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Gestational diabetes mellitus (GDM) not only has short-term side effects on offspring but also has an increased risk of developing chronic diseases in adulthood. The thymus gland is a vital organ of immune system and thymoquinone (TQ) has an immunomodulatory effect. This study aimed to investigate the long-term adverse effects of GDM on offspring’s thymus gland and the ameliorating effect of TQ. Pregnant rats were divided into four groups: C-group, T-group, GD-group, and GD + T-group. Offspring of all groups were subdivided into two subgroups, one sacrificed on day 21 and the other on day 42. The thymus of the offspring in the GD-group at both time points revealed a significant decrease in thymic weight, superoxide dismutase (SOD), and reduced glutathione (GSH) levels with a significant increase in malondialdehyde (MDA), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α) levels. Moreover, there were microscopic degenerative changes, a significant decrease in C/M ratio, CD3, CD4, and CD8 immune expression, and a significant increase in activated caspase-3 immune expression. Interestingly, TQ administration revealed a significant increase in thymic weight, thymic SOD and GSH, C/M ratio, and CD3, CD4, and CD8 immune expression with a significant decrease in MDA, IL-8, TNF-α and activated caspase-3. For the first time, this study has shown that GDM causes long-term oxidative stress, apoptosis, and inflammation in offspring’s thymus and these changes could be attenuated by TQ.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine and reproductive disorders throughout female reproductive age. Cell free therapy [conditioned media (CM) & exosomes (EXO)] is a promising approach in regenerative medicine. This study aimed to compare between the therapeutic effects of stem cell-derived CM and exosomes on induced animal model of polycystic ovary. Polycystic ovary (PCO) was induced in female rats (3–4 weeks old, weighing 70–80 g) by letrozole with a dose of 1 mg/kg/day dissolved in carboxymethylcellulose 1% orally once daily for 5 weeks. Animals were divided into four groups: control group, PCO group, EXO-treated group, and CM-treated group. Serum levels of testosterone hormone, leutinizing hormone, follicle stimulatimg hormone, and insulin hormone were estimated. Immunohistochemistry using anti-P53, anti-AMP-dependent protein kinase antibodies were done. Six rats/group were used for matting with adult male rats for testing fertility. The results showed that CM had significant superior therapeutic effects on exosomes in restoring the normal histological architecture of the ovary and fertility. In summary, cell free treatment is a safe approach for tissue regeneration. Stem cell-derived CM was more effective than exosomes in restoring normal histological structure of the ovaries and fertility in animal models of polycystic ovary.

Intermittent fasting (IF) has several beneficial effects on most age-related degenerative changes in the body. Here we aimed to investigate the impact of IF on the biochemical and morphological abnormalities associated with normal aging in rat prostate. Thirty male albino rats were used and divided into three equal groups: adult group, rats aged 3 months; aged group, rats aged 15 months; and IF-aged group, rats aged 15 months maintained on intermittent fasting. After 3 months, prostates were excised and processed for biochemical, histological, and immunohistochemical study. Aging resulted in prostatic histological changes that resemble those of benign prostatic hyperplasia (BPH) with increased malondialdehyde (MDA) level, decreased glutathione (GSH) level, reduction of autophagy, and increased proliferation. Intermittent fasting ameliorated these described age-related prostatic changes. It could be concluded that IF could prevent age-induced BPH. This occurs via its anti-inflammatory and anti-proliferative effects, suppression of oxidative stress, and by improving autophagy via Beclin-1/P62 modulation. These mechanisms underlie the IF-mediated protection against age-related BPH. Because of IF safety and easy availability over BPH medications, it might be promising for managing BPH after further clinical studies.

The cardiotoxicity of anticancer drugs such as 5-fluorouracil (5FU) is a major complication that challenges their clinical usefulness. Thus there is a critical need to find new protective drugs to defend against these harmful side effects. Up to now, there have been no studies evaluating the possible cardioprotective effects of fenofibrate (FEN) in 5FU-induced cardiotoxicity. Therefore, we aimed in the current model to evaluate such an effect of FEN and to explore different mechanisms mediating it. We used FEN (25, 50, 100 mg/kg/day) administered orally for 7 days with induction of cardiotoxicity by intraperitoneal (i.p.) injection of 5FU (150 mg/kg) on the fifth day. The current study showed that 5FU succeeded in inducing cardiotoxicity, manifested by significantly elevated levels of cardiac enzymes, tissue malondialdehyde (MDA), interleukin 6 (IL-6), signal transducer and activator of transcription 4 (STAT4), and caspase-3. Furthermore, the 5FU group showed toxic histopathological changes including marked cardiac damage and a significant decrease in reduced glutathione (GSH), total antioxidant capacity (TAC), and peroxisome proliferator-activated receptor alpha (PPARα) expression. FEN reversed 5FU-induced cardiotoxicity by various mechanisms including upregulation of PPARα, inhibition of the IL-6/STAT signaling pathway, and anti-inflammatory, antiapoptotic, and antioxidant properties. FEN demonstrated a significant cardioprotective effect against 5FU-induced cardiac damage.

