterone and luteinizing hormone; the expression of steroidogenic genes; the protein levels of angiotensin II type 1 receptor and angiotensin converting enzyme 1, in addition to its activity, they were significantly reduced. Amongst all treatments, only TTE and E were able to revert these reproductive changes. In conclusion TTE and E were able to protect against Cu overload-induced impairment of testicular steroidogenesis. Thus, they might be considered as prophylactic drugs of choice against hypertension and testicular dysfunction to ameliorate Cu overload risk.

The present study aimed to investigate the inhibitory effects of 10-dehydrogingerdione (10-DHGD) and pentoxifylline (PTX) either individually or in combined form on calcium deposition in high cholesterol diet (HCD)-fed rabbits as compared to atorvastatin (ATOR), and to clarify the underlying mechanisms. Three-months-old male New Zealand white rabbits received either normal chow or HCD for 12 weeks. The latter group was subdivided into five groups and concurrently treated either with vehicle (dyslipidemic control), ATOR, 10-DHGD, PTX or combined 10-DHGD and PTX. Blood samples and aortic tissue were collected for biochemical and histological analyses. HCD-fed rabbits displayed dyslipidemia, inflammation, atherosclerotic lesions, and calcium deposition in aortas as compared to normal group. This was associated with up-regulation of bone morphogenetic protein-2 (BMP-2), wingless-type MMTV integration site family 3A (Wnt3a) mRNA levels and osteopontin expression in their aortic tissue, along with higher serum alkaline phosphatase and osteocalcin levels. Furthermore, a marked decrease in osteoprotegerin, along with a significant increase in receptor activator of NF-κB(RANK) levels, was found in aortic tissue of dyslipidemic rabbits. 10-DHGD and PTX monotherapy significantly modulated the afore-mentioned calcification markers and attenuated aortic calcification to greater extent than ATOR. Combination of 10-DHGD and PTX exerted more anti-calcifying effect than either individual drug. Our findings suggested therapeutic roles of 10-DHGD and PTX against aortic calcium deposition in dyslipidemic rabbits, likely mediated by HDL-raising effect and attenuation of associated inflammation. Combination of 10-DHGD and PTX may represent a promising therapeutic strategy for aortic calcification associated with atherosclerosis.

Policosanol (POL) is a hypocholesterolemic drug of natural origin and has been shown to reduce circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) in healthy participants. Recently, we have reported that POL can attenuate aortic calcification in diabetic dyslipidemic rats; however, the underlying mechanism is not fully elucidated. We aimed to investigate the effect of POL on aortic calcification and whether PCSK9 has a contributory role and also to examine whether the combination of POL with pentoxifylline (PTX) as anti–tumor necrosis factor α would offer additional benefits. Thirty adult male New Zealand rabbits weighing 1.5 to 2 kg were randomly assigned to 5 groups. One group received standard chow diet and served as normal control group (NC). The other 4 groups received 0.5% wt/wt cholesterol-rich diet for 12 weeks and concurrently treated with placebo, POL, PTX, or a combination of POL and PTX. Sera samples and aortic tissue were collected for biochemical measurements and histological assessment. Rabbits fed a cholesterol-rich diet demonstrated dyslipidemia, increased inflammatory state, and elevated serum levels of PCSK9, compared to the NC group. Aortic calcification was evident in dyslipidemic rabbits, represented by increased calcium deposition and osteopontin expression in aortic tissue, along with elevated serum levels of alkaline phosphatase and osteocalcin. Dyslipidemic rabbits showed a significant upregulation of wingless-type MMTV integration site family 3A and bone morphogenetic protein 2 genes in their aortic tissue. Policosanol significantly reduced circulating PCSK9 levels, suppressed calcification markers, and attenuated aortic calcification. Combination of POL with PTX alleviated aortic calcification to a greater extent than either monotherapy, which may be attributed to further suppression of PCSK9 and calcification markers. These findings suggested that POL exerted anticalcifying effect partly via inhibition of PCSK9. Combination of POL and PTX offered additional benefits and might represent a promising therapeutic option for aortic calcification.

Aluminum (Al) is an environmental xenobiotic that stimulates free radical generation and hence reproductive toxicity. Coenzyme Q10 (CoQ10) effectively counteracts free radical-induced tissue damage. Omega-3 polyunsaturated fatty acids present in fish oil (FO) exert beneficial effects on reproduction in male animals. This study therefore investigated the effects of both agents on testicular dysfunction induced by aluminum chloride (AlCl3). Fifty male rats were gavaged with either 1% gum acacia (control group) or AlCl3 (34 mg/kg/day) for ten weeks. Concurrently, AlCl3-treated rats received no treatment, CoQ10 (10 mg/kg/day, p.o.), and/or FO (400 mg/kg/day, p.o.) for ten weeks. AlCl3 caused a significant decrease in serum testosterone, luteinizing hormone (LH), and follicular stimulating hormone (FSH), as well as testicular weight, antioxidant enzyme gene expression and activities, reduced glutathione, zinc, adenosine 3',5'-cyclic monophosphate (cAMP) contents, and number of Leydig cells, along with down-regulation of 3beta-hydroxysteroid dehydrogenase (3β-HSD), 17β-HSD, steroidogenic acute regulatory protein (STAR), and cholesterol side-chain cleavage enzyme (P450scc) gene expression. However, testicular Al, malondialdehyde (MDA), and nitric oxide (NO) levels were markedly increased. Treatment with CoQ10 and FO, alone or in combined form led to an improvement in the aforementioned biomarkers. Overall, individual or combined treatment with CoQ10 and FO could ameliorate the toxic effects of AlCl3 on testicular tissues by mechanisms related to their potent antioxidant potential and stimulatory effects on steroidogenic enzymes transcription. CoQ10 seems to be better than FO regarding oxidative and nitrosative stress, Zn deficiency, and Al overload. However, FO showed more pronounced effect than CoQ10 on hormones, steroidogenic markers, and cAMP. A cocktail of both demonstrated greater protective effects on testicular tissues than monotherapy.

Selenium nanoparticles (Se-NPs) are customizable drug delivery vehicles that show good bioavailability, higher efficacy and lower toxicity than ordinary Se. Pre-treatment of male rats with these NPs has been recently shown to exert a protective effect against chromium-induced thyroid dysfunction. This study, therefore, aimed to investigate and characterize the potential protective mechanism of Se-NPs against lead (Pb) acetate-induced thyrotoxicity. We found that prophylactic and concurrent treatment of Pb acetate-exposed rats with Nano-Se (0.5 mg/kg, i.p) for 15 wk significantly alleviated the decrease in free triiodothyronine (fT3) and free thyroxine (fT4) levels as well as fT3/fT4 ratio% and the increase in thyroid stimulating hormone (TSH) levels to approach control values. This was accompanied by a reduction in the accumulation of Pb in serum and thyroid tissues as well as maintenance of thyroidal pro-oxidant/antioxidant balance and iodothyronine deiodinase type 1 (ID1), an essential enzyme for metabolizing of T4 into active T3, gene expression. Surprisingly, miR-224, a direct complementary target of ID1 mRNA, expression in the thyroid tissues was significantly down-regulated in Nano-Se-pre- and co-treated Pb acetate intoxicated animals. Such changes in miR-224 expression were negatively correlated with the changes in ID1 gene expression and serum fT3 level. These results suggest that Se-NPs can rescue from Pb-induced impairment of thyroid function through the maintenance of selenoproteins and down-regulation of miR-224.

In vivo and in vitro studies suggested that chromium enhances insulin sensitivity by promoting insulin receptor signaling. However, its effect on insulin clearance has not been yet identified. Nigella sativa, a widely used spice, possesses an antidiabetic activity. We, therefore, hypothesized that chromium picolinate may alter insulin clearance by modulating insulin-degrading enzyme (IDE) in insulin-resistant rats. We evaluated also the effect of Nigella sativa oil on insulin signaling and degradation with respect to chromium picolinate. To assess these hypotheses, insulin resistance was induced in 30 male Wistar albino rats through daily oral administration of high-fructose water (HFW, 20% w/v) for 45 days. These rats were then divided into three groups (n = 10/group). They were given either no treatment (control group) or Nigella sativa oil (500 mg/kg bw/day) or chromium picoloinate (200 μg/kg bw/day) orally along with HFW (20% w/v) for 45 days. Nigella sativa oil or chromium picolinate concurrent administration with HFW significantly decreased body weight, serum lipids, glucagon, insulin resistance, and hepatic IDE level but increased its mRNA expression and insulin receptor phosphorlyation as well as high-density lipoprotein cholesterol (HDL-C) level as compared to control group values, suggesting their potential as modulators for insulin signaling and clearance. However, Nigella sativa oil exerted better improvement in feeding efficacy ratio as well as the levels of glucagon, insulin, insulin resistance, hepatic IDE level and insulin receptor phosphorylation than chromium picolinate, suggesting its greater insulin sensitizing capacity. Our data, for the first time, prove that Nigella sativa oil and chromium picolinate monotherapy can reduce fructose-induced insulin resistance by reduction of hepatic IDE protein and activation of insulin receptor signaling.

