Tunable Polymeric Mixed Micellar Nanoassemblies of Lutrol F127/Gelucire 44/14 for Oral Delivery of Praziquantel: A Promising Nanovector against Hymenolepis nana in Experimentally-Infected Rats.

Hymenolepiasis represents a parasitic infection of common prevalence in pediatrics with intimidating impacts, particularly amongst immunocompromised patients. The present work aimed to snowball the curative outcomes of the current mainstay of hymenolepiasis chemotherapy, praziquantel (PRZ), through assembly of polymeric mixed micelles (PMMs). Such innovative nano-cargo could consolidate PRZ hydrosolubility, extend its circulation time and eventually upraise its bioavailability, thus accomplishing a nanoparadigm for hymenolepiasis tackling at lower dose levels. For consummating this goal, PRZ-PMMs were tailored via thin-film hydration technique integrating a binary system of Lutrol F127 and Gelucire 44/14. Box-Behnken design was planned for optimizing the nanoformulation variables employing Design-Expert® software. Also, in Hymenolepis nana-infected rats, the pharmacodynamics of the optimal micellar formulation versus the analogous crude PRZ suspension were scrutinized on the 1st and 3rd days after administration of a single oral dose (12.5 or 25 mg/kg). Moreover, in vitro ovicidal activity of the monitored formulations was estimated utilizing Fuchsin vital stain. Furthermore, the in vivo pharmacokinetics were assessed in rats. The optimum PRZ-PMMs disclosed conciliation between thermodynamic and kinetic stability, high entrapment efficiency (86.29%), spherical nanosized morphology (15.18 nm), and controlled-release characteristics over 24 h (78.22%). 1H NMR studies verified PRZ assimilation within the micellar core. Additionally, the in vivo results highlighted a significant boosted efficacy of PRZ-PMMs manifested by fecal eggs output and worm burden reduction, which was clearly evident at the lesser PRZ dose, besides a reversed effect for the intestinal histological disruptions. At 50 µg/mL, PRZ-PMMs increased the percent of non-viable eggs to 100% versus 47% for crude PRZ, whilst shell destruction and loss of embryo were only clear with the applied nano-cargo. Moreover, superior bioavailability by 3.43-fold with elongated residence time was measured for PRZ-PMMs compared to PRZ suspension. Practically, our results unravel the potential of PRZ-PMMs as an oral promising tolerable lower dose nanoplatform for more competent PRZ mass chemotherapy.

The modulatory effect of carvacrol on viral shedding titer and acute phase response in broiler chickens experimentally infected with infectious bronchitis virus.

Infectious bronchitis virus (IBV) is one of the major respiratory diseases of broiler causing huge economic losses. The inability to control IBV using different vaccination programs owing to the high mutation rate and recombination ability of the RNA genome generates IBV variants. This study was designed to give a specific perspective of carvacrol effect on early immune response, viral shedding titer, oxidative stress, serum biochemical parameters and clinical consequences in broilers experimentally infected by IBV. One hundred and twenty-one-day old commercial broiler chicks were equally divided into 4 groups. First group was considered as control. Second group was given carvacrol, third group was infected with IBV and fourth group was given carvacrol and infected with IBV. Infection with variant IBV induced significant upregulation of chicken interferon-inducible transmembrane protein 3 (chIFITM3) gene in trachea, elevations in serum levels of Alpha-1 acid glycoprotein (α1-AGP) and Interleukin 6 (IL-6), total leucocytic count (TLC), heterophil/lymphocyte (H/L) ratio and oxidative stress in lung and kidney tissues. Beside, histopathological changes in trachea, lung and kidney induced by IBV, elevation of kidney function tests was detected. The pretreatment with carvacrol significantly reduced viral shedding titer, chIFITM3 gene expression, IL-6 and α1-AGP levels, leucocytic response and H/L ratio with minimization of clinical signs intensity. Also, carvacrol relieved oxidative stress, ameliorated the increased uric acid level and histopathological alterations in kidney and lung caused by viral infection.

Combinatory Effects of Bone Marrow-Derived Mesenchymal Stem Cells and Indomethacin on Adjuvant-Induced Arthritis in Wistar Rats: Roles of IL-1ß, IL-4, Nrf-2, and Oxidative Stress.

Rheumatoid arthritis (RA) is a disorder triggered by autoimmune reactions and related with chronic inflammation and severe disability. Bone Marrow-derived Mesenchymal Stem Cells (BM-MSCs) have shown a hopeful immunomodulatory effect towards repairing cartilage and restoring joint function. Additionally, indomethacin (IMC), a nonsteroidal compound, has been considered as a potent therapeutic agent that exhibits significant antipyretic properties and analgesic effects. The target of the current research is to assess the antiarthritic efficacy of BM-MSCs (106 cells/rat at 1, 6, 12 and 18 days) and IMC (2 mg/kg body weight/day for 3 weeks) either alone or concurrently administered against complete Freund's adjuvant-induced arthritic rats. Changes in paw volume, body weight, gross lesions, and antioxidant defense system, as well as oxidative stress, were assessed. The Th1 cytokine (IL-1ß) serum level and Th2 cytokine (IL-4) and Nrf-2 ankle joint expression were detected. In comparison to normal rats, it was found that the CFA-induced arthritic rats exhibited significant leukocytosis and increase in paw volume, LPO level, RF, and IL-1ß serum levels. In parallel, arthritic rats that received BM-MSCs and/or IMC efficiently exhibited decrease in paw edema, leukocytosis, and enhancement in the antioxidant enzymatic levels of SOD, GPx, GST, and GSH in serum besides upregulation of Nrf-2 and anti-inflammatory IL-4 expression levels in the ankle articular joint. Likewise, these analyses were more evidenced by the histopathological sections and histological score. The data also revealed that the combined administration of BM-MSC and IMC was more potent in suppressing inflammation and enhancing the anti-inflammatory pathway than each agent alone. Thus, it can be concluded that the combined therapy with BM-MSC and IMC may be used as a promising therapeutic choice after assessing their efficacy and safety in human beings with RA, and the antiarthritic effects may be mediated via modulatory effects on Th1/Th2 cytokines, ozidative stress, and Nrf-2.

Screening of human bocavirus in surgically excised cancer specimens.

Human bocavirus (HBoV) is a prevalent virus worldwide and is mainly associated with respiratory disorders. Recently, it was detected in several disease conditions, including cancers. Colorectal cancer (CRC) is the third main cause of cancers worldwide. Risk factors that initiate cell transformation include nutritional, hereditary and infectious causes. The aim of the current study was to screen for the presence of HBoV in solid tumors of colorectal cancer and to determine the genotypes of the detected strains. Surgically excised and paraffin-embedded colorectal cancer tissue specimens from 101 male and female patients with and without metastasis were collected over the last four years. Pathological analysis and tumor stages were determined. The presence of HBoV was screened by polymerase chain reaction, and the genotype of the detected HBoV was determined by direct gene sequencing. Most of the examined specimens were adenocarcinoma with mucinous activity in many of them. Twenty-four out of 101 (23.8 %) CRC tissue specimens were found to contain HBoV-1. Low sequence diversity was recorded in the detected strains. The virus was detected in both male and female patients with an age range of 30-75 years. It is proposed that HBoV-1 could play a potential role in the induction of CRC.

Ellagic acid alleviates adjuvant induced arthritis by modulation of pro- and anti-inflammatory cytokines.

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown aetiology, but it is now clear that pro-inflammatory cytokines play a central role in its pathogenesis. Ellagic acid (EA) has a variety of biological activities including anti-oxidant, anti-inflammatory, and anti-cancer properties. The aim of the present study was to evaluate the potential effect of ellagic acid on the prevention and/or treatment of adjuvant induced arthritis (AIA) model in mice. Ellagic acid treatment was started one week before AIA induction and continued for three weeks after induction of AIA. Ellagic acid treatment significantly (p < 0.01) inhibited foot paw oedematous swelling and attenuated AIA-associated pathology. Ellagic acid significantly (p < 0.01) reduced serum levels of pro-inflammatory cytokines: interleukin 1ß (IL-1ß), tumor necrosis factor α (TNF-α), and interleukin 17 (IL-17). However, serum levels of IL-10 and interferon γ (IFN-γ) significantly increased (p < 0.01 and p < 0.05, respectively), while serum level of transforming growth factor ß (TGF-ß) did not significantly alter with EA treatment. In conclusion, these results suggest that EA attenuated AIA-associated pathology in the mouse model by downregulation of pro-inflammatory cytokines and upregulation of anti-inflammatory cytokines.

Immune stimulation improves endocrine and neural fetal outcomes in a model of maternofetal thyrotoxicosis.

The potentiation of the immune system in pregnant rats was performed with Complete Freund's Adjuvant [CFA; 20µl, subcutaneous at gestation day (GD) 18] in experimentally-induced hyperthyroidism by Levo-thyroxine (L-T4; 10µg/100g of b.w., intraperitoneal from GD 2 to 17). The potential effects on the fetal neuroendocrine function were evaluated by observing some histopathological investigations in pregnant rats and measuring some biochemical parameters in dams and their fetuses at GD 20. In hyperthyroid group, an increase in maternofetal serum thyroxine (T4), triiodothyronine (T3) and a decrease in thyrotropin (TSH) levels were noticed, while the concentrations of fetal serum growth hormone (GH) and insulin-like growth factor-1 (IGF1) levels were increased at tested GD with respect to control and CFA groups. Moreover, the activity of uterine and placental myeloperoxidase (MPO) was increased (P<0.001) in CFA and CFA-treated hyperthyroid groups in respect to control or hyperthyroid groups, respectively. The gestational thyrotoxicosis led to some histopathological lesions in uterine and placental tissues characterized by severe degeneration in trophoblast spongioblast cell layer with congestion, mild congested blood vessels in the endometrium and deficient in spiral artery remodeling. Although, the elevation in fetal serum transforming growth factor-beta (TGFß) and cerebellar monoamines [norepineprine (NE), epinephrine (E), dopamine (DA) and 5-hydroxytryptamine (5-HT)] was observed, the reduction in fetal serum tumor necrosis factor-alpha (TNFα) and adipokines (Leptin and adiponectin) was detected. Treatment of dams with CFA showed an obviously reversing and protecting effect against hyperthyroid perturbations. Thus, the maternal CFA can be used in treatment of the fetal neuroendocrine dysfunctions.