MiR-155 affects proliferation and apoptosis of bladder cancer cells by regulating GSK-3ß/ß-catenin pathway.

Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, "MiR-155 affects proliferation and apoptosis of bladder cancer cells by regulating GSK-3ß/ß-catenin pathway, by Z.-C. Dong, D. Zhang, X.-X. Zhang, Z.-Q. Yao, H. Wu, C.-H. Chen, J.-Q. Tian, published in Eur Rev Med Pharmacol Sci 2019; 23 (13): 5682-5690-DOI: 10.26355/eurrev_201907_18305-PMID: 31298320" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/18305.

MiR-155 affects proliferation and apoptosis of bladder cancer cells by regulating GSK-3ß/ß-catenin pathway.

OBJECTIVE: GSK-3ß negatively regulates Wnt/ß-catenin signaling pathway. The abnormal miR-155 expression is associated with bladder cancer. Bioinformatics analysis revealed a complementary binding site between miR-155 and GSK-3ß mRNA. This study investigated the role of miR-155 in the proliferation and apoptosis of bladder cancer cells. PATIENTS AND METHODS: The dual luciferase reporter gene assay validated the targeted regulation between miR-155 and GSK-3ß. Tumor tissues and adjacent tissues were collected from bladder cancer patients and the expression of miR-155 and GSK-3ß mRNA was detected by RT-PCR. Bladder cancer cell line BIU-87 cells were cultured in vitro and divided into miR-NC group and miR-155 inhibitor group. The expressions of miR-155, GSK-3ß and ß-catenin were compared, cell apoptosis was detected by flow cytometry, and cell proliferation was detected by EdU staining. RESULTS: Compared with adjacent tissues, miR-155 expression was significantly increased in bladder cancer tissues, and GSK-3ß mRNA expression was significantly decreased. There was a targeted regulatory relationship between miR-155 and GSK-3ß. Compared with SV-HUC-1 cells, miR-155 expression in bladder cancer BIU-87 and 5637 cells was significantly increased, and GSK-3ß expression was significantly decreased. Transfection of miR-155 inhibitor significantly increased GSK-3ß expression in BIU-87 and 5637 cells, decreased ß-catenin expression, increased cell apoptosis, and decreased cell proliferation. CONCLUSIONS: The increased expression of miR-155 plays a role in reducing the expression of GSK-3ß and in promoting the pathogenesis of bladder cancer. Inhibition of miR-155 can up-regulate the expression of GSK-3ß, inhibit the activity of Wnt/ß-catenin pathway, attenuate proliferation and promote apoptosis of bladder cancer cells.

Reversed aqueductal cerebrospinal fluid net flow in idiopathic normal pressure hydrocephalus.

OBJECTIVES: The changes of CSF flow dynamics in idiopathic normal pressure hydrocephalus (iNPH) are not fully elucidated. Most previous studies took the whole cardiac cycle as a unit. In this work, it is divided into systole and diastole phase and compared between iNPH patients and normal elderly and paid special attention to the change of netflow direction. MATERIALS AND METHODS: Twenty iNPH patients according to international guideline and twenty healthy volunteers were included in this study and examined by MRI. Three categories of CSF flow parameters were measured: peak velocity (Vpeak ), stroke volume (SV), and minute flow volume (MinV) covering the whole cycle; peak velocity (Vpeak-s , Vpeak-d ) and flow volume (Vols , Vold ) of the systole and diastole, respectively; net flow. Evans index (EI) was also measured and compared statistically between the two groups. RESULTS: EI, Vpeak , SV, MinV, Vols , Vold , and Vpeak-d significantly increased in iNPH group (P<0.05). Vpeak-s of the two groups were not significantly different (P>0.05). The net flow of 16 iNPH patients (16/20) was in the caudo-cranial direction, while 15 volunteers (15/20) were in the opposite direction, which showed statistically significant differences (P=.001). CONCLUSIONS: INPH patients present hyperdynamic flow with increased velocity and volume both in systole and diastole phase. Degree of rising in diastole phase exceeds that of systole phase. The resulting reversal of netflow direction may play a key role in the occurrence of ventriculomegaly in iNPH patients.

Active immunization with glucose-dependent insulinotropic polypeptide vaccine influences brain function and behaviour in rats.

Glucose-dependent insulinotropic polypeptide (GIP) is involved in the aetiology of obesity induced by overnutrition, and blocking GIP activity may be valuable to anti-obesity treatment. However, GIP and GIP receptor are closely related to various brain functions which have caused very little data to be published concerning this cerebral functionality after blocking GIP activity. Here, we showed that active vaccination of mature rats with GIP immunoconjugates [GIP-keyhole limpet haemocyanin (KLH)] was associated with changes in body weight. Furthermore, we also observed significant changes in brain function and behaviour. Data indicated that GIP-KLH-immunized rats showed decreased spontaneous activity in the open field test, decreased cerebral glucose utilization assessed by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT), and increased apoptosis and proliferation of hippocampal granule cells marked by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) or proliferating cell nuclear antigen method. In conclusion, we have shown that vaccine-induced antibodies inhibited GIP activity in vivo and led to significant changes in brain function and behaviour, which underscore the need to address any potential problems GIP-targeted immunotherapy may involve in further research.

p27(Kip1) is an inducer of intestinal epithelial cell differentiation.

Constant renewal of the intestinal epithelium is a highly coordinated process that has been subject to intense investigation, but its regulatory mechanisms are still essentially unknown. In this study, we have demonstrated that forced expression of the cyclin-dependent kinase inhibitors (CKIs) p27(Kip1) and p21(Cip1/WAF1) in human intestinal epithelial cells led to expression of differentiation markers at both the mRNA and protein levels. Cell differentiation was temporally dissociated from inhibition of retinoblastoma protein phosphorylation and growth arrest, already established 1 day after infection with recombinant adenoviruses. p27(Kip1) proved significantly more efficient than p21(Cip1/WAF1) in induction of cell differentiation. In contrast, forced expression of p16(INK4a) resulted in growth arrest without induction of differentiation markers. These results implicate both p27(Kip1) and p21(Cip1/WAF1) in the differentiation-timing process, but p21(Cip1/WAF1) may act indirectly by increasing p27(Kip1) levels. These results also suggest that induction of intestinal epithelial cell differentiation by CKIs is not related to their effects on the cell cycle and may involve interactions with cellular components other than cyclins and cyclin-dependent kinases.

Glucocorticoids have pleiotropic effects on small intestinal crypt cells.

Glucocorticoids have long been known to accelerate maturation of the intestinal tract, but the molecular mechanisms that account for their physiological function in the epithelium remain poorly characterized. Using rat intestinal epithelial cell lines (IEC-6, IEC-17, and IEC-18) as models, we have characterized glucocorticoid receptors in crypt cells and documented striking morphological, ultrastructural, and functional alterations induced by these hormones in intestinal cells. They include arrest of growth, formation of tight junctions, appearance of long, slender microvilli, reorganization of the endoplasmic reticulum and trans-Golgi network, and downregulation of the cell cycle regulatory proteins cyclin-dependent kinase 6 and p27(Kip1). These effects are consistent with the activation or modulation of multiple genes important in the physiological function of absorptive villous cells but are probably not directly involved in the induction of cell differentiation.

Involvement of p21(WAF1/Cip1) and p27(Kip1) in intestinal epithelial cell differentiation.

Using the conditionally immortalized human cell line tsFHI, we have investigated the role of cyclin-dependent kinase inhibitors (CKIs) in intestinal epithelial cell differentiation. Expression of cyclins, cyclin-dependent kinases (Cdk), and CKIs was examined under conditions promoting growth, growth arrest, or expression of differentiated traits. Formation of complexes among cell cycle regulatory proteins and their kinase activities were also investigated. The tsFHI cells express three CKIs: p16, p21, and p27. With differentiation, p21 and p27 were strongly induced, but with different kinetics: the p21 increase was rapid but transient and the p27 increase was delayed but sustained. Our results suggest that the function of p16 is primarily to inhibit cyclin D-associated kinases, making tsFHI cells dependent on cyclin E-Cdk2 for pRb phosphorylation and G1/S progression. Furthermore, they indicate that p21 is the main CKI involved in irreversible growth arrest during the early stages of cell differentiation in association with D-type cyclins, cyclin E, and Cdk2, whereas p27 may induce or stabilize expression of differentiated traits acting independently of cyclin-Cdk function.

Dissociation between growth arrest and differentiation in Caco-2 subclone expressing high levels of sucrase.

Growth arrest and cell differentiation are generally considered temporally and functionally linked phenomena in small intestinal crypt cells and colon tumor cell lines (Caco-2, HT-29). We have derived a Caco-2 subclone (NGI3) that deviates from such a paradigm. In striking contrast with the parental cells, proliferative and subconfluent NGI3 cells were found to express sucrase-isomaltase (SI) mRNA and to synthesize relatively high levels of SI, dipeptidyl peptidase IV, and aminopeptidase N (APN). In postconfluent cells, little difference was seen in SI mRNA levels between Caco-2 and NGI3 cells, but the latter still expressed much higher levels of SI that could be attributed to higher rates of translation. APN expression was also greatly enhanced in NGI3 cells. To determine whether high levels of brush-border enzymes correlated with expression of cell-cycle regulatory proteins, we investigated their relative cellular levels in growing and growth-arrested cells. The results showed that the cyclin-dependent kinase inhibitors (p21 and p27) and D-type cyclins (D1 and D3) were all induced in postconfluent cells, but NGI3 cells expressed much higher levels of p21. This study demonstrated that cell growth and expression of differentiated traits are not mutually exclusive in intestinal epithelial cells and provided evidence indicating that posttranscriptional events play an important role in regulation of SI expression.

Acute inflammatory response of the rat pawskin to acid injury is attenuated by corticotropin-releasing factor.

Increased vascular permeability, as measured by changes in skin weight and Evans blue dye extravasation, was produced in the skin after immersion of the anesthetized rat's paw in 12 N hydrochloric, 18N sulfuric, or 14N hydrofluoric acids for 2 min. Corticotropin-releasing factor (CRF), a 41-residue peptide having the rat/human sequence, injected 28 micrograms/kg i.v. 10 min before immersion, was efficacious in reducing these indices of skin injury.

Protective actions of corticotropin-releasing factor on thermal injury to rat pawskin.

Corticotropin-releasing factor (CRF), a 41-residue peptide, inhibits the edema and protein extravasation produced by heat applied to the rat pawskin. Here, the time course of CRFs actions against heat-induced swelling was investigated. The paws of pentobarbital-anesthetized rats were immersed in 58 degrees C water for 30 sec and the resultant swelling was measured by the fluid displacement method. Human/rat CRF, 28 micrograms/kg s.c., injected 0.5 to 2 hr before heat exposure reduced swelling by over 50%. Pretreatment at 4 hr before heat was also effