Fatma A. Morsy

Cadmium impact and osteoporosis: mechanism of action.

Context: Cadmium (Cd) is a widespread environmental pollutant that is associated with increased risk of osteoporosis. It has been proposed that Cd’s toxic effect on bone is exerted via impaired activation of vitamin D, secondary to the kidney effects. Objective: The present study was designed to investigate the damaging impact of Cd in drinking water on bone from biochemical and histopathological point of view. Materials and methods: This study was conducted on 30, 3-months-old female Sprague Dawley rats exposed to cadmium chloride in a dose of 50u2009mg Cd/L in drinking water for 3 months. Serum was taken for determination of calcium, phosphorous levels, parathyroid hormone, 1,25 dihydroxy vitamin D3, osteocalcin (OC) and bone specific alkaline phosphatase (BALP) activity. Results: The result revealed that Cd administration induces significant increase in serum calcium (Ca), phosphorous (P) and parathyroid hormone (PTH) levels in concomitant with significant reduction in serum vitamin D3, osteocalcin (OC) levels and bone specific alkaline phosphatase (BALP) activity. Conclusion: The present study provided clear evidence that long-term exposure to cadmium chloride produced marked abnormalities in bone biomarkers and increasing risk of fracture.

Effects of biphenyldimethyl-dicarboxylate administration alone or combined with silymarin in the CCL4 model of liver fibrosis in rats.

The effect of biphenyldimethyldicarboxylate (DDB), a synthetic compound, in use for the treatment of chronic hepatitis was studied on hepatic injury caused in rats by administration of carbon tetrachloride (CCl4). Starting at time of administration of the first dose of CCl4, rats received DDB at four dose levels (3, 15, 75 or 375 mg/kg), silymarin (22 mg/kg), a combination of DDB (75 mg/kg) and silymarin (22 mg/kg) or saline (control) once orally daily for 30 days. The administration of DDB in CCl4-treated rats at 75 or 375 mg/kg resulted in 61.2-76.2% decrease in alanine aminotransferase (ALT) and 46.9-60.8% decrease in aspartate aminotransferase (AST), respectively compared with the CCl4 control group. Silymarin treatment resulted in 34.6 and 30% decrease in ALT and AST, while DDB (75 mg/kg) combined with silymarin (22 mg/kg) resulted in 58.2 and 31% decrease in ALT and AST, respectively. Serum creatinine increased by 50% by DDB at 375 mg/kg. After treatment with DDB at 75 or 375 mg/kg or DDB combined with silymarin, the development of liver necrosis and fibrosis caused by CCl4 was markedly reduced, while after DDB combined with silymarin no DNA aneuploid cells could be observed. The decrease in glycogen and protein contents in hepatocytes caused by CCl4 was markedly prevented by co-treatment with DDB at 75 or 375 mg/kg or DDB combined with silymarin. It is concluded that in the model of hepatic injury caused by chronic administration of CCl4 in rats, the synthetic compound DDB, limits hepatocellular injury and exerts antifibrotic effect. Better improvement in protein, DNA, mucopolysaccharide content was seen after both DDB and silymarin compared to DDB alone. It is suggested, therefore, that DDB alone or in combination with silymarin might prove of benefit in the therapy of chronic liver disease. Monitoring of kidney functions in patients taking DDB is warranted.

Histological and Histochemical Study on the Protective Effect of Curcuminon Ultraviolet Irradiation Induced Testicular Damage in Albino Rats

Decrease in the ozone layer leads to increase in the amount of dangerous ultraviolet radiation that reaches the earth’s surface. Exposure to ultraviolet radiation leads to tissue damage. This study aimed to investigate the possible protective effects of curcumin on testicular damage induced by Ultraviolet Irradiation (UVR) histologically, histochemically and morphometrically. 60 albino rats were divide into 5 groups (twelve rats each) the first group served as control. The second group was exposed to ultraviolet C rays for ½ an hour (900 joule) for three consecutive days. The third group was treated with curcumin at a dose level of 5 mg/kg body weight. The fourth group was treated with curcumin at a dose level of 25 mg/kg body weight at. The fifth group was treated with curcumin at a dose level of 50 mg/kg body weight. Rats in the last three groups were treated with curcumin for 4 weeks prior to exposure to ultraviolet rays. Sections were used for histopathological study on image analysis and morphometric measurments. Histochemical stain were used to demonstrate the DNA and glycogen content. Results of this study revealed that exposure to ultraviolet rays led to changes blood vessels and disturbance of spermatogenic layers, while using curcumin prior to exposure to ultraviolet rays in a small dose (5 mg/kg) led to restoration of the normal structure in most of the seminiferous tubules. A dose of 25 mg/kg of curcumin as a protecting agent led to depletion of spermatogenic cells above the level of spermatocytes in many of the tubules, while a dose of 50 mg/kg of curcumin led to exfoliation of spermatogenic cells in some tubules and depletion of long spermatids. In conclusion, the present work reported that the treatment of rats with curcumin in a dose of 5mg/kg body weight prior to exposure to ultraviolet rays led to a good protection against the harmful effects of ultraviolet C irradiation, while higher doses of curcumin (25 and 50 mg/kg body weight ) had much less protecting effects.

Cannabis sativa exacerbates hepatic injury caused by acetaminophen or carbon tetrachloride in rats

The effect of Cannabis sativa extract on acute liver injury caused by acetaminophen or carbon tetrachloride (CCl4) was studied in rats. Cannabis sativa was given at doses of 5 or 10xa0mg/kg (expressed as Δ9-tetrahydrocannabinol) once daily intraperitoneally (i.p.) for 2xa0days and simultaneously with acetaminophen or CCl4. Rats were killed 24xa0h after acetaminophen or CCl4 administration. Reduced glutathione (GSH), lipid peroxidation (malondialdehyde; MDA) and nitric oxide (nitrite/nitrate) concentrations were measured in the liver. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were determined in serum. Hepatic injury was also determined via histological examination of liver sections. The administration of only cannabis for 2xa0days had no significant effect on serum liver enzymes or on the hepatic levels of GSH, MDA or nitric oxide. However, in rats intoxicated with acetaminophen, Cannabis sativa at 5 or 10xa0mg/kg resulted in a significant increase in serum GOT by 17.6% and 19.5%, respectively, compared with the acetaminophen control group. In the CCl4-induced acute liver injury, the levels of AST, ALT and ALP in serum were significantly elevated by Cannabis sativa extract in a dose-dependent manner by 23.7–29.1%, 14.4–21.3% and 17.6–22.1%, respectively. In both models of hepatic injury, Cannabis sativa resulted in a significant increase in the level of liver MDA and nitric oxide and a significant decrease in GSH compared with the corresponding acetaminophen or CCl4 control group. These changes were dose dependent. Histological examination showed an increase in centrilobular necrotic areas in acetaminophen or CCl4-treated rats administered with Cannabis sativa. Histochemical investigation revealed a decrease in intracellular protein contents caused by CCl4 or acetaminophen, and these were further decreased by Cannabis sativa. It is concluded that short-term administration of Cannabis sativa enhances acute hepatic damage caused by CCl4 or acetaminophen in rats.