The current experiment aimed to identify the possible protective role of rivastigmine (RIVA) in gentamicin (GNT)-induced acute kidney injury (AKI) in rats. RIVA was administered in the presence and absence of GNT. Kidney function markers and serum and renal GNT concentrations were measured. Renal oxidative stress parameters as well as inflammatory and apoptotic biomarkers were evaluated. Renal histopathological assessment and nuclear factor kappa-B (NF-κB) immunohistochemical study were performed. GNT administration increased serum creatinine, urea, and cystatin C concentrations. RIVA ameliorated these changes via mitigating GNT-induced increases of renal oxidative stress, inflammation, and apoptotic parameters. RIVA showed a prompt improvement in the histopathological renal damage and a decrease in NF-κB immunoexpression. In conclusion, RIVA protective effects against GNT-induced AKI are mediated by decreasing GNT concentration in renal tissue and other effects like antioxidant and antiapoptotic effects possibly through its cholinergic anti-inflammatory action.

Cadmium (Cd) has potential hazards on human beings. Consequently, this study was performed to explore the protective effects of agomelatine (AGO), a melatonin receptor agonist, against Cd-induced toxicity in rats. AGO (40 mg/kg/day) was administered orally concomitant with intra peritoneal injection of Cd (0.4 mg/kg/day) for 14 days. Then, blood, biochemical parameters and histological examination of affected organs including, heart and testis, were evaluated. Interestingly, AGO significantly counteracted Cd-induced elevation of serum cardiac enzymes. Similarly, AGO significantly improved the deterioration of serum testosterone level with Cd administration. The oxidative balance was corrected by AGO, as evidenced by decrease malondialdehyde (MDA), and superoxide dismutase activity in cardiac and testicular tissues. Additionally, AGO increased silent information regulator 1 protein (SIRT-1) and decreased High mobility group box 1 (HMGB1), Toll like receptor-4 (TLR-4), and Myd88 levels that subsequently reduced expression of nuclear factor-κB (NF-κB). Moreover, level of apoptotic marker; caspase-3 was inhibited by AGO. In accordance with the biochemical and molecular results, AGO restored structure of cardiac myofibers and seminiferous tubules. Collectively, AGO mitigated cardiac and testicular toxicity of Cd via modulation of SIRT-1/HMGB1 and its downstream pathway.

Background The use of acetaminophen (APAP) is increasing recently, especially with COVID-19 outbreaks. APAP is safe at therapeutic levels, however, an overdose can cause severe liver injury. This study aims to explore possible mechanisms involved in APAP‑induced hepatotoxicity and compare different hepatoprotective agents, namely vitamin E, hydrogen sulfide (H2S) and necrostatin-1 (NEC-1). Methods Adult male albino rats were divided into groups: Control group, APAP‑induced hepatotoxicity group, Vitamin E‑treated group, H2S‑treated group and NEC-1‑treated group. Serum levels for aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin-33 (IL-33), tumor necrosis factor alpha (TNF-α), reduced glutathione (GSH) and lipid profile were measured. Histopathological examinations of liver tissue with H(et)E stain and immunohistochemistry for activated caspase-3 were also done. Results APAP‑treated group showed elevated liver transaminases, hyperlipidemia, and deficient liver anti-oxidative response together with disturbed hepatic architecture and increased immune-expression of activated caspase-3 in hepatic tissue. Pretreatment with vitamin E, H2S or NEC-1 reversed the affected parameters. Vitamin E and H2S showed greater improvement when compared to NEC-1. Conclusion Vitamin E, H2S and NEC-1 showed protective effects against APAP-induced hepatotoxicity, thus they may be used as an adjuvant therapy when APAP is indicated for long periods as is the case in COVID-19 patients (Tab. 2, Fig. 2, Ref. 45). Text in PDF www.elis.sk Keywords: acetaminophen, hepatotoxicity, apoptosis, necrostatin-1, vitamin E, H2S.

The adrenal gland is an important endocrine gland in the body that secrets the adrenal hormones. One of the important clinical issues is the hepatic ischemia-reperfusion (IR) injury. Liver IR injury results in many distant organs dysfunctions such as lung, kidney, intestine, pancreas, and myocardium. The aim of the present study was to investigate the possible remote effects of hepatic IR on the structure of the adrenal cortex. Twenty healthy males, Sprague-Dawley albino rats aged 6-8 weeks were randomly divided into two groups (10 rats each): the sham control group (SC-group) and the ischemia-reperfusion group (IR-group). Sera were estimated for the following: aspartate transaminase (AST), alanine transaminase (ALT), lactic dehydrogenase (LDH), and corticosterone levels. Also oxidative markers such as malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α), and the antioxidative enzyme, catalase were measured. Adrenal glands were processed for light and transmission electron microscopic study. The results showed a significant increase in serum liver enzymes (AST, ALT, and LDH), corticosterone, MDA, and TNF-α levels and a significant decrease in serum levels of catalase in IR-group compared with SC-group. Adrenal cortical tissue of IR-group showed the loss of normal appearance. Some cells of zona glomerulosa and most of the zona fasciculata cells appeared swollen and degenerated with highly vacuolated cytoplasm. Other cells were shrunken with deeply acidophilic cytoplasm and pyknotic nuclei. Degenerated mitochondria with disrupted cristae, lipid droplets were confluent and dilated smooth endoplasmic reticulum were seen. Few zona reticularis cells had the dark nucleus and cytoplasmic vacuolations. In the different zones, blood capillaries were markedly congested and some inflammatory cells infiltrations were observed. Liver IR affected the structure of the adrenal cortex.

