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.

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.

Rebamipide protects against experimentally induced intestinal ischemia/reperfusion-promoted liver damage: Impact on SIRT1/ß-catenin/FOXO1and NFκB signaling.

Rebamipide (Reba) is a well-known gastroprotective agent. However, its potential protective efficacy against intestinal ischemia/reperfusion (I/R)-induced liver injury remains elusive. Therefore, this study aimed to assess the modulatory effect of Reba on SIRT1/ß-catenin/FOXO1-NFκB signaling cascade. Thirty-two male Wistar albino rats were randomized into four groups: G1 (sham): rats were subjected to surgical stress without I/R, GII (I/R): rats were subjected to 60 min/4-h I/R, GIII (Reba + I/R): rats received Reba 100 mg/kg/day, p.o. for three weeks, then were subjected to 60 min/4-h I/R, and GIV (Reba + EX527 + I/R): rats received Reba (100 mg/kg/day p.o.) + EX527 (10 mg/kg/day, ip) for three weeks before I/R. Reba pretreatment decreased the serum levels of ALT and AST, improved I/R-induced histological alterations of both intestine and liver, increased hepatic Silent information regulator 1 (SIRT1) expression/content, ß-catenin expression/immunoreactivity, and FOXO1 expression, while suppressed NF-κB p65 expression/protein content. In addition, Reba increased hepatic total antioxidant capacity (TAC), while suppressed malondialdehyde (MDA), tumor necrosis factor (TNFα), and caspase-3 activity. Furthermore, Reba inhibited BAX expression, while upregulated Bcl-2 expression. Reba exhibited a plausible protective effect against intestinal I/R-mediated liver injury by modulating SIRT1/ß-catenin/FOXO1-NFκB signaling mechanisms.