Study of the effect of antidepressant drugs and donepezil on aluminum-induced memory impairment and biochemical alterations in rats

Alzheimer’s disease is the leading cause of dementia in the elderly. Depression is a common psychiatric disorder affecting individuals across life span and often arises in the context of pre-dementia, dementia, and Alzheimer’s disease. The present study aimed to investigate the effects of the antidepressant drugs clomipramine (14.2 and 56.9xa0μmol/kg), fluoxetine (14.5 and 57.8xa0μmol/kg), and sertraline (14.6 and 58.4xa0μmol/kg) compared with acetylcholinesterase inhibitor donepezil (12xa0μmol/kg) on oxidative stress, memory impairment, and depressant-like behavior in a model of Alzheimer’s disease induced by prolonged intraperitoneal administration of aluminum chloride (AlCl3) (10xa0mg/kg/day for 60xa0days) in rats. Results indicated that the latency to find the hidden platform in Morris water maze (MWM) test increased by 100xa0%, while the immobility duration in forced swimming test (FST) increased by 51xa0% in AlCl3-treated rats. The administration of AlCl3 resulted in increased brain malondialdehyde (MDA) by 58.6xa0% and nitric oxide (nitrite) concentrations by 71.7xa0%, while reduced glutathione (GSH) decreased by 35.6xa0% compared with the vehicle-treated group. Catalase and paraoxonase 1 (PON1) activities in the brain decreased by 41.8 and 18.3xa0%, respectively. Serum acetylcholinesterase (AChE) increased by 47.8xa0% and brain butyrylcholinesterase (BuChE) decreased by 23.1xa0% after AlCl3 treatment. In AlCl3-treated rats, memory performance in the MWM test improved following donepezil and the highest dose of clomipramine, fluoxetine, and sertraline. The immobility duration in the FST was decreased by sertraline. Significant decrease in brain MDA occurred after treatment with clomipramine, fluoxetine, and a lower dose of sertraline. Reduced glutathione level increased by donepezil, clomipramine, and 57.8xa0μmol/kg fluoxetine. The level of nitric oxide decreased by donepezil (42.6xa0%), clomipramine (45.0 and 62.9xa0%), fluoxetine (21.9 and 40.9xa0%), and 14.6xa0μmol/kg sertraline (28.7xa0%). Catalase activity was restored by donepezil, fluoxetine, and sertraline and markedly increased by 56.9xa0μmol/kg clomipramine. Paraoxonase 1 activity was increased by 14.2xa0μmol/kg clomipramine. BuChE activity was unaltered, but AChE activity was decreased by donepezil, clomipramine, and fluoxetine compared with the AlCl3 control group. AlCl3 resulted in neurodegeneration (gliosis), extensive dark neurons with corkscrew dendrites, and degeneration of some Purkinje cell. Following donepezil treatment, no dark neurons were observed, while increased granular cell layer was observed after the administration of a high dose of clomipramine, fluoxetine, or sertraline. The results suggested that in rats treated with AlCl3, (i) donepezil, sertraline, clomipramine, and fluoxetine improve memory performance; (ii) sertraline was particularly effective in improving depressive-like behavior in this model and might be of value in the treatment of depressive symptoms associated with Alzheimer’s disease; (iii) donepezil, clomipramine, and fluoxetine alleviated oxidative stress; and (iv) neurodegeneration in this model could be modulated by antidepressant drugs and donepezil.

DNA Cytometry and Nuclear Morphometry in Ovarian Benign, Borderline and Malignant Tumors

BACKDROUND: Ovarian carcinoma is a leading cause of death in gynecological malignancy. Ovarian surface epithelial serous and mucinous tumours are classified as benign, borderline, and malignant. The identification of borderline tumours most likely to act aggressively remains an important clinical issue. AIM: This work aimed to study DNA ploidy and nuclear area in ovarian serous and mucinous; benign, borderline and malignant tumours. MATERIAL AND METHODS: This study included forty ovarian (23 serous and 17 mucinous) tumours. Paraffin blocks were sectioned; stained with haematoxylin and eosin for histopathologic and morphometric studies and with blue feulgen for DNA analysis. RESULTS: All four serous and six out of nine mucinous benign tumours were diploid. All eight serous and five mucinous malignant tumours were aneuploid. Nine of eleven (81.8%) serous and all three mucinous borderline tumours were aneuploid. There were highly significant differences in mean aneuploid cells percentage between serous benign (1.5%), borderline (45.6%) and malignant (74.5%) (p = 0.0001) and between mucinous benign (13.2%) and both borderline (63.7%) and malignant (68.4%) groups (p = 0.0001). There were significant differences in nuclear area between serous benign (26.191%), borderline (45.619%) and malignant (67.634 %) and a significant positive correlation between mean percentage aneuploid value and mean nuclear area in all serous and mucinous groups. CONCLUSION: We suggest that DNA ploidy and nuclear area combined, may be adjuncts to histopathology; in ovarian serous and mucinous benign, borderline and malignant neoplasms; identifying the aggressive borderline tumours.