The cardiotoxicity of anticancer drugs such as 5-fluorouracil (5FU) is a major complication that challenges their clinical usefulness. Thus there is a critical need to find new protective drugs to defend against these harmful side effects. Up to now, there have been no studies evaluating the possible cardioprotective effects of fenofibrate (FEN) in 5FU-induced cardiotoxicity. Therefore, we aimed in the current model to evaluate such an effect of FEN and to explore different mechanisms mediating it.We used FEN (25, 50, 100 mg/kg/day) administered orally for 7 days with induction of cardiotoxicity by intraperitoneal (i.p.) injection of 5FU (150 mg/kg) on the fifth day.The current study showed that 5FU succeeded in inducing cardiotoxicity, manifested by significantly elevated levels of cardiac enzymes, tissue malondialdehyde (MDA), interleukin 6 (IL-6), signal transducer and activator of transcription 4 (STAT4), and caspase-3. Furthermore, the 5FU group showed toxic histopathological changes including marked cardiac damage and a significant decrease in reduced glutathione (GSH), total antioxidant capacity (TAC), and peroxisome proliferator-activated receptor alpha (PPARα) expression. FEN reversed 5FU-induced cardiotoxicity by various mechanisms including upregulation of PPARα, inhibition of the IL-6/STAT signaling pathway, and anti-inflammatory, antiapoptotic, and antioxidant properties.FEN demonstrated a significant cardioprotective effect against 5FU-induced cardiac damage.

Sepsis is an extensive life-threatening illness that occurs due to an abnormal host response that extends through the initial storm of inflammation and oxidative stress and terminates at the late stage of immunosuppression. Among global intensive care units, sepsis-induced acute kidney injury is reported with high mortality rate. The purpose of this study was to evaluate the protective effect of the renin angiotensin aldosterone system (RAAS) inhibition on sepsis outcomes. Cecal ligation and puncture (CLP) procedure was applied for sepsis induction. The experimental design constituted of five groups of rats: sham, CLP-nontreated and CLP-treated with ramipril (10 mg/kg, p.o.), losartan (20 mg/kg, i.p.) and spironolactone (25 mg/kg, p.o.). Twenty-four hours after surgery, rats were euthanized for blood and tissue samples, which were used for assessment of serum inflammatory markers, and oxidative stress parameters, as well as to kidney function parameters. The tissue samples were used for histological and caspase-3 assessment. A survival study was conducted using another set of animals. Our results showed that the different RAAS inhibitors showed protective effects evidenced by enhanced overall survival following sepsis (80% in ramipril and spironolactone-treated and 60% in losartan-treated vs. 10% in the septic group), in addition to improved renal function parameters and reduction of oxidative stress and inflammation. The timely use of RAAS inhibitors during sepsis might represent a new therapeutic approach in septic patient.

Purpose: Cardiotoxicity of anticancer drugs such as 5-fluorouracil (5FU) and anthracyclines is a major complication that challenges their clinical usefulness. There is a critical need for finding new protecting drugs to defense against these harmful side effects. Up till now, there are no studies evaluate the possible cardioprotective effects of fenofibrate (FEN) in 5FU-induced cardiotoxicity. So that, we aimed in current model to evaluate such effect of FEN and explore different mechanisms mediating it.Methods: we used FEN (25, 50,100 mg/kg/day) orally for 7days with induction of cardiotoxicity by intraperitoneal (i.p.) injection of 5FU (150 mg/kg) on 5th day. Results: current study showed that 5FU succeeded in induction of cardiotoxicity and manifested by significant elevation of cardiac enzymes, tissue malondialdehyde (MDA), interleukin 6 (IL6), signal transducer and activator of transcription 4(STAT4) and caspase 3 levels. Furthermore, 5FU group showed toxic histopathological changes of marked cardiac damage and significant decrease in reduced glutathione (GSH), total antioxidant capacity (TAC) and peroxisome proliferator activated receptor alpha (PPARα) expression. FEN could reverse 5FU-induced cardiotoxicity by different mechanisms including upregulation of PPARα, inhibition of IL6/STAT signaling pathway, anti-inflammatory, anti-apoptotic and anti-oxidant properties.Conclusion: FEN had a significant cardioprotective effect against 5FU induced cardiac damage.

Sepsis is a leading cause of death among intensive care patients. During sepsis, exaggerated reaction to infection leads to massive production of reactive oxygen species and inflammatory mediators, which eventually leads to multiple organ damage. Silymarin is a well-known antioxidant and cytoprotective agent, which showed protective effects in different models of disease. Thus, we hypothesized that silymarin would be protective against sepsis-induced liver and kidney injury. Sepsis was induced in rats by the cecal ligation and puncture (CLP) method. Rats were divided into sham, CLP-non-treated and CLP treated with silymarin (100 mg/kg, i.p. 1 h following CLP). After 24 h, rats were euthanized for blood and tissue samples, which were used for assessment of MDA, NO, GSH, IL-6 and TNF-α levels and SOD activity, in addition to renal and hepatic function parameters. Survival study was conducted using another set of animals following the same previously mentioned procedure. Silymarin showed protective effects evidenced by enhanced overall survival following sepsis (80% in silymarin-treated vs. 20% in septic group), in addition to improvement of hepatic and renal function parameters and reduction of MDA, NO, IL-6 and TNF-α levels. Moreover, silymarin supported the endogenous antioxidant mechanisms via elevation of GSH levels and reinforcement of SOD activity. In conclusion, silymarin protects against sepsis-induced hepatic and renal injury, possibly via antioxidant and anti-inflammatory mechanisms.

