Edaravone mitigates hemorrhagic cystitis by modulating Nrf2, TLR-4/NF-κB, and JAK1/STAT3 signaling in cyclophosphamide-intoxicated rats.

Hemorrhagic cystitis is a potentially deadly complication associated with radiation therapy and chemotherapy. This study explored the protective effect of edaravone (ED) on cyclophosphamide (CP)-induced hemorrhagic cystitis, oxidative stress, and inflammation in rats. The animals received 20 mg/kg ED for 10 days and a single injection of 200 mg/kg CP on day 7. CP induced tissue injury manifested by the diffuse necrotic changes, disorganization of lining mucosa, focal hemorrhagic patches, mucosal/submucosal inflammatory cells infiltrates, and edema. CP increased malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha, and interleukin 6 (IL-6), decreased IL-10, and upregulated toll-like receptor 4 (TLR-4), nuclear factor-kappa B (NF-κB) p65, Janus kinase 1 (JAK1), and signal transducer and activator of transcription 3 (STAT3) in the urinary bladder of rats. ED effectively prevented the histopathological alterations, decreased MDA, NO, and inflammatory mediators, and downregulated TLR-4, NF-κB, JAK1, and STAT3 in CP-induced rats. Treatment with ED upregulated ikß kinase ß, IL-10, nuclear factor-erythroid 2 related factor 2 (Nrf2), and cytoglobin, and boosted glutathione, superoxide dismutase, and glutathione S-transferase. Molecular docking simulations revealed the ability of ED to bind TLR-4, NF-κB, JAK1, and STAT3. In vitro, ED increased the cytotoxic activity of CP against HeLa, Caco-2, and K562 cell lines. In conclusion, ED prevented CP-induced hemorrhagic cystitis in rats by attenuating oxidative stress, suppressing TLR-4/NF-κB, and JAK1/STAT3 signaling and boosted Nrf2, cytoglobin, and antioxidants.

Effects of hydrogen sulphide on oxidative stress, inflammatory cytokines, and vascular remodelling in l-NAME-induced hypertension.

This study was designed to evaluate the protective effects of hydrogen sulphide (H2 S) against NG-Nitro l-Arginine Methyl Ester (l-NAME)-induced hypertension and its possible effects on the inflammatory process, oxidative stress, and vascular remodelling in rats. Forty male Wistar Albino rats were assigned to four equal groups: the control group, the H2 S control group, the hypertensive group, and the treated group, which received concomitant treatment with sodium hydrosulphide (NaHS) and l-NAME. Systolic blood pressure (SBP) was measured weekly. Serum levels of nitric oxide (NO), total peroxide, and total antioxidant capacity (TAC) were measured and the oxidative stress index (OSI) was calculated. Aortic weight and length were measured and the aortic weight/length ratio determined. Aortic fold expression of interferon-γ (IFN-γ) and vascular cell adhesion molecule-1 (VCAM-1) mRNA was measured using qPCR. Aortic media thickness and elastin content were measured morphometrically. l-NAME administration increased SBP, serum levels of total peroxide and OSI, but reduced serum levels of NO and TAC. Aortic fold expression of IFN-γ and VCAM-1 mRNA, aortic weight, aortic weight/length ratio, aortic media thickness, and elastin area percentage were increased in the hypertensive group. Concurrent administration of l-NAME and H2 S attenuated these changes. Thus, H2 S could attenuate the increase in ABP through restoration of the NO level, reduction in the oxidative state, and attenuation of the inflammatory process, thereby reduced vascular remodelling.

Alleviation of Simvastatin-Induced Myopathy in Rats by the Standardized Extract of Ginkgo Biloba (EGb761): Insights into the Mechanisms of Action.