Grape Seed Extract Alone or Combined with Atropine in Treatment of Malathion Induced Neuro- and Genotoxicity

The aim of this study was to investigate the effect of treatment with grape seed extract (GSE) on the neurotoxic and genotoxic effects of acute malathion exposure. Rats received malathion (150 mg/kg by i.p. injection) for two successive days alone or combined with GSE at doses of 150 or 300 mg/kg, orally or with GSE at 300 mg/kg and atropine at a dose of 2 mg/kg, i.p. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, paraoxonase (PON1) were determined in cortex, striatum, and rest of brain tissue (subcortex). Interleukin-1β (IL-1β), and butyrylcholinesterase (BChE) activities were determined in brain regions. Cytogenetic analyses for chromosomal aberrations in somatic and germ cells, micronucleus test, Comet assay, DNA fragmentation of liver cells and histopathological examination of brain and liver sections were also performed. Malathion resulted in an increase in MDA, nitric oxide; a decrease in GSH and PON1 activity in different brain regions. IL-1β increased, while BChE activity decreased in brain after the administration of malathion. The insecticide also caused marked structural and numerical chromosomal aberrations and increased liver DNA fragmentation. The Comet assay showed a significant increase in DNA damage of peripheral blood lymphocytes. These effects of malathion were alleviated with the administration of GSE alone or combined with atropine. Addition of atropine to treatment with GSE was associated with significant decrease in MDA, BChE and chromosomal aberrations compared with GSE only treatment. Our data indicate that GSE protects against malathion neurotoxic and genotoxic effects, most likely through reducing brain oxidative stress and inflammatory response.

Cerebrolysin attenuates oxidative stress and neurodegeneration in acute malathion toxicity in the rat

Neurotoxicity caused by organophosphate insecticides in a recognized health problem [1]. These agents are widely used in agriculture, veterinary and in the household [2]. Acute toxicity is largely due to excessive cholinergic activity [3]. Organophosphates bind to and inhibit the cholinesterases; acetylcholinesterase (EC 3.1.1.7; AChE) and butyrylcholinesterase (EC 3.1.1.8’ BChE). In the central and peripheral nervous system, acetylcholinesterase (AChE) is the enzyme that hydrolyzes the neurotransmitter acetylcholine (ACh), thereby, terminating its action at the cholinergic synapse [4]. Organophosphates thus cause the accumulation of ACh in the synaptic cleft and over stimulation of the cholinergic receptors at postsynaptic cells and/or end organs, and the development of signs of acute toxicity such as excessive salivation, lacrimation, bradycardia, tremors, convulsions, and ultimately respiratory depression and coma [3-6]. Long term exposure to organophosphate insecticides is also associated with central and peripheral neurotoxicity in the form of cognitive and memory impairments, ataxia, delayed peripheral neuropathy [7-9]. Organophosphates have also been incriminated in the development of neurodegenerative diseases like Parkinson’s disease [10-12]. In this context, individuals with inefficient catalytic activity of paraoxonase 1, an enzyme important for the detoxification of organophosphates are more prone to develop Parkinson’s disease upon exposure to these insecticides [12-14].

Preventive effects of cannabis on neurotoxic and hepatotoxic activities of malathion in rat

Objective: To investigate the effect of Cannabis sativa extract on the development of neuro- and hepato-toxicity caused by malathion injection in rats. Methods: The extract of Cannabis sativa was obtained from the plant resin by chloroform treatment. Δ-Tetrahydrocannabinol content of the extract (20%) was quantified using gas chromatography–mass spectrometry. The doses of cannabis extract were expressed as Δ -tetrahydrocannabinol content of 10 or 20 mg/kg. Malathion (150 mg/kg) was intraperitoneally administered followed after 30 min by the cannabis extract (10 or 20 mg/kg, subcutaneously). Rats were euthanized 4 h later. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide and paraoxonase-1 (PON-1) activity were determined in brain and liver. Brain 5-lipoxygenase and butyrylcholinesterase (BChE) activity were measured as well. Histopathological examination of brain and liver tissue was also performed. Results: Compared to controls, malathion resulted in increased oxidative stress in brain and liver. MDA and nitric oxide concentrations were significantly increased (P<0.05) and GSH significantly decreased with respect to control levels (P<0.05). Malathion also significantly inhibited PON-1 and BChE activities but had no effect on brain 5-lipoxygenase. Brain MDA concentrations were not altered by cannabis treatment. Cannabis at 20 mg/kg, however, caused significant increase in nitric oxide and restored the GSH and PON-1 activity. Brain BChE activity significantly decreased by 26.1% (P<0.05) after treatment with 10 mg/kg cannabis. Cannabis showed no effect on brain 5-lipoxygenase. On the other hand, rats treated with cannabis exhibited significantly higher levels of liver MDA, nitric oxide and PON-1 activity compared with the malathion control group. Rats treated with only malathion exhibited spongiform changes, neuronal damage in the cerebral cortex and degeneration of some Purkinje cells in the cerebellum. There were also hepatic vacuolar degeneration and dilated and congested portal vein. These histopthological changes induced by malathion in brain and liver were reduced to great extent by cannabis administration at 20 mg/kg. Conclusions: Our data suggest that acute treatment with cannabis alleviates the malathion-induced brain and hepatic injury in rats possibly by maintaining the levels of GSH and PON-1 activity.

Lycopene: an effective neuroprotective option against neurodeterioration induced by formaldehyde inhalation

To address the mechanisms underlying the pathophysiology of formaldehyde (FA)-induced neurotoxicological impact and to examine the neuroprotective potency of lycopene (Lyco) against neuronal damage produced by formaldehyde inhalation in rats. Fifty adult female rats were divided into five groups: G1 negative control, G2 formaldehyde-challenged group (FA 10xa0ppm), G3 formaldehyde-challenged group (FA 20xa0ppm), G4 formaldehyde-challenged group pre-treated with Lyco (Lyco + FA 10xa0ppm), and G5 formaldehyde-challenged group pre-treated with Lyco (Lyco + FA 20xa0ppm). Brain nitric oxide (NO), malonaldehyde (MDA) Bcl-2 levels, and catalase (CAT) activity were increased significantly, while, brain superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity were decreased significantly in FA-challenged rats. Also, FA inhalation elicited significant depletion in brain brain-derived neurotrophic factor (BDNF), dopamine (DA), noradrenaline (NA), and adrenaline (AD) levels. Moreover, FA inhalation induced significant upregulation in brain X-linked inhibitor of apoptosis protein (XIAP) gene expression levels. Survivin immunopositive cells in the brain were increased in FA-challenged rats when compared to the negative control counterparts. On the other side, pre-treatment with Lyco along with FA inhalation could attenuate the adverse impacts of FA on the brain. Histopathological examination of the brain tissue revealed that the treatment with Lyco prior FA inhalation could preserve the structural organization of the brain. The present data offered a mechanistic explanation to formaldehyde neurotoxicity. Also, our findings clearly identified that the neuroprotection of Lyco is contributed to the preservation of oxidant/antioxidant homeostasis and maintenance of neuronal survival, functions, and integrity.