Activation of hepatic stellate cells is a central event in hepatic fibrogenesis that offers multiple potential sites for therapeutic interventions. Peroxisome proliferator-activated receptors are implicated in liver fibrosis. We aimed to evaluate the effect of bezafibrate and pioglitazone on a thioacetamide (TAA) rat model of liver fibrosis and to clarify the possible underlying mechanisms. Rats received intraperitoneal injections of TAA for 6 weeks. Daily oral treatments with bezafibrate or pioglitazone were started with the first day of TAA intoxication. Serum liver function tests, hepatic malondialdehyde (MDA), total nitrite and nitrate (NOx), superoxide dismutase, and hepatic histopathology were assessed to evaluate hepatic damage. Alpha smooth muscle actin (α-SMA) and tissue inhibitor metalloproteinase-1 (TIMP-1) and caspase-3 were also assessed. The TAA group experienced significant deterioration of liver functions, increased oxidative stress, and increased liver tissue NOx. Administration of bezafibrate or pioglitazone resulted in significant improvement of all liver functions and reduced oxidative stress in hepatic tissues. Only administration of bezafibrate significantly reduced NOx levels. Liver tissues from the TAA-treated group showed disrupted normal architecture. Administration of bezafibrate or pioglitazone attenuated this picture. Stronger α-SMA expression was detected in the TAA group. Treatment with bezafibrate or pioglitazone decreased the α-SMA expression.

Ketamine is increasingly used in clinical practice, and ketamine addiction is common in young individuals. There are limited reviews on the chronic effects of ketamine on the testes. Three groups of rats received saline or ketamine 50 mg/kg/day intraperitoneally for 6 weeks with or without a subsequent 4-week drug-free period. Serum follicle-stimulating hormone, luteinizing hormone, prolactin, and testosterone levels, as well as testicular malondialdehyde concentrations, were measured. Epididymal sperm parameters were assessed. Testicular tissues were examined by hematoxylin and eosin staining and immunohistochemical staining using caspase-3 and vimentin antibodies. Chronic ketamine injection significantly decreased the levels of the examined hormones and adversely affected sperm parameters. Testicular tissue showed a significant increase in caspase-3 expression. In addition, Sertoli cell shape and position were disrupted. These effects disappeared 4 weeks after drug withdrawal. Chronic ketamine treatment has revisable hazardous effects on the rat reproductive function. There is a need to increase the knowledge of physicians and the public regarding these harmful effects of ketamine.

Objectives: Cyclophosphamide (CYC) is the most common cytotoxic alkylating agent which considered as chemotherapy but its clinical usefulness is challenged with different forms of organ damage incl...

Background Alzheimer’s disease (AD) is the most common cause of dementia in elderly. Quercetin is a well-known flavonoid with low bioavailability. Recently, quercetin nanoparticles (QNPs) has been shown to have a better bioavailability. Aims This study aimed to investigate the protective and therapeutic effects of QNPs in Aluminum chloride (AlCl3) induced animal model of AD. Materials and Methods AD was induced in rats by oral administration of AlCl3 (100 mg/kg/day) for 42 days. QNPs (30 mg/kg) was given along with AlCl3 in the prophylactic group and following AD induction in the treated group. Hippocampi were harvested for assessments of the structural and ultrastructural changes using histological and histochemical approaches. Results and Discussion AD hippocampi showed a prominent structural and ultrastructural disorders both neuronal and extraneuronal. Including neuronal degeneration, formation of APs and NFTs, downregulation of tyrosine hydroxylase (TH), astrogliosis and inhibition of the proliferative activity (all P ≤ 0.05). Electron microscopy showed signs of neuronal degeneration with microglia and astrocyte activation and disruption of myelination and Blood Brain Barrier (BBB). Interestingly, QNPs administration remarkably reduced the neuronal degenerative changes, APs and NFTs formation (all P ≤ 0.05). Furthermore, it showed signs of regeneration (all P ≤ 0.05) and upregulation of TH. The effect was profound in the prophylactic group. Thus, QNPs reduced the damaging effect of AlCl3 on hippocampal neurons at the molecular, cellular and subcellular levels. Conclusion For the best of our knowledge this is the first study to show a prophylactic and therapeutic effect for QNPs in AD model. This might open the gate for further research and provide a new line for therapeutic intervention in AD.

Objectives. Thyroid gland regulates the body’s metabolic rate and plays an exquisitely important role in the human health. Fluoride exposure can affect thyroid function. Curcumin is a potent antioxidant that works through several mechanisms. The aim of the present study was to demonstrate the hormonal, histological, and ultrastructural changes occurred in the thyroid gland induced by exposure to sodium fluoride (NaF) and study the possible protective effect of curcumin on the NaF-induced effects. Methods. Thirty male albino rats were randomly divided into 3 equal groups (10 rats each): the control group, NaF group, and NaF+Curcumin (NaF+Cur) group. Thyroid-stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) levels were assayed and thyroid tissues processed for light and transmission electron microscopic study. Results. In NaF group, serum T3 and T4 levels were significantly decreased whereas TSH level was significantly increased compared to the control group. Thyroid tissues showed flattening of the epithelial lining with several follicular cell degenerations, hyperplasia, decreased colloid, disrupted basement membrane, cytoplasmic vacuolations, degenerated mitochondria, widening of rough endoplasmic reticulum cisternae, and vascular congestion compared to the control group. In the NaF+Cur group, serum TSH levels were significantly decreased in comparison with NaF group and no significant difference in comparison with the control group. Thyroid sections appeared apparently normal compared to the control group and NaF group. Conclusions. Sodium fluoride affected both the function and structure of the thyroid gland while curcumin was protective against these toxic effects.

Liver fibrosis is an excessively reversible wound healing process and the fibrotic disorder is the activation of hepatic stellate cell that requires extensive alterations in gene expression. As reversible deacetylation of histone proteins modulate gene expression, we examined the effect of valproic acid (VPA) as selective histone deacetylase inhibitor on CCl-4 induced liver fibrosis. Thirty rats were divided into three equal groups; control group, fibrotic group and VPA-treated group. The rats were sacrificed after 6 weeks of liver fibrosis induction. The histopathological effect on liver tissue was examined. The expression of α-SMA and Smad-4 mRNA and serum levels of TGF-β1, alanine aminotransferase, and aspartate aminotransferase were determined. Treatment of rats with VPA attenuated carbon tetrachloride-induced liver fibrosis. Moreover, α-SMA and Smad-4 expression was repressed under VPA treatment and both serum TGF-β1 and liver enzymes were significantly decreased. The histone deacetylase inhibitor-1 VPA inhibits the epithelial-mesenchymal transition and affects hepatic stellate cell activation during liver fibrosis through downregulation of Smad4 and α-SMA expression which may serve as a promising agent in liver fibrosis treatment. © 2018 IUBMB Life, 70(6):511-518, 2018.

Carrageenan, is one of the food additives and is used as a firming agent in healthcare products like toothpaste. The aim of this study was to analyze the chronic toxic effects of kappa carregeenan (k- CGN) on the thyroid gland and pancreas in experimental rats and to evaluate the possible ameliorative effect of Diacerein. This study was done on fifty adult male albino rats. The rats were divided into 5 groups (10 rats in each group) in the form of; control group, Carboxymethylcellulose group (1.2ml/Kg), Diacerein group (30mg/Kg), Carrageenan group (50mg/Kg), and Diacerein( 30mg/kg) + Carrageenan (50mg/kg) combination group All drugs were given orally for 3 months. By the end of the 3rd month, thyroid and pancreatic functions were assessed by biochemical, histological, and immunohistochemical investigations. Rats group that were given Carrageenan alone had significantly higher thyroid MDA (malondialdehyde), lower thyroid GSH (reduced glutathione) and serum T4 levels than the untreated control rats group, but co- treatment of Carrageenan- exposed rats with diacerein had an ameliorative effect on the previous results. Light microscopic examinations of thyroid gland sections revealed that Carrageenan caused significant marked hypothyroid changes, and significant mild hypothyroid changes were observed in the rats which received Carrageenan + diacerein combination. Immunohistochemical studies of thyroid gland showed that carrageenan caused significant marked expression of PCNA and significant mild expression was observed in rats received combination of diacerein + carrageenan. Regarding pancreas, this study revealed no significant statistical changes in serum amylase level, MDA and GSH levels. Also, there were not any significant pathological changes of pancreatic tissues of carrageenan group. Thus, it appears that carrageenan can induce oxidative damage in the thyroid gland of rats and diacerein has an ameliorative effect against this damage.

Benign prostatic hyperplasia (BPH) is a common male disorder. Febuxostat is a non-purine, selective inhibitor of xanthine oxidase (XO), which has a strong antioxidant capacity and pleiotropic pharmacological properties. This study's objective was to explore the potential ameliorative effects of febuxostat against testosterone-induced BPH in rats. Febuxostat (10 mg/kg/day, per os [p.o.]) prevented increased prostate index levels, serum levels of prostate-specific antigen (PSA), and testosterone levels compared to animals treated with testosterone alone, when administered for 28 days. Histological examination indicated that febuxostat dramatically ameliorated pathological changes in the prostate architecture compared to the testosterone group. Similarly, febuxostat markedly improved testosterone-induced oxidative stress by inhibiting the increase in lipid peroxide and nitrite content, and by reducing the level of depletion of reduced glutathione (GSH) and superoxide dismutase (SOD) activity, which significantly reduced the prostate content of pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). Furthermore, febuxostat significantly reduced the prostatic content, both in terms of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) messenger ribonucleic acid (mRNA) levels, and of protein levels. Moreover, compared to the testosterone group, febuxostat's beneficial effects prevented the increase in growth factors, comprising vascular endothelial cell growth factor A (VEGF-A) and transforming growth factor beta (TGF-β) protein levels. Its ameliorating effects were equal to those of finasteride, which is the most widely used remedy for BPH. In conclusion, this study provides novel evidence that febuxostat experimentally attenuates testosterone-induced BPH in rats, at least in part by inhibiting iNOS/COX-2 and VEGF/TGF-β pathways.

Cerebellum seems to be a specific target for both the decrease of estrogen and hypertension in menopause. The aim of this study was to investigate the hypertension and menopause-induced changes in rat's cerebellar cortex and the possible mechanisms of these changes. Rats were divided into four groups: the sham-operated control (SC-group), the ovariectomized (OVX-group), the hypertensive (H-group), and the ovariectomized-hypertensive (OVX-H-group) group. The mean arterial pressure (MAP), serum nitric oxide (NO), lipid peroxides and antioxidant catalase enzyme levels were assayed. Cerebellar tissue homogenization for analysis of lipid peroxides, antioxidant catalase enzyme, tumor necrosis factor-α (TNF-α), and estradiol was done. Quantification of adrenomedullin (AM) and interleukin-10 (IL-10) mRNA was also done. Cerebella were processed for histological, immunohistochemical and transmission electron microscopic examination. In the OVX-group, insignificant structural and biochemical changes were observed compared with the SC-group apart from the significantly increased lipid peroxides and decreased NO and catalase levels in serum. The H-group showed an elevated lipid peroxides and TNF-α levels, reduced catalase level, numerous degenerated Purkinje cells, vacuolations of the neuropil, some axonal degeneration, and few ghosts in the granular cell layer (GL). However, in OVX-H-group, oxidative stress, inflammation, and cerebellar damage were exacerbated and cerebellar estrogen was reduced associated with reduction in GL thickness and decreased Purkinje cells number. Most axoplasms had degenerated neurofilaments with abnormal myelination. The immunoexpression of glial fibrillary acidic protein were significantly increased in both OVX-group and H-group and significantly decreased in OVX-H group. Gene expression of AM and IL-10 were increased in cerebellar tissues of H-group compared with the SC-group but it was significantly decreased in OVX-H-group compared with H-group. Taken together, postmenopausal rats with hypertension suffered from structural cerebellar changes than rats with only hypertension or estrogen deficiency separately due to augmentation of the increased oxidative stress markers and the proinflammatory cytokines (TNF-α) with down regulation of the anti-inflammatory cytokine (IL-10) and the blood pressure regulator, AM. These suggested that high blood pressure is a critical factor for postmenopausal cerebellum.

Antidepressants are the most commonly prescribed drugs for psychiatric treatment, and venlafaxine (VEN) is one of the most popular options. Venlafaxine is a nontricyclic dual-acting serotonin–norepinephrine reuptake inhibitor. Although an increased incidence of acute toxicity and addiction has been reported, controlled studies examining its toxic effects on different organs are still lacking. This study investigated the possible toxic effects of VEN on the liver, kidney, and gastric tissues. Three groups of rats were administered saline, a single LD50 dose (350 mg/kg), or 100 mg/kg VEN daily, followed by increases in the dose of 50 mg/kg every 10 days for 30 days (about 10 times the therapeutic doses). The following parameters of liver and kidney injury were then assayed: alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, prothrombin time, partial thromboplastin time, blood urea nitrogen, and serum creatinine. A histopathological examination was then conducted. Both acute and subchronic administration of VEN produced multiple clinical manifestations in the experimental animals, including seizures, coma, and even death. Moreover, the liver and renal function tests indicated injury in these tissues. Furthermore, the histopathological examination showed signs of organ toxicity after both acute and chronic VEN exposure. This study has shown that VEN has harmful effects on the liver, kidney, and stomach in either a single high dose (LD50) or repeated exposure to 10 times the therapeutic doses. As a result, strategies to increase awareness of these effects among physicians and the public are needed because this drug may be addictive.

Background: Preeclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality. Patients with severe PE exhibit significantly lower serum progesterone concentrations. There is limited information about the use of progesterone to manage or treat PE.Aim of the work: To investigate the possible protective and/or therapeutic effects of 17-hydroxyprogesterone caproate (17-OHPC) therapy in a rat model of PE and the possibly involved mechanisms that monitored biochemically, histologically, and immunohistochemically.Methods: Twenty-four pregnant female albino rats were randomly divided into 4 groups (6 rats/each): The control group, preeclampsia group (PE-group), prophylactic group, and treated group. The mean arterial blood pressure (MAP) and 24-hour protein in urine were determined. Rats were sacrificed at day 22 of gestation and placentae were processed for paraffin.Results: The MAP and proteinuria in the PE-group were significantly higher compared to the control group. The prophylactic and treated groups showed significant decrease in MAP and proteinuria as compared to PE-group. In the treated group, they nearly returned to the normal levels. The histological examination of the PE-group showed dilated maternal blood sinuses, depositions of hemosiderin granules and numerous phagocytic trophoblastic cells containing cytoplasmic hemosiderin granules. Fetal blood vessels showed homogenous acidophilic material occluding their lumen, edema of the extra-embryonic fetal membranes and intra-villous tissue, and numerous nucleated RBCs. The prophylactic group showed some improvement while the treated group showed more or less normal maternal blood sinuses and interhemal membrane with few hemosiderin granules and few nucleated RBCs. There was a significant increase in caspase-3 expression and a significant decrease in the eNOS expression in PE-group compared to the control group. While the prophylactic and the treated groups had a significant decrease in caspase-3 expression and a significant increase in the eNOS expression compared to PE-group.Conclusion: The biochemical, morphological and morphometric findings suggested that the administration of 17-OHPC to preeclamptic rat decreased blood pressure, proteinuria, inflammation, apoptosis, and improved vascular eNOS expression in placenta. The 17-OHPC possessed curative effect on L-NAME induced PE changes in rat placenta which was more obvious than its protective effect.