Hairdressers are chronically exposed to several occupational hazards during their work including potentially genotoxic chemicals. Hair dying, hair smoothening and straightening products are hazardous chemicals that affect human health and are frequently used in beauty salons. So, this study aimed to evaluate the genotoxic risk among the studied hairdressers, to estimate the level of p-phenylenediamine (p-PDA) in urine and to assess the degree of adherence of the studied hair- dressers to occupational safety measures at work. A comparative cross sectional study was carried out on 40 hairdressers working in beauty salons in Zagazig city, Egypt and 40 administrative staff at faculty of medicine as a control group. The results of the study revealed a significant increase in mean concentration of urinary p-PDA as well as significant increase in DNA damage assessed by Comet assay in lymphocytes among studied hairdressers than among their controls. Also, there was a statistically significant decrease in adherence to most of the occupational safety precaution measures that should be followed by the studied hairdressers. The significant risk factors of high Comet total mean score among the studied hairdressers were occupational use of hair straightening ≥8 times/week, use of hair dyes at work ≥15 times/week, length of service ≥13 years, negligence of wearing gloves during work, use of bleaching agents ≥12/week and negligence of hand wash after handling chemicals. So, it was concluded that the hairdressers are occupationally exposed to the risk of genotoxic hazards from chemicals frequently used in their work. The lack of commitment to occupational safety measures at beauty salons like wearing gloves during work and hand washing increases the risk of genotoxicity.

Alpha-cypermethrin (α-CYP) is one of the most widely used insecticides. It may become an air pollutant and adversely affect the health. The present study was designed to determine whether treatment with N-acetyl cysteine (NAC), a well-known antioxidant, can be useful for the management of the deleterious effects of α-CYP on lung tissues. For this purpose, thirty two male rats were divided into four different groups (eight rats for each). Group (I) gavaged with corn oil (control group), group (II) gavaged daily with NAC (150 mg kg−1 body weight), group (III) gavaged with α-CYP (14.5 mg kg−1 body weight/day, dissolved in corn oil), group (IV) gavaged with NAC then with α-CYP 2 h later for 12 weeks. α-CYP significantly increased serum lactate dehydrogenase (LDH) and pulmonary malondialdehyde (MDA) levels, while decreased the activities of catalase (CAT) and superoxide dismutase (SOD) as well as reduced glutathione (GSH) content in lung. It also provoked higher levels of serum nitric oxide (NO), lung interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), hydroxyproline (Hyp) as well as heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-КB) gene expression in lung tissues. Histopathological alterations in lung with congestion, cellular infiltration, necrotic changes and thickening of inter-alveolar septa were observed following α-CYP administration. NAC reduced the adverse effects of α-CYP on lung tissues and improved the histological architecture of lung since it showed antioxidant, anti-inflammatory and antifibrotic effects on lung tissues. Our results indicate that NAC exerts a potent protective effect against α-CYP-induced oxidative damage and inflammation in lung tissues. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 26–43, 2015.

Carbon monoxide (CO) poisoning is a leading cause of toxicity-related mortality and morbidity worldwide. Recent studies focused on CO-induced cardiovascular toxicity. Oxidative stress plays an important role in the pathophysiology of CO toxicity. The aim of this study was to elucidate the relationship between cardiac damage biomarkers and oxidative stress biomarkers in patients with CO-induced cardiotoxicity. This study was carried out on 36 CO-poisoned patients admitted to Zagazig University Hospitals. Forty healthy individuals (age- and sex-matched) were selected as a control group. Clinical examination and electrocardiography (ECG) were performed for CO-poisoned patients. These patients have been investigated for carboxyhaemoglobin percent (COHB%) and cardiac damage biomarkers; cardiac troponin I (cTn-I), heart-type fatty acid-binding protein 3 (H-FABP3). Oxidative stress biomarkers comprising malondialdehyde (MDA), asymmetric dimethylarginine (ADMA), and total antioxidant capacity (TAC) have been also assessed. All biomarkers have been assessed on admission (0 h) and 6 h after treatment of CO-poisoned patients with high-flow oxygen and compared with those of the control groups. ECG findings were abnormal in 31 patients (86.11%), where sinus tachycardia was the commonest finding (58.33%). There was a statistically significant increase of COHB%, MDA, ADMA, and H-FABP3 levels, and a significant decrease of TAC level in CO-poisoned patients compared to controls with no significant changes in cTn-I. Six hours following treatment, all measured parameters were significantly improved except for cTn-I, which was significantly increased when compared with admission status (0 h). Furthermore, H-FABP3 showed a significant positive correlation with COHB%, MDA, ADMA, and a negative correlation with TAC, while cTn-I was significantly correlated with COHB% only. ADMA and MDA seem to be the strongest determinants for the prediction of H-FABP3 changes and hence cardiovascular toxicity. Thus, cardiac damage in patients with CO poisoning could be partially mediated by CO-induced oxidative stress, where H-FABP3 level was directly and strongly associated with MDA and ADMA levels.

Summary Bisphenol A (BPA) is a key monomer in the production of plastics. It has been shown to be hepatotoxic. Inflammation and oxidative stress are closely linked with liver fibrosis, the major contributing factor to hepatic failure. Therefore, the aim of this study was to evaluate the impact of chronic exposure to BPA on the development of hepatic fibrosis in male rats and to determine the cross-talk between the hepatic cytokine network, oxidative stress and apoptosis. For this purpose, 30 male Wistar albino rats were divided into three equal groups as follows: the first group was given no treatment (normal control group); the second group was given corn oil once daily by oral gavage for 8 weeks (vehicle control group); and the third group received BPA (50 mg/kg body weight/day, p.o.) for 8 weeks. BPA administration induced liver fibrosis as reflected in an increase in serum hepatic enzymes activities, hepatic hydroxyproline content and histopathological changes particularly increased collagen fibre deposition around the portal tract. In addition, there was inflammation (as reflected in increase in interleukin-1beta ‘IL-1β’, decrease in interleukin-10 ‘IL-10′ serum levels and increase in IL-1β/IL-10 ratio), oxidative stress (as reflected in increase in malondialdehyde (MDA) level, reduction in reduced glutathione (GSH) content and inhibition of catalase (CAT) activity) and apoptosis [as reflected in an increase in caspase-3 level and a decrease in numbers of B-cell lymphoma 2 (BCL2)-immunopositive hepatocytes]. Interestingly, BPA had an upregulating effect on an extracellular matrix turnover gene [as reflected in matrix metalloproteinase-9 (MMP-9)] and a downregulating effect on its inhibitor gene [as reflected in tissue inhibitor of matrix metalloproteinase-2 (TIMP-2)] expression. Thus, the mechanism by which BPA induced liver fibrosis seems to be related to stimulation of the inflammatory response, along with oxidative stress, the apoptotic pathway and activation of extracellular matrix turnover.

Objectives The protective effects of estrogen replacement therapy (ERT) against oxidative injury and endothelial dysfunction in the aortic tissues induced with nicotine in ovariectomized (OVX) rats were investigated. Methods Female rats were divided into a sham-operated group (n = 8) and four groups in which OVX rats received either vehicle (0.1 ml sesame oil, i.m., n = 8), or nicotine (0.1 mg/kg, s.c., n = 8), or estradiol benzoate (0.1 mg/kg, i.m., n = 8), or both nicotine and estradiol benzoate (n = 8) starting at week 5 after the surgery and continuing for the following 6 weeks. Key findings ERT was effective in preventing the rise in plasma lipid profile, atherogenic index and the level of induced endothelin-1 (ET-1) in nicotine-treated OVX rats. It also reduced aortic malondialdehyde, hydroxyproline levels, calcium content and caspase-3 expression induced in nicotine-treated OVX rats. ERT increased serum estradiol, high-density lipoprotein cholesterol and nitric oxide levels in nicotine-treated OVX rats. Furthermore, ERT was effective in restoring reduced glutathione and cyclic guanosine monophosphate contents and endothelial nitric oxide synthase expression in aortic tissues of nicotine-treated OVX rats. Conclusions Short-term ERT could be a promising therapeutic strategy to minimize nicotine-induced oxidative stress and vascular endothelial dysfunction in menopausal women subjected to environmental smoke.

Iron deficiency anemia represents a common nutritional problem which affects many societies allover the world and iron fortified diet has been suggested as one of possible tools to combat and solve such problem. Present study was designed to illustrate the effect of dietary iron intake on certain biochemical markers dealing with oxidative stress, inflammatory response and cellular alterations of testicular tissues. Adult male rats which were fed on biscuits fortified with iron (0.3% ferrous sulfate) daily for 10 weeks (iron group) showed increased serum iron, ferritin, tumor necrosis factoralpha (TNF-α), nitric oxide (NO) and decreased Testosterone level (p < 0.05). Testicular tissues content of Malondialdehyde (MDA), hydroxyproline (Hyp), iron showed significant increase (p < 0.05) and decreased glutathione (GSH) as compared to control group. Testicular tissues demonstrated massive iron distribution in sertoli interstial tissues and degeneration of germinal epithelial cells. Apparent reduction in number of sperms and spermatogenic cells were also observed. These symptoms may demonstrate that prolonged intake of Biscuit fortified with iron causes certain testicular damage through certain mechanism.

Aim of work: Cannabis is the most frequently abused illicitsubstance in Egypt. An increase in the number of cases of pediatric accidental cannabis poisoning has been documented. We described a case of accidental cannabis poisoning with acute mega colon in a ten month old infant in Zagazig University hospitals. Findings: Clinical presentation included reduced level of consciousness, vomiting, severe abdominal distention, hypotonia,and shock. Abdominal scan showed severe colonic dilatation without mechanical obstruction. Tetrahydrocannabinol (THC) was detected by urine screening for cannabinoids and confirmed by HPLC. The patient was admitted to PICU and treated with supportive care. The patient recovered uneventfully and was discharged after 24 hours of admission. This case represents the first case of megacolon in accidental cannabis poisoning in previously healthy infant.

The Mediterranean lifestyle culture was adopted by people who lived around the Mediterranean Sea. Those people consume a simple diet from natural resources. The Mediterranean diet (MeDi) was based on consumption of marine products, vegetables, and polyunsaturated fatty acids but little red meat. It is composed of olive oil, red wine polyphenols (antioxidants), whole-grain phenolic acids, flavonoids, tannins, lignans, and other active compounds. These components also produce several health benefits. In addition to regular exercise, exposure to sunlight and avoiding a sedentary lifestyle ameliorate emotional stress and improve health. Adiponectin gene variations have been positively correlated with obesity, body weight gain, and cardiovascular risk. This correlation can be diminished by keeping on the MeDi. Additionally, prolonged intake of the MeDi in obese men ameliorates cardiovascular risk, reduced oxidative stress, and improved insulin sensitivity. Moreover, such dietary intervention halts cognitive impairment and progression of Alzheimer’s disease. In this chapter, we will focus on the evidence-based findings in the relationship of the MeDi and its constituents with adiponectin, brain amyloid precursor protein, apolipoprotein E, and caspase-3 expression.

Obesity represents a complex universal health problem that has merely increased worldwide over the past decades. It is a multifactorial status that arises mainly from an imbalance between energy intake and energy expenditure. Genetic and environmental factors such as sedentary lifestyle and intake of foods rich in fats and sugars but poor in vitamins and minerals are major risk factors for obesity. Brain aging is associated with neurodegeneration. However, the basis of this alteration remains to be investigated. Obesity has been strongly linked with neural degeneration. High-fat diet and cholesterol consumption induced metabolic dysfunction and enhanced the brain-aging rate along with neurodegenerative disorders. Moreover, middle-age obesity is considered as a risk factor for Alzheimer’s disease (AD). Therefore, reduced consumption of nutritional risk factors is a very efficient strategy for the prevention of obesity-associated neurodegenerative disorders.

Micro and macrovascular complications occurring during hyperlipidemia are mostly attributed to haemostatic impairment and vascular endothelial dysfunction. Cholesteryl ester transfer protein (CETP) inhibitors have been emerged recently as promising hypocholesterolemic agents to confer protection against lipid-mediated atherosclerosis. Therefore, 10-dehydrogingerdione (DHGD), a novel CETP inhibitor isolated from ginger rhizomes, was selected as a natural product in the present study to illustrate its effect on haemostatic impairment associated with hyperlipidemia as compared to a currently used hypocholesterolemic agent, atorvastatin (ATOR). Rabbits were fed a high cholesterol diet (HCD) and divided into three groups. One group served as control group while the other groups received DHGD or ATOR. Dyslipidemic rabbits showed a significant increase in serum endothelin-1, ischemia modified albumin, plasminogen activator inhibitor-1, prothrombin fragments (1+2) and plasma fibrinogen along with a decrease of nitric oxide level in serum. Daily administration of ATOR or DHGD significantly decreased the aforementioned coagulation and ischemia biomarkers and increased serum nitric oxide. DHGD (natural) results seem to be more remarkable as compared to ATOR (synthetic).

Cadmium is a potential environmental and industrial pollutant affecting human tissues and organs including liver and testes. The protective role of fenugreek seed powder (FSP) was investigated in male rats subjected to cadmium-induced testicular injury and hepatic dysfunction. Testicular damage and hepatotoxicity were induced by oral administration of cadmium chloride (5 mg/kg body weight, once a day) for 7 weeks. FSP was given at 5% w/w in chow diet for 8 weeks, starting 1 week before cadmium administration. FSP intake significantly increased serum testosterone level and testis weight that were reduced by cadmium. FSP also compensated deficits in hepatic and testicular antioxidant defense system, interleukin-4 and nitric oxide levels, reduced serum liver function enzyme activities and suppressed lipid peroxidation in hepatic and testicular tissues resulted from cadmium administration. Additionally, FSP attenuated the cadmium-induced elevations in hepatic and testicular tumor necrosis factor-α and transforming growth factor-beta1 levels as well as cadmium deposition and hydroxyproline content. The protective effect afforded by FSP was mainly due its antioxidant, antifibrotic and anti-inflammatory effects. In conclusion, the results of the present work indicated that FSP may represent a promising medicinal herb to protect hepatic and testicular tissues from the detrimental effects of cadmium.

Monosodium glutamate (MSG), a flavor enhancer, is used in modern nutrition to improve food palatability. The objectives of the current study were to investigate the effect of MSG on thymus as well as spleen structures and functions. Also, to evaluate the possibility of recovery after cessation of administration. Adult male rats were divided into three groups: control, MSG (3 g MSG/kg body weight daily for 8 weeks by oral gavages), and Recovery (MSG for same period and then left untreated for additional 4 weeks). The results showed that MSG treatments significantly increased serum interleukin (IL)-1β as well as thymic and splenic malondialdehyde and decreased serum levels of IL-10 and also reduced glutathione (GSH) levels and both catalase and superoxide dismutase activities in the thymus and spleen. Histological examination showed that MSG induced a remarkable disruption in the lobular architecture of the thymus with marked decrease of the T lymphocytes with darkly stained nuclei and dilated blood sinusoid in the cortical region. Medullary region were enlarged and repopulated with small lymphocytes and dilated blood sinusoids. The cortical-medullary differentiation was difficult to be determined. Small sized splenic lymphatic follicles with absence of germinal centers and large congested blood vessels were also noticed. The differentiation between the red and the white pulps was indistinct. Recovery groups showed preserved thymic lobular architecture with repopulation of the cortical thymocytes enclosing the paler staining medulla .Splenic lymphatic follicles of different sizes with absence of germinal centers were noticed. Marginal zone is differentiated from the red pulp. Immunohistochemical staining of MSG group demonstrated a marked decrease in CD3-positive T-lymphocytes in both thymus and spleen that significantly increased in recovery group. Taken together, the data showed that MSG consumption may have immunotoxic effects on the thymus and spleen of adult rats which is reversible but the normal structure of the spleen would need time to be regained. It is recommended that further studies aimed at corroborating these findings be carried out.