Statins are the most widely prescribed cholesterol-lowering drugs to reduce the risk of cardiovascular diseases. Statin-induced myopathy is the major side effect of this class of drugs. Here, we studied whether standardized leaf extracts of ginkgo biloba (EGb761) would improve simvastatin (SIM)-induced muscle changes. Sixty Wistar rats were allotted into six groups: control group, vehicle group receiving 0.5% carboxymethyl cellulose (CMC) for 30 days, SIM group receiving 80 mg/kg/day SIM in 0.5% CMC orally for 30 days, SIM withdrawal group treated with SIM for 16 days and sacrificed 14 days later, and EGb761-100 and EGb761-200 groups posttreated with either 100 or 200 mg/kg/day EGb761 orally. Muscle performance on the rotarod, serum creatine kinase (CK), coenzyme Q10 (CoQ10), serum and muscle nitrite, muscle malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) activities were estimated. Additionally, muscle samples were processed for histopathological evaluation. We found that SIM decreased muscle performance on the rotarod, serum CoQ10, as well as muscle SOD and CAT activities while it increased serum CK, serum and muscle nitrite, as well as muscle MDA levels. SIM also induced sarcoplasmic vacuolation, splitting of myofibers, disorganization of sarcomeres, and disintegration of myofilaments. In contrast, posttreatment with EGb761 increased muscle performance, serum CoQ10, as well as muscle SOD and CAT activities while it reduced serum CK as well as serum and muscle nitrite levels in a dose-dependent manner. Additionally, EGb761 reversed SIM-induced histopathological changes with better results obtained by its higher dose. Interestingly, SIM withdrawal increased muscle performance on the rotarod, reduce serum CK and CoQ10, and reduced serum and muscle nitrite while it reversed SIM-induced histopathological changes. However, SIM withdrawal was not effective enough to restore their normal values. Additionally, SIM withdrawal did not improve SIM-induce muscle MDA, SOD, or CAT activities during the period studied. Our results suggest that EGb761 posttreatment reversed SIM-induces muscle changes possibly through its antioxidant effects, elevation of CoQ10 levels, and antagonizing mitochondrial damage.

Folic acid protects against experimental prenatal nicotine-induced cardiac injury by decreasing inflammatory changes, serum TNF and COX-2 expression.

Nicotine administration has been shown to increase the risk for cardiovascular diseases and death. The present study was designed to investigate the impact of nicotine administration on serum level tumor necrosis factor and cycloxygenase -2 (COX-2) expression mediated cardiac injury in rat off springs, and the possible protective effect of folic acid. Eighteen pregnant female rats were randomly divided into three groups, six animals each. Control group received the vehicle, nicotine group received a dose of nicotine 0.1 mg/kg body weight, daily with subcutaneous injection from day 3 of gestation until weaning on postnatal day 21. Nicotine treated group received daily oral supplementation with folic acid 200 mg/kg body weight by intragastric tube prior to injection of nicotine. In serum of the pups, levels of tumor necrosis factor (TNF), nitric oxide (NO), total antioxidant capacity (TAC) and malondialdehyde (MDA) were measured. Histopathological studies of cardiac tissues using hematoxylin-eosin (H&E) were carried out. The expression of COX-2 was evaluated using immunohistochemistry. Serum TNF and MDA were significantly increased, while serum NO and TAC were significantly decreased in nicotine group. Moreover, nicotine-exposed rats showed complete lysis of cardiac myocytes, marked cytoplasmic vacuolation of myocytes, muscle fibers show loss of striation and increased COX-2 expression. Concomitant folic acid administration resulted in a significant alleviation of biochemical and structural alteration-induced by nicotine. In conclusion, folic acid has a protective role against nicotine induced cardiac injury by reduction of COX-2 expression, decreasing TNF production and lipid peroxidation mediated cell injury.

Two Genetic Variants Associated with Plantar Fascial Disorders.

Plantar fascial disorder is comprised of plantar fasciitis and plantar fibromatosis. Plantar fasciitis is the most common cause of heel pain, especially for athletes involved in running and jumping sports. Plantar fibromatosis is a rare fibrous hyperproliferation of the deep connective tissue of the foot. To identify genetic loci associated with plantar fascial disorders, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 21,624 cases of plantar fascial disorders and 80,879 controls. One indel (chr5:118704153:D) and one SNP (rs62051384) showed an association with plantar fascial disorders at genome-wide significance (p<5×10-8) with small effects (odds ratios=0.93 and 1.07 per allele, respectively). The indel chr5:118704153:D is located within TNFAIP8 (encodes a protein induced by TNF alpha) and rs62051384 is located within WWP2 (which is involved in proteasomal degradation). These DNA variants may be informative in explaining why some individuals are at higher risk for plantar fascial disorders than others.

A Genetic Marker Associated with De Quervain's Tenosynovitis.