Introduction: Diabetes mellitus is a global problem and several restoration approaches have been developed to induce beta (β) cells regeneration. Platelet rich plasma (PRP) is an autogenous and economical source of growth factors which nowadays used in the tissue repair. Aim: To test the hypothesis that PRP could play a role in the improvement of the structural changes occurred in the endocrine pancreas of experimentally- induced diabetic rats and the possible mechanisms through which PRP induced its effects to shed a light on the possible use of such application in the clinical field. Material and methods: Sixty male albino rats were used; 20 for obtaining the PRP and 40 were divided into 4 equal groups (10 rats each): control, PRP-group, diabetic group, PRP/diabetic group. Diabetes was induced by single intra-peritoneal injection of streptozotocin (50-60 mg/kg). The PRP was administered by SC injections in a dose of 0.5 mg/kg twice weekly for 3 weeks. Results: The diabetic group showed a significant increase in blood glucose levels compared to the control. Treatment with PRP significantly reduced the blood glucose levels compared to the diabetic group. The diabetic group showed variable marked morphological changes which diminished by the PRP administration. PRP/diabetic group had a significant increase in the mean number of pancreatic islets and β-cells/islet compared to the diabetic group. The islet cells appeared normal with scarcely seen vacuolations. The duct system showed several changes; stratifications, invagination of the surface epithelium to the underlying connective tissue, and sprouting of the ductal epithelial cells in between the lobules. Numerous small islets were noticed in a close association with the intralobular ducts. Small newly lobules with abundant connective tissue were organized. There were significant increases in the insulin immunopositive β-cells and PCNA positive cells in PRP/diabetic group compared to diabetic group. Conclusion: This study provides an evidence of the diabetic pancreatic islet regeneration in response to PRP treatment. The PRP stimulated islet cell regeneration and stimulated the induction of other sources of β-cells generation as the exocrine portion of the pancreas; ductal and acinar cells. In addition, PRP might put the pancreas into an environment similar to the postnatal developmental one where new lobules were formed. These will pave the future for a novel treatment for diabetes.

Introduction Telocytes (TCs) are recently described to integrate a variety of different cells. Aim of the work. The aim was to investigate the presence of TCs in the rat mammary gland at its different physiological stages. Material and methods Twenty four adult female albino rats were classified into 4 groups: resting, mid-pregnancy, lactating, and involution groups. Inguinal mammary glands were processed for immunohistochemical and transmission electron microscopic (TEM) examination. Results TCs were immune-positive for c-kit and CD34 and showed significant differences in the different studied groups indicating variable roles at the different stages. TEM results characterized TCs by its shape and the long slender and moniliform telopodes linking the cells into stromal networks. The extracellular exosomes, homo-cellular synapsis and hetero-cellular synapsis were observed. Conclusion Our study provides evidence for the presence of TCs in all stages of the gland; not only in the resting stage as proved by other studies, but with immune-labeling differences suggesting different structural and physiological roles of TCs according to the stage requirements. These functions might via controlling the proliferation during pregnancy and lactation and the involution of the gland after weaning. Thus, more future functional studies of TCs will be important to help understanding the mechanism by which TCs contribute to tissue homeostasis concerning the role of the stromal/epithelial interactions in mammary gland biology and pathology including breast cancer which would be revolutionary for future therapeutic applications.

Deltamethrin is a broad spectrum, non- cumulative, fast acting neurotoxic synthetic pyrethroid. The aim of this study was to analyze the neurotoxicity induced by deltamethrin which caused neuro-oxidative stress, histopathological & immunohistochemical changes in adult male Wistar rats and to evaluate the possible ameliorative effect of melatonin. Melatonin (10mg/Kg, once daily), ethanol 99% (1 ml/kg, once daily), corn oil (0.005ml/Kg, once daily), deltamethrin (12.5mg/Kg, once daily), and melatonin (10mg/Kg) + deltamethrin (12.5mg/Kg) combination were given to rats I.P for 8 weeks. By the end of 8th week, rats given deltamethrin alone had significantly higher MDA (malondialdehyde), lower reduced glutathione and catalase levels in the hippocampus and lower ACTH (adrenocortocotrophic hormone) & cortisol hormone levels than the control group. Co- treatment of deltamethrin with melatonin had an ameliorative effect on the previous parameters. Light microscopic investigations revealed that deltamethrin caused marked degenerative changes in the hippocampus & pituitary gland of rats. Mild degenerative changes were observed in rats received deltamethrin + melatonin combination. Immunohistochemical studies revealed that deltamethrin caused marked expression of P-53 (a marker for apoptosis) in the hippocampus & pituitary gland. Mild expression of P-53 was observed in rats received deltamethrin & melatonin combination. Thus, deltamethrin can induce oxidative damage in rat brain & melatonin has an ameliorative effect against this damage.