The possible effectiveness of resveratrol, a polyphenol present in different plants comprising berries, grapes and peanuts, on the prevention of doxorubicin-induced cardiac toxicity and fibrosis was investigated. Forty adult male Wistar albino rats were divided into four groups. Group I received normal saline, group II gavaged with resveratrol (20 mg/kg, daily for 4 weeks), group III received doxorubicin (2.5 mg/kg i.p. in six injections for 2 weeks; accumulative dose of 15 mg/kg), and group IV received doxorubicin + resveratrol (starting resveratrol intake 2 weeks before doxorubicin administration). Resveratrol significantly alleviated the increase in left ventricular lipid peroxidation, hydroxyproline, and tumor necrosis factor alpha levels as well as serum creatine kinase-myocardial band (CK-MB) activity and prevented the decrease in body and heart weights in doxorubicin-treated group. However, a marked protection against reduced glutathione content depletion and superoxide dismutase activity reduction was observed in the left ventricles of rats pretreated with resveratrol in combination with doxorubicin. Resveratrol also ameliorated the up-regulation of left ventricular caspase-3 and transforming growth factor-beta1 gene expression as well as left ventricular histopathological changes including necrosis and fibrosis induced by doxorubicin. Collectively, our results suggest that resveratrol provides a significant protection against doxorubicin-induced cardiotoxicity and fibrosis in rats. Therefore, it may be used as a promising cardioprotective agent in patients treated with doxorubicin due to malignant diseases. So, further clinical trials are required to confirm these findings.

Ammonia is a bi-product of protein metabolism in the body. It is able to cross the blood-brain barrier and elevated ammonia levels are toxic to the brain. Rats with hyperammonemia showed impaired learning ability and impaired function of the glutamate-nitric oxide-cyclic guanosine monophosphate (glutamate-NO-cGMP) pathway in the brain. Chronic treatment with sildenafil restored learning ability. We therefore tested the hypothesis that sildenafil has a protective effect on the brains of hyperammonemic rats. Hyperammonemia was induced in male rats by daily intraperitoneal (i.p.) injection of ammonium chloride (100 mg/kg body weight) for 8 weeks. Sildenafil citrate was administered intraperitoneally (10 mg/kg body weight/3 days) for 8 weeks. Treatment with sildenafil resulted in a significant reduction in plasma liver enzymes, lipid profile as well as brain lipid peroxidation and caspase-3 mRNA. Meanwhile, plasma NO as well as cGMP, antioxidants and endothelial nitric oxide synthase (eNOS) gene expression were significantly elevated in the brains of hyperammonemic rats. Our results showed that sildenafil exerts a protective effect on the brain by reversing oxidative stress during hyperammonemia and this could be due to (i) cytoprotective, antioxidant and anti-apoptotic effects (ii) increasing cGMP and enhancing the proper metabolism of fats which could suppress oxygen radical generation and thus preventing oxidative damage in the brain. The exact protective mechanism of sildenafil has to be still investigated and further studies are warranted. Consequently, therapeutic modulation of the NO/cGMP pathway might have important clinical applications to improve brain functions in patients with hyperammonemia or clinical hepatic encephalopathy.

Background Immunoglobulin like transcript (ILT3) is an immunohibitory transmembrane receptor expressed by plasmacytoid dendritic cells (PDCs), monocytoid dendritic cells (MDCs), and monocytes/macrophages. ILT3 has been previously utilized as a highly sensitive and specific marker for the identification of aggressive chronic lymphocytic leukemia (CLL) and to distinguish AML with monocytic differentiation from other types of AML. Aim and Methods0 Therefore, in the current study, we investigated the diagnostic impact of ILT3 receptor expression in 72 Egyptian patients having AML with monocytic differentiation and 20 healthy volunteer using flow cytometry technique. Results Our results demonstrated significant overexpression of ILT3 receptor (P Conclusion These data present a significant role for ILT3 receptor expression in combination with CD14, CD64, MPO and NSE in diagnosis of AML with monocytic differentiation. Further clinical studies should be directed towards ILT3 receptor blockade as a future target for AML immunotherapy.