De Quervain's tenosynovitis is a repetitive strain injury involving synovial inflammation of the tendons of the first extensor compartment of the wrist. It is relatively common in the general population, and is the most common radial-sided tendinopathy seen in athletes. Identifying a genetic marker associated with de Quervain's tenosynovitis could provide a useful tool to help identify those individuals with an increased risk for injury. A genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health (RPGEH) including 4,129 cases and 98,374 controls. rs35360670 on chromosome 8 showed an association with de Quervain's tenosynovitis at genome-wide significance (p=1.9×10-8; OR=1.46; 95% CI=1.38-1.59). This study is the first genome-wide screen for de Quervain's tenosynovitis and provides insights regarding its genetic etiology as well as a DNA marker with the potential to inform athletes and other high-risk individuals about their relative risk for injury.

Two Genetic Loci associated with Medial Collateral Ligament Injury.

Medial collateral ligament (MCL) injuries are a common knee injury, especially in competitive athletes. Identifying genetic loci associated with MCL injury could shed light on its etiology. A genome-wide association screen was performed using data from the Research Program in Genes, Environment and Health (RPGEH) including 1 572 cases of MCL injury and 100 931 controls. 2 SNPs (rs80351309 and rs6083471) showed an association with MCL injury at genome-wide significance (p<5×10-8) with moderate effects (odds ratios=2.12 and 1.57, respectively). For rs80351309, the genotypes were imputed with only moderate accuracy, so this SNP should be viewed with caution until its association with MCL injury can be validated. The SNPs rs80351309 and rs6083471 show a statistically significant association with MCL injury. It will be important to replicate this finding in future studies.

A Genetic Marker Associated with Shoulder Dislocation.

Shoulder dislocations are common shoulder injuries associated with athletic activity in contact sports, such as football, rugby, wrestling, and hockey. Identifying genetic loci associated with shoulder dislocation could shed light on underlying mechanisms for injury and identify predictive genetic markers. To identify DNA polymorphisms associated with shoulder dislocation, a genome-wide association screen was performed using publically available data from the Research Program in Genes, Environment and Health including 662 cases of shoulder dislocation and 82 602 controls from the European ancestry group. rs12913965 showed an association with shoulder dislocation at genome-wide significance (p=9.7×10-9; odds ratio=1.6) from the European ancestry group. Individuals carrying one copy of the risk allele (T) at rs12913965 showed a 69% increased risk for shoulder dislocation in our cohort. rs12913965 is located within an intron of the TICRR gene, which encodes TOPBP1 interacting checkpoint and replication regulator involved in the cell cycle. rs12913965 is also associated with changes in expression of the ISG20 gene, which encodes an antiviral nuclease induced by interferons. This genetic marker may one day be used to identify athletes with a higher genetic risk for shoulder dislocation. It will be important to replicate this finding in future studies.

Effects of opioid (tramadol) treatment on testicular functions in adult male rats: The role of nitric oxide and oxidative stress.

Nowadays, tramadol hydrochloride is frequently used as a pain reliever, and for the treatment of premature ejaculation. Decreased semen quality was noted in chronic tramadol users. The present study aimed to elucidate the effects of tramadol on the testicular functions of adult male rats. A total of 40 albino adult male rats were divided into control and tramadol groups, with 20 rats for each group. Rats of the tramadol group were subcutaneously injected with 40 mg/kg three times per week for 8 weeks. The control group received normal saline 0.9%. Blood samples from each animal were obtained. Plasma levels of different biochemical substances were determined. Nitric oxide was measured in testicular tissue samples. Those samples together with epididymal tissue samples were processed for histopathological examination. Tramadol significantly reduced plasma levels of luteinizing hormone, follicle-stimulating hormone, testosterone and total cholesterol, but elevated prolactin and estradiol levels compared with the control group. In addition, tramadol increased the testicular levels of nitric oxide and lipid peroxidation, and decreased the anti-oxidant enzymes activities significantly compared with the control group. The tramadol group showed decreased sperm count and motility, and numbers of primary spermatocytes, rounded spermatid and Leydig cells. Immunohistochemical examinations showed that tramadol increased the expression of endothelial nitric oxide synthase in testicular tissues. The present study showed that tramadol treatment affects the testicular function of adult male rats, and these effects might be through the overproduction of nitric oxide and oxidative stress induced by this drug.

