Role of cytokines and Th17/Tregs imbalance in the pathogenesis of otitis media with effusion. Modulation of Notch1/Hes1/mTORC1/S6k1 signalling pathway underlies the protective effect of astaxanthin.

Otitis media with effusion (OME) is a recurrent middle ear inflammatory condition. It may be complicated by acquired hearing loss and speech impairment especially in children. Accordingly, the current study aimed to assess the role of cytokines and the imbalance of Th17/Tregs in the pathogenesis of OME. Additionally, the protective effect of astaxanthin and its mechanisms related to Notch1/ Hes1/mTORC1/S6K1 signalling were investigated. METHODS: Forty-eight children were grouped as follow: G1: control healthy group G2: acute otitis media (AOM) group, G3: OME group. In the lipopolysaccharide (LPS) induced OME rat model, 15 rats were randomised into: G1: normal control group, G2: LPS group, and G3: astaxanthin treated group. RESULTS: Biochemical analysis of the children's peripheral blood samples showed that IL1ß, IL-2, IL-4, IL-6, IL-17, and IL-23 were significantly elevated, while TGF-ß was significantly decreased in AOM and OME patients (group 2 and 3). In the LPS- induced OME rat model, astaxanthin treatment resulted in suppression of IL-17, IL-6, TNF-α, Muc5A, TFF3, NICD, Hes1, mTORC1, and S6K1 in rat middle ear mucosa. Furthermore, astaxanthin significantly downregulated RORγ while upregulating FoxP3 and restored the balance between Th17/Tregs. Moreover, astaxanthin improved the histopathological picture of the inflamed middle ear mucosa. CONCLUSIONS: Proinflammatory cytokines as well as Th17/Tregs imbalance play a crucial role in the pathogenesis of AOM and OME. Additionally, astaxanthin alleviated LPS- induced OME in rats through suppression of Notch1/ Hes1/mTORC1/S6K1 pathway, and regulation of Th17/Tregs.

miRNAs: novel noninvasive biomarkers as diagnostic and prognostic tools in neonatal sepsis.

The study aimed to assess the diagnostic and prognostic value of 3 specific microRNAs (miRNAs) in early-onset neonatal sepsis (NS). We examined miR-1, miR-124, and miR-34a in 70 NS patients upon admission and compared them to 70 healthy controls by RT-PCR. The main finding of the study was the difference in miRNA expression levels between NS patients and controls. Higher expression levels of miR-1 and miR-124 were significantly associated with NS, while miR-34a expression was reduced. Among the studied miRNAs, miR-34a exhibited the highest specificity (97%) as a confirmatory test for NS. In the multivariate model, miR-1 and miR-124 were found to be significant predictors of disease progression or mortality. Overall, the study suggests that miR-1, miR-124, and miR-34a could serve as potential biomarkers for diagnosing and predicting outcomes in early-onset NS.

Parthenolide repressed endometriosis induced surgically in rats: Role of PTEN/PI3Kinase/AKT/GSK-3ß/ß-catenin signaling in inhibition of epithelial mesenchymal transition.

AIM: PI3K/AKT/GSK-3ß/ß-catenin signaling pathway is a triggering factor for epithelial to mesenchymal transition (EMT) which plays a pivotal role in the pathogenesis of endometriosis. Parthenolide is a sesquiterpene lactone extract that has anti-inflammatory, analgesic and anticancer properties. Hence, we investigated the effect of parthenolide against EMT in the endometrial tissue implants and immortalized epithelial endometriotic cell lines 12Z. MAIN METHODS: Twenty- four female Rats with surgically induced endometriosis were treated with parthenolide (2, 4 mg/kg), for 4 weeks. Endometriotic cell line 12Z was used to identify the effect of parthenolide on the wound healing, cellular migration and invasion properties of endometriotic cells. KEY FINDINGS: Parthenolide decreased the endometriotic implant tissue expression of total PI3K, PI3K-p85, p-AKT, p/total AKT, p-GSK-3ß, P/total GSK-3ß, and nß-catenin, as well as increased E-cadherin and decreased vimentin mRNA expression. Parthenolide upregulated PTEN immunoreactivity as well as the endometriotic tissue caspase-3, caspase-9, BAX levels while reducing Bcl2 level. Additionally, parthenolide decreased endometriotic tissue implants surface area and histopathological score of the epithelial growth. SIGNIFICANCE: Our findings showed that parthenolide in a dose dependent manner inhibited PI3K/AKT/GSK-3ß/nß-catenin cascade via enhancement of PTEN with subsequent inhibition of EMT evidenced by elevation of the epithelial marker, E-cadherin and reduction of mesenchymal marker, vimentin, of the endometriotic implants in addition to reversal of invasion and migration properties of epithelial endometriotic cell lines. These findings provide a valuable therapeutic approach for treatment of endometriosis.

Vinpocetine alleviates intestinal ischemia/reperfusion injury and enhances M2 macrophage polarization in rats: Role of SIRT1/SOCS3/STAT3 signaling pathway.

Vinpocetine (Vinpo) is a neuroprotective vasodilator drug. It is an effective therapeutic agent for a variety of cerebrovascular and cognitive disorders. However, its potential protective efficacy on intestinal ischemia/reperfusion (I/R) injury remains elusive. The present study aimed to investigate the effect of Vinpo on intestinal I/R injury and to explore its modulatory effect on sirtuin (SIRT1)/ Suppressor of cytokine signaling (SOCS3)/ Signal Transducer and Activator of Transcription (STAT3) signaling. Twenty-four male Wistar albino rats were randomly allocated into four groups. G1 (sham): rats were subjected to surgical stress without I/R, GII (I/R): rats were subjected to 60 min/2-h I/R, GIII (Vinpo + I/R): rats were pre-treated with Vinpo (20 mg/kg/day, P.O. daily) for 2 weeks before intestinal I/R; GIV (EX527 + Vinpo + I/R): rats received both Vinpo (20 mg/kg/day, P.O.) and EX527 (5 mg/kg, once every 2 days, i.p) for 2 weeks before intestinal I/R. The current results showed that Vinpo improved the intestinal histopathological picture, enhanced M1 to M2 macrophage polarization and alleviated the I/R-induced increase in interleukins (IL-6, IL-1ß), tumor necrosis factor (TNF-α), inducible nitric oxide synthase (i-NOS), and nitric oxide (NO). Additionally, Vinpo pretreatment upregulated SIRT1 mRNA expression/protein level and SOCS3 mRNA expression while downregulating P-STAT3 immunoreactivity. The effects of Vinpo were attenuated by the SIRT1 inhibitor EX527. We concluded that Vinpo ameliorated the intestinal I/R injury and enhanced M2 anti-inflammatory macrophage polarization through modulation of SIRT1/SOCS3/STAT3/i-NOS cascade.

Structural and molecular changes in the rat myocardium following perfluoroctane sulfonate (PFOS) exposure are mitigated by quercetin via modulating HSP 70 and SERCA 2.

Perfluorooctane sulfonate (PFOS) is a man-made fluorinated compound employed in a variety of industrial and civilian applications. Due to its long elimination half-life and promotion of oxidative stress and inflammation, it is one of the most abundant organic contaminants. The present study was designed to determine the cytotoxic effect of PFOS on adult male rat cardiac tissue and to assess the cardioprotective role of the flavonoid quercetin (Que), which possesses antioxidant, anti-inflammatory, and anti-apoptotic properties. Twenty-four adult male Sprague-Dawley rats were randomly divided into four equal groups: Group I (Control). Group II (Que) received Que (75 mg/kg/day for 4 weeks) by oral gavage. Group III (PFOS group): supplemented orally with PFOS (20 mg/kg/day for 4 weeks) and Group IV (PF OS/Que). The rat heart was processed for histological, immunohistochemical, and gene expression studies. The PFOS group showed histological alterations in the myocardium that were partially reversed by the administration of Que. The inflammatory biomarkers (TNF, IL-6, and IL-1), lipid profile, TSH, MDA, and serum cardiac enzymes (LDH and CK-MB) were all altered. These findings collectively suggest that PFOS had adverse effects on the cardiac muscle structure, and these effects were alleviated by quercetin, which is a promising cardioprotective flavonoid.

Genetic variant of endothelial protein C receptor genes and its serum level in B thalassemic children.

BACKGROUND: Due to their chronic hypercoagulable status, thalassemic individuals are at an elevated risk of developing thromboembolic sequence consequences. The goal of the current study is to assesses the EPCR gene polymorphism and soluble EPCR in Egyptian thalassemic children and its role in hypercoagulable state. RESEARCH DESIGN AND METHODS: Eighty children diagnosed as thalassemia major and 80 healthy youngsters as a control group. The EPCR gene was identified using a restriction fragment length polymerase chain reaction (RFLP PCR). Additionally, we assessed the soluble EPCR levels using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Frequency of 1651C-G EPCR, the GC genotype was strongly related with an increased risk of coagulation (OR = 1.83 (0.64-5.26), P = 0.0.016). In addition, soluble EPCR was considerably higher in patients with thalassemia than in controls, P value <0.001. Our study revealed significance difference between soluble EPCR and different genotypes. CONCLUSION: Polymorphisms in the EPCR gene and an elevated soluble EPCR level in patients with ß-thalassemia major may contribute to these patients' hemostatic derangement in thalassemic Egyptian children.

Correlation between Serum Interleukin-17 level and Serum Reactive Oxygen Species levels among Children experiencing Otitis Media with Effusion.

Introduction The detection of inflammatory mediators in the serum of children with have otitis media with effusion (OME) and their correspondence with clinical considerations may enable the use of a modern nonsurgical curative treatment for OME. Objective To determine the relation between interleukin-17 (IL-17) serum level and reactive oxygen species (ROS) serum levels in children suffering from OME and to disclose if any variation occurs in the level of IL-17 Will affect the ROS and antioxidant equilibrium in the serum, which indicates the entire body's reaction to OME. Methods The present study was a case-control study. A total of 24 children experienced OME, and 24 healthy controls were recruited. All participants in the study were subjected to a systematic clinical investigation including otoscopic, audiometric, and tympanometric examination. Also, venous blood samples were collected from all children to determine the levels of IL-17 and ROS. Results The mean ± standard deviation (SD) age ranges of the patients and the control group were 6.8 ± 2.7 and 6.2 ± 3.4 years, respectively. A stylistically significant difference in the levels of serum nitric oxide (NO), catalase (CT), myeloperoxidase (MPO), and malondialdehyde (MDA) ( p < 0.05) was detected between OME and control patients. No significant difference was found in serum levels of superoxide dismutase (SOD) and glutathione peroxidase (GPX) between OME and control patients. The serum levels of MDA, NO, and MPO positively correlated with the serum levels of IL-17 in OME patients. Conclusion In the present study, there is a reasonable role of the IL-17 pathway in OME pathogenesis through an increase in ROS levels.

Histological and Biochemical Changes in Adult Male Rat Liver after Spinal Cord Injury with Evaluation of the Role of Granulocyte-Colony Stimulating Factor.

Spinal cord injury (SCI) is a devastating disease leading to motor disability. Metabolic dysfunction is another complication of SCI. Thus, we aimed to study the effect of SCI on the histological and biochemical structure of the liver in adult male rats and to delineate the role of post-injury administration of G-CSF. Thirty adult male Sprague-Dawley rats were assigned into three groups: Group I; control (18 rats subdivided equally into three subgroups), and 12 rats underwent SCI and were divided into an SCI group II and G-SCF-treated group III. Twenty-one days post-injury, liver sections were processed for light and electron microscopic examinations and immunohistochemical staining for PCNA and CD68 antibodies. The biochemical assay was carried out for detection of serum levels of ALT, AST, total proteins, albumin, total cholesterol, triglycerides, HDL-c, GSH and MDA. Liver tissue levels of GPx and MDA as well as semiquantitative RT-PCR analysis of hepatic cytokine expression were also conducted. In the SCI group, results showed liver tissue damage in the form of lipid infiltration, blood vessel congestion, vacuolated cells with apoptotic nuclei and increased collagen deposition. Increased CD68-positive macrophages and a decreased number of PCNA-positive cells was detected. Moreover, liver enzymes, total cholesterol and triglycerides were increased while serum albumin, total proteins and HDL-c were decreased in the SCI group. Oxidative stress and increased expression of inflammatory cytokines were detected. Administration of G-CSF induced significant liver improvement with retained liver function by anti-inflammatory, immune-modulatory and antioxidant mechanisms.