Wound age estimation is one of the most critical issues for forensic pathologists. This study aimed to assess the time dependant histological changes versus the expression of Caspase 3 histochemically during contused skeletal muscle healing to discuss the practical suitability of the latter as a parameter for wound age determination in the living instead of histological change. Forty -six male albino rats were used in this study and divided into five groups, control group and four contused groups. At 12 hours, 3, 5 and 7 days after contusion, rats were killed and muscle samples were dissected from right hind limb of all rats. Histological examination was made and changes of Caspase-3 activity were assessed by imunohistochemistry, the results showed normal morphology of striated muscles and no Caspase-3 was detected in skeletal muscle in the control group. Light microscopic examination of contused groups revealed that polymorphonulcear cells (PMNs) were detected at 12 hours post contusion. Degenerated skeletal muscle fibers were phagocytosed gradually at 3 days, while most of degenerated fibers were phagocytosed and disappeared at 5 days post injury. From 3 days post-injury, fibroblast cells were present in the wound zones, and multinucleated myotubes augmented remarkably at 5–7 days. The expression level of Caspase-3 in the peripheral area of contused rat skeletal muscle increased gradually and maximized on the fifth day after injury, and then decreased gradually. Caspase-3 was also detected in the regenerated skeletal muscle within 7 days after injury. In conclusion, the expression of Capase-3 in the peripheral area of contused rat skeletal muscle indicated that it may play a pivotal role in apoptosis of the wounded skeletal muscle and may be used as a marker for wound age estimation in the living human being instead of histological changes

Cyclophosphamide is the most commonly used agent as antineoplastic chemotherapy. The aim of this study was to detect its chronic effect on urinary bladder & liver which included biochemical, histopathological and immunohistochemical changes in adult rats and to evaluate the possible protective effects of nigella sativa oil (NSO). Fifty adult albino rates were assigned equally to 5 groups (control, physiological saline (0.15ml I.P daily), NSO (2ml/kg orally daily), Cyclophosphamide (15mg/kg I.P daily) and Cyclophosphamide + NSO (the same previous doses). All drugs were given for 8 weeks. By the end of 8th week, rats given cyclphosphamide alone had significantly higher MDA (malonodialdahyde), blood glucose level, liver functions and plasma lipid profile but it had lower reduced glutathione and hemoglobin concentration levels than the untreated control rats. Pre- treatment of cyclophosphamide with NSO had ameliorative effect on the studied parameters. Light microscopic examination revealed apoptotic like picture in urinary bladder and liver's rats induced by cyclophosphamide. Immunohistochemical study showed obvious high immunolabelling for activated Caspase-3 in the same organs. Mild apoptotic changes were observed in rats received combined cyclophosphamide and NSO (group V). Consequently, NSO significantly ameliorates chronic cyclophospamide toxicity.

BackgroundAcute liver diseases constitute a global concern. Medical treatments for these diseases have limited efficacy. Lipopolysaccharide (LPS) and D-galactosamine (D-GaIN) cause hepatic failure in rodents. Glycyrrhizin (GL) was reported to treat increased serum aminotransferase activity in chroni

Nephrotoxicity is one of the limiting factors for using doxorubicin (DOX). Interleukin 1 has major role in DOX-induced nephrotoxicity, so we investigated the effect of interleukin 1 receptor antagonist diacerein (DIA) on DOX-induced nephrotoxicity. DIA (25 and 50 mg/kg/day) was administered orally to rats for 15 days, in the presence or absence of nephrotoxicity induced by a single intraperitoneal injection of DOX (15 mg/kg) at the 11th day. We measured levels of serum urea, creatinine, renal reduced glutathione (GSH), malondialdehyde (MDA), total nitrites (NOx), catalase, and superoxide dismutase (SOD). In addition, caspase-3, tumor necrosis factor alpha (TNFα), nuclear factor kappa B (NFκB) expressions, and renal histopathology were assessed. Our results showed that DOX-induced nephrotoxicity was ameliorated or reduced by both doses of DIA, but diacerein high dose (DHD) showed more improvement than diacerein low dose (DLD). This protective effect was manifested by significant improvement in all measured parameters compared to DOX treated group by using DHD. DLD showed significant improvement of creatinine, MDA, NOx, GSH, histopathology, and immunohistochemical parameters compared to DOX treated group.

Background: Insulin dependent diabetes mellitus is a chronic metabolic disease. Many drugs used in its treatment which have a number of serious adverse effects. Natural agent as quercetin (QCT) has been suggested in the alternative medicine for treatment of diabetes mellitus. Aim of the work: To evaluate the effect of QCT on the histological changes which occur in the islet of Langerhans of the streptozotocin (STZ)-induced diabetic rats and the possible mechanisms through which QCT produces its protective effect. Materials and methods: Fourty five male albino rats were divided into 3 groups: Group I, control group; 15 rats received single intraperitoneal injection of citrate buffer saline. Group II, diabetic group; 15 rats received single intraperitoneal injection of STZ. Group III; QCT-treated group, 15 rats received daily intraperitoneal injections of QCT for 30 days prior to, and for 30 days after the single injection of STZ. Blood samples were taken for monitoring blood glucose levels. Pancreas was taken out and processed for light microscopic, immunocytochemical and morphometrical studies. Results: Blood glucose levels showed a significant increase in group II compared to the control, while a significant decrease was observed in groups III compared to group II (all p