Comparative study of the effect of verapamil and vitamin D on iron overload-induced oxidative stress and cardiac structural changes in adult male rats.

The present study was designed to compare the effect of verapamil and vitamin D on the expression of the voltage-dependent LTCC alpha 1c subunit (Cav1.2) and thereby on iron overload-induced cardiac dysfunction in adult male rat. Forty rats were randomly divided into four groups. Control group received the vehicle, iron overload group received ferrous sulfate intraperitoneally (IP) for 4 weeks, iron overload+verapamil received ferrous sulfate and verapamil IP concurrently for 4 weeks and iron overload+vitamin D group received ferrous sulfate IP and vitamin D3 orally concurrently for 4 weeks. Serum ferritin, total antioxidant capacity (TAC), total peroxide (TP) and cardiac iron and calcium were determined. Oxidative stress index (OSI) was calculated. Histopathological studies using H&E, Masson trichrome and Prussian blue stains and immunohistochemical studies using Cav1.2 antibody were also carried out. Administration of ferrous sulfate induced a significant increase in serum ferritin, OSI, cardiac iron and calcium contents. Moreover, cardiomyocytes were degenerated and the expression of Cav1.2 protein was increased in iron overload group as compared to control. Verapamil decreased ferrous sulfate-induced increase in serum ferritin, OSI and cardiac iron deposition. In addition, verapamil improved myocardial degeneration and decreased the expression of Cav1.2 protein. In contrast, vitamin D produced insignificant changes in ferrous sulfate-induced increase in cardiac iron content, myocardial degeneration and the expression of Cav1.2 protein. These results indicate that verapamil has a protective effect against iron overload-induced cardiac dysfunction, oxidative stress and structural changes, while vitamin D has an insignificant effect on these parameters.

Role of vitamin C and selenium in attenuation of nicotine induced oxidative stress, P53 and Bcl2 expression in adult rat spleen.

UNLABELLED: Forty adult female rats were randomly divided into four groups: control, nicotine, nicotine+vitamin C and nicotine+selenium group. Splenic tissues concentrations of thiobarbituric acid reactive substances (TBARS), nitric oxide, superoxide dismutase (SOD) and catalase (CAT) activities were measured. The P53 and Bcl2 proteins were detected by Western blot and their expression in splenic tissues were measured by quantitative real time PCR in all groups. Compared to control group, nicotine increased the concentrations of TBARS and nitric oxide significantly. However, Vit. C or Se supplementation with nicotine caused a significant decrease in these concentrations. SOD and CAT activities of nicotine group decreased significantly compared to control group. Treatment with Vit. C or Se plays a significant role in elevation of SOD and CAT activities. In splenic tissues, nicotine significantly decreases the protein levels and the mRNA expression of P53 and increases the protein levels of Bcl2 and its expression. Administration of Vit. C. to nicotine-treated rats completely reversed the decrease in P53 levels and its mRNA expression and the increase in Bcl2 levels and its mRNA expression to the control values. In contrast, Se administration did not induce any significant changes in these genes levels or expressions compared to nicotine group. CONCLUSION: Vit. C supplementation to nicotine treated rats was more effective than selenium in attenuation of nicotine-induced oxidative stress, p53 and Bcl2 expression in rat spleen tissues.

Role of cAMP/pCREB and GSK-3ß/NF-κB p65 signaling pathways in the renoprotective effect of mirabegron against renal ischemia-reperfusion injury in rats.

Acute kidney injury and other renal disorders are thought to be primarily caused by renal ischemia-reperfusion (RIR). Cyclic adenosine monophosphate (cAMP) has plenty of physiological pleiotropic effects and preserves tissue integrity and functions. This research aimed to examine the potential protective effects of the ß3-adrenergic receptors agonist mirabegron in a rat model of RIR and its underlying mechanisms. Male rats enrolled in this work were given an oral dose of 30 mg/kg mirabegron for two days before surgical induction of RIR. Renal levels of kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), Interleukin-10 (IL-10), cAMP, cAMP-responsive element binding protein (pCREB), and glycogen synthase kinase-3 beta (GSK-3ß) were assessed along with blood urea nitrogen and serum creatinine. Additionally, caspase-3 and nuclear factor-kappa B (NF-κB) p65 were explored by immunohistochemical analysis. Renal specimens were inspected for histopathological changes. RIR led to renal tissue damage with elevated blood urea nitrogen and serum creatinine levels. The renal KIM-1, MCP-1, TNF-α, and GSK-3ß were significantly increased, while IL-10, cAMP, and pCREB levels were reduced. Moreover, upregulation of caspase-3 and NF-κB p65 protein expression was seen in RIR rats. Mirabegron significantly reduced kidney dysfunction, histological abnormalities, inflammation, and apoptosis in the rat renal tissues. Mechanistically, mirabegron mediated these effects via modulation of cAMP/pCREB and GSK-3ß/NF-κB p65 signaling pathways. Mirabegron administration could protect renal tissue and maintain renal function against RIR.

Vildagliptin ameliorates intrapulmonary vasodilatation and angiogenesis in chronic common bile duct ligation-induced hepatopulmonary syndrome in rat.

INTRODUCTION: Experimental hepatopulmonary syndrome (HPS) is best reproduced in the rat common bile duct ligation (CBDL) model. Vildagliptin (Vild) is an anti-hyperglycemic drug that exerts beneficial anti-inflammatory, anti-oxidant and anti-fibrotic effects. Therefore, the present search aimed to explore the possible effectiveness of Vild in CBDL-induced HPS model. METHODS: Four groups of male Wistar rats which weigh 220-270 g were used, including the normal control group, the sham control group, the CBDL group and CBDL+Vild group. The first three groups received i.p. saline, while the last group was treated with i.p. Vild (10 mg/kg/day) from the 15th to 28th day of the experiment. RESULTS: CBDL decreased the survivability and body weight of rats, increased diameter of the pulmonary vessels, and altered the arterial blood gases and the liver function parameters. Additionally, it increased the pulmonary expressions of endothelin-1 (ET-1) and tumor necrosis factor-α (TNF-α) mRNA as well as endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor-A (VEGF-A) proteins. The CBDL rats also exhibited elevation of the pulmonary interleukin-6 (IL-6), dipeptidyl peptidase-4 (DPP-4) and nitric oxide (NO) levels along with reduction of the pulmonary total anti-oxidant capacity and glucagon-like peptide-1 (GLP-1) levels. Vild mitigated these alterations and improved the histopathological abnormalities caused by CBDL. CONCLUSION: Vild effectively attenuated CBDL-induced HPS through its anti-oxidant and anti-inflammatory effects along with its modulatory effects on ET-1/NOS/NO and TNF-α/IL-6/VEGF-A signaling implicated in the regulation of intrapulmonary vasodilatation and angiogenesis, respectively.

A generic approach based on long-lifetime fluorophores for the assessment of protein binding to polymer nanoparticles by fluorescence anisotropy.

Quantitation of protein-nanoparticle interactions is essential for the investigation of the protein corona around NPs in vivo and when using synthetic polymer nanoparticles as affinity reagents for selective protein recognition in vitro. Here, a method based on steady-state fluorescence anisotropy measurement is presented as a novel, separation-free tool for the assessment of protein-nanoparticle interactions. For this purpose, a long-lifetime luminescent Ru-complex is used for protein labelling, which exhibits low anisotropy when conjugated to the protein but displays high anisotropy when the proteins are bound to the much larger polymer nanoparticles. As a proof of concept, the interaction of lysozyme with poly(N-isopropylacrylamide-co-N-tert-butylacrylamide-co-acrylic acid) nanoparticles is studied, and fluorescence anisotropy measurements are used to establish the binding kinetics, binding isotherm and a competitive binding assay.

Temperature-Responsive Magnetic Nanoparticles for Bioanalysis of Lysozyme in Urine Samples.

Highly selective multifunctional magnetic nanoparticles containing a thermoresponsive polymer shell were developed and used in the sample pretreatment of urine for the assessment of lysozymuria in leukemia patients. Crosslinked poly(N-isopropylacrylamide-co-acrylic acid-co-N-tert-butylacrylamide) was grown onto silica-coated magnetic nanoparticles by reversible addition fragmentation chain transfer (RAFT) polymerization. The lysozyme binding property of the nanoparticles was investigated as a function of time, protein concentration, pH, ionic strength and temperature and their selectivity was assessed against other proteins. High-abundant proteins, like human serum albumin and γ-globulins did not interfere with the binding of lysozyme even at elevated concentrations characteristic of proteinuria. A sample cleanup procedure for urine samples has been developed utilizing the thermocontrollable protein binding ability of the nanoparticles. Method validation was carried out according to current bioanalytical method validation guidelines. The method was highly selective, and the calibration was linear in the 25 to 1000 µg/mL concentration range, relevant in the diagnosis of monocytic and myelomonocytic leukemia. Intra- and inter-day precision values ranged from 2.24 to 8.20% and 1.08 to 5.04%, respectively. Intra-day accuracies were between 89.9 and 117.6%, while inter-day accuracies were in the 88.8 to 111.0% range. The average recovery was 94.1 ± 8.1%. Analysis of unknown urine samples in comparison with a well-established reference method revealed very good correlation between the results, indicating that the new nanoparticle-based method has high potential in the diagnosis of lysozymuria.

Pioglitazone and/or irbesartan ameliorate COPD-induced endothelial dysfunction in side stream cigarette smoke-exposed mice model.

AIMS: Cigarette smoking (CS) is the main cause of chronic obstructive pulmonary disease (COPD). Endothelial dysfunction is related to the severity of pulmonary disease in COPD. This study aimed to evaluate the effectiveness of single and combined administration of pioglitazone (Pio) and irbesartan (Irb) against COPD-induced endothelial dysfunction in mice and the involvement of NO and H2S in their effects. MATERIALS AND METHODS: Adult male Swiss mice (n = 40, weighing 25-30 g) were assigned into 5 groups. The normal control group received 1% carboxy methyl cellulose (CMC). The CS group was exposed to CS and administered 1% CMC for 3 months. The CS + Pio, CS + Irb, and CS + Pio/Irb groups were subjected to CS and received Pio (60 mg/kg), Irb (50 mg/kg), and their combination respectively, daily orally for 3 months. Body weight gain, mean blood pressure, urinary albumin, serum NO and ET-1 levels with TNF-α and IL-2 levels in lung tissue and bronchoalveolar lavage were measured. Lung H2S and ET-1 levels, protein expression of PPARγ in lung and VEGF in lung and aortic tissues with histological changes were assessed. KEY FINDINGS: Our results illustrated that CS induced a model of COPD with endothelial dysfunction in mice. Pio/Irb singly and in combination elicited protective effects against the pathophysiology of the disease with more improvement in the combined group. There is a strong correlation between NO and H2S as well as the other measured parameters. SIGNIFICANCE: Collectively, both drugs performed these effects via their anti-inflammatory potential and increasing H2S and NO levels.

Involvement of H2 S, NO and BDNF-TrkB signalling pathway in the protective effects of simvastatin against pentylenetetrazole-induced kindling and cognitive impairments in mice.

Cognitive dysfunction was observed in pentylenetetrazole (PTZ)-kindled mice. The potential effectiveness of simvastatin (SIM) on PTZ-induced kindling and cognitive impairments in mice was evaluated. The influence of SIM on hydrogen sulphide (H2 S), nitric oxide (NO), reactive aldehydes and brain-derived neurotrophic factor/tyrosine receptor kinase B (BDNF-TrkB) signalling was also investigated. Kindling and cognitive impairments in mice were induced by 12 ip injections of PTZ (35 mg/kg) once every alternate day. The levels of reactive aldehydes and nitrite were increased while H2 S was decreased in PTZ-treated mice. These results were accompanied by a reduction in the gene expression of aldehyde dehydrogenase 2, cystathionine ß-synthase, BDNF and TrkB. In PTZ-kindled mice, a rise in brain inducible nitric oxide synthase protein expression associated with histopathological changes was observed. SIM administration (1, 5 and 10 mg/kg, daily orally) along with alternate day of PTZ (35 mg/kg) resulted in a decrease in PTZ-induced kindling with a dose-dependent improvement in cognitive function. SIM (10 mg/kg) prevented, to variable extent, the disturbances associated with PTZ-kindled mice with cortical, cerebellar and hippocampal structural improvement. These results suggested that SIM triggers multiple mechanisms that improve cognitive function in PTZ-kindled mice through modulation of oxidative stress, H2 S, NO and BDNF-TrkB signalling pathway.

