YAP1 Expression in Lichen Planus and Squamous Cell Carcinoma: Role in Disease Pathogenesis and Potential Therapeutic Target.

BACKGROUND: Lichen planus (LP), especially oral type, reported a potential risk of malignant transformation to squamous cell carcinoma (SCC). Yes-Associated Protein (YAP1), a key component of the Hippo pathway, acts as a transcription cofactor regulating expression of genes involved in cell proliferation, apoptosis, and migration. Therefore, it has been implicated in carcinogenesis of a wide variety of human cancers. OBJECTIVES: To study YAP1 expression in LP and SCC in comparison to normal control (NC) specimens. PATIENTS AND METHODS: This study was conducted on 50 NC specimens, 50 LP specimens, and 50 SCC specimens. They were categorized into 2 main groups; cutaneous (25 NC, 25 LP, 25 SCC), and oral (25 NC, 25 LP, 25 SCC). All specimens were examined for YAP1 antibody expression by immunohistochemistry and YAP1 mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In both cutaneous and oral groups; significant upregulation of YAP1 expressions was observed in SCC specimens followed by LP and then NC specimens in the same sequence. Its expression in SCC was found to be significantly higher in poorly and moderately differentiated types than well differentiated types. CONCLUSION: YAP1 may have a potential role in the pathogenesis of LP and oncogenesis and progression of SCC. Moreover, it could be considered as a novel therapeutic target for such cases.

Berberine ameliorates renal injury in a rat model of D-galactose-induced aging through a PTEN/Akt-dependent mechanism.

This study aimed to investigate the protective effects of berberine (BBR) against D-galactose (D-gal)-induced renal aging in rats, pointing to its ability to modulate phosphatase and tensin homolog deleted on chromosome ten (PTEN)/Akt signalling, and to attenuate oxidative stress, inflammation and apoptosis. Renal aging was induced by subcutaneous injection of D-gal for six consecutive weeks along with simultaneous oral administration of BBR and compared to control rats and rats received individual doses of either drug. BBR treatment significantly reduced the serum levels of urea and creatinine, retrieved the alterations in kidney histopathology, and restored redox balance evidenced by alleviations of the level of malondialdehyde, 8-hydroxy-2'-deoxyguanosine and activating heme oxygenase-1 enzyme. Moreover, it markedly reduced the serum levels of pro-inflammatory mediators, along with down-regulation of PTEN expression, enhanced Akt activity, as well as significantly higher immunostaining of the anti-apoptotic marker (Bcl-2). These findings hold a great promise for the use of BBR as a protecting agent against renal aging.

Modulatory effects of resveratrol on endoplasmic reticulum stress-associated apoptosis and oxido-inflammatory markers in a rat model of rotenone-induced Parkinson's disease.

The mechanisms leading to neuronal death in Parkinson's disease (PD) are not fully elucidated; however, mounting evidence implicates endoplasmic reticulum (ER) stress, oxidative damage, and inflammatory changes are the crucial factors in its pathogenesis. This study was undertaken to investigate the modulatory effects of resveratrol on ER stress-mediated apoptosis, inflammatory and oxidative stress markers in a rat model of rotenone-induced PD. mRNA expression levels of ER stress markers; C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78), were estimated in the rat brain using quantitative real-time PCR. Caspase-3 activity, IL-1ß levels and Nuclear Factor Erythroid 2-related factor (Nrf2) DNA-binding activity were estimated by ELISA, while glutathione peroxidase and Xanthine oxidase activities, as well as protein carbonyl contents in the rat brain were evaluated spectrophotometrically. Our data revealed that Resveratrol ameliorated rotenone-induced ER stress by downregulating CHOP and GRP78 genes expression and hampered caspase-3 activity in the brain of rotenone exposed rats. It also restored redox balance as evident by suppressing Xanthine oxidase activity and protein carbonyls formation; in addition to preservation of intracellular antioxidants status via activating glutathione peroxidase and Nrf2 signaling pathway. In conclusion; our study launched promising avenues for the potential use of resveratrol as a neuroprotective therapeutic agent in Parkinson's disease.

Significance of suppressor of cytokine signaling-3 expression in bladder urothelial carcinoma in relation to proinflammatory cytokines and tumor histopathological grading.

BACKGROUND: Bladder cancer is among the five most common malignancies worldwide. Altered expression of suppressor of cytokine signaling -3 (SOCS-3) has been implicated in various types of human cancers; however, its role in bladder cancer is not well established. AIM: The present study was undertaken to investigate the mRNA expression of SOCS-3 in normal and cancerous bladder tissue and to explore its correlation with urinary levels of some proinflammatory cytokines, cytokeratin-18 (CK -18) and with tumor histopathological grading, in order to evaluate their role as potential diagnostic markers. MATERIALS AND METHODS: SOCS3 mRNA expression levels were evaluated using quantitative real time PCR. Urinary levels of interleukins 6 and 8 were estimated by enzyme linked immunosorbent assay (ELISA). Cytokeratin-18 expression was analyzed by immuunohistochemistry then validated by ELISA. RESULTS: SOC3 m RNA expression levels were significantly lower in high grade urothelial carcinoma (0.36±0.12) compared to low grade carcinoma (1.22±0.38) and controls (4.08±0.88), (p<0.001). However, in high grade urothelial carcinoma the urinary levels of IL-6, IL-8, total CK-18(221.33±22.84 pg/ml, 325.2±53.6 pg/ ml, 466.7±57.40 U/L respectively) were significantly higher than their levels in low grade carcinoma (58.6±18.6 pg/ ml, 58.3±50.2 pg/ml, 185.5±60.3 U/L respectively) and controls (50.9±23.0 pg/ml, 7.12±2.74 pg/ml, 106.7±47.3U/L respectively), (p<0.001). CONCLUSIONS: Advanced grade of urothelial bladder carcinoma is significantly associated with lowered mRNA expression of SOC3 as well as elevated urinary levels of proinflammatory cytokines and CK-18. Furthermore, our results suggested that urinary IL-8, IL-6 and CK-18 may benefit as noninvasive biomarkers for early detection as well as histopathological subtyping of urothelial carcinoma.

Activity and expression pattern of NF-κB /P65 in peripheral blood from hepatocellular carcinoma patients - link to hypoxia inducible factor -1α.

BACKGROUND: Hepatocellular carcinoma is a complex and heterogeneous tumor with poor prognosis due to frequent intrahepatic spread and extrahepatic metastasis. The molecular mechanisms underlying HCC pathogenesis still remain obscure. OBJECTIVES: We aimed to investigate the abundance and the DNA binding activity of nuclear factor kappa B/p65 subunit in peripheral blood mononuclear cells from patients with HCC and to assess its prognostic significance and association with hypoxia inducible factor one alpha (HIF-1α) in blood. SUBJECTS AND METHODS: This study was carried out on 40 patients classified equally into liver cirrhosis (group I) and HCC (group II), in addition to 20 healthy volunteers (group III). All groups were subjected to measurement of NF-κB /P65 subunit expression levels by real time-PCR, and DNA binding activity was evaluated by transcription factor binding immunoassay. Serum HIF-1α levels were estimated by enzyme-linked immunosorbent assay (ELISA). Significant increase of both the expression level and DNA binding activity of NF-κB /P65 subunit together with serum HIF-1 alpha levels was noted in HCC patients compared to liver cirrhosis and control subjects, with significant positive correlation with parameters for bad prognosis of HCC. In conclusion, NF-κB signaling is activated in HCC and associated with disease prognosis and with high circulating levels of HIF-1 alpha.