Perindopril Ameliorates Hepatic Ischemia Reperfusion Injury Via Regulation of NF-κB-p65/TLR-4, JAK1/STAT-3, Nrf-2, and PI3K/Akt/mTOR Signaling Pathways.

Hepatic ischemia reperfusion (IR) is an inevitable clinical problem for surgical procedures such as liver transplantation and liver resection. This study was designed to evaluate the protective effect of perindopril (PER) against hepatic IR injury. Thirty-two rats were used and randomly allocated into four groups. Sham control group was subjected to sham operation and received saline only, IR group was subjected to IR and received vehicle, PER group was pretreated with PER (one milligram per kilogram per day i.p. for 10 consecutive days), and IR+PER group was pretreated with PER then subjected to IR. Liver function biomarkers (aspartate aminotransferase and alanine aminotransferase), oxidative stress (glutathione, malondialdehyde, myeloperoxidase, and superoxide dismutase) and inflammation markers (tumor necrosis factor-alpha, interferon-gamma, and inteleukin-10 [IL-10]), mRNA expression of NF-κB-p65 and TLR-4, as well as protein expression of JAK1, STAT-3, PI3K, mTOR, Akt, and Nrf-2 were investigated concomitantly with histopathological examination. The results indicated that, hepatic IR induced a significant alteration in liver function biomarkers and structure, oxidative stress, and inflammation. At the molecular level, up-regulation of NF-κB-p65, TLR-4, JAK1, and STAT-3 concomitantly with down-regulation of Nrf-2, IL-10, PI3K, Akt, and mTOR were observed. These disturbances were alleviated by pretreatment of IR rats with PER in concomitant with hepatic structural improvement. Conclusively, the protective effect of PER presumably may be relevant to its ability to reduce oxidative stress, ameliorate the inflammatory processes, and modify the related signaling pathways. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:1935-1949, 2020. © 2019 American Association for Anatomy.

Epidemiological and Histopathological Investigation of Sarcoptic Mange in Camels in Egypt.

Mange has been considered one of the most common parasitic infestations among camels. It adversely impacts animal productivity and poses a risk to human health. Given the scarcity of available data about mange in camels, the current study focused on the prevalence of camel mange and its associated risk factors in Aswan Governorate, Egypt. Towards this end, a general visual inspection was conducted on camels (N = 210) in different markets and slaughterhouses in Aswan Governorate. Skin scrapings from suspect infected camels were also examined microscopically. Importantly, these findings were further checked and confirmed by histopathology on samples from suspected cases collected post-slaughter in abattoirs. The possible risk-associated factors, which include the camel's age, sex and sampling season, were recorded and statistically analyzed. Interestingly, the data showed that a total of 100 camels (47.6%) were found exclusively infested by sarcoptic mange. Furthermore, the predominant histopathological changes included burrowing tunnel of mites in the skin, hyperkeratosis and acanthosisconsis of the epidermis, while the dermis showed hemorrhage, mononuclear inflammatory cell infiltration around the blood vessels and perifolliculitis. These major histopathological findings are consistent with sarcoptic mange. Furthermore, the statistical analysis of the possible associated risk factors, camel's age (p = 0.006), gender (p = 0.032) and sampling season (p = 0.004), were all found to be significantly affected and related to the disease. In this regard, camels ≥2 years old were found at higher risk of infection (odds ratio (OR) = 2.75; 95% confidence interval (CI), 1.345 to 5.604) versus younger animals (OR = 0.36; 95 CI, 0.1784 to 0.743). Females had higher odds of exposure (OR = 2.02; 95% CI, 1.096 to 3.708) compared to males (OR = 0.50; 95% CI, 0.269 to 0.912). Moreover, the exposure to infection was reported higher in winter (OR = 2.30; 95% CI, 1.297 to 4.098) than in summer (OR = 0.43; 95% CI, 0.244 to 0.771). Collectively, our data provide novel epidemiological and histopathological support for sarcoptic mange being widespread among camels in the studied area. Sarcoptic mange is extremely contagious and zoonotic. Therefore, our baseline investigation indicates an urgent need for additional multicenter-studies to investigate the occurrence of this disease in camels and humans combined with the appropriate control measures of camel importation for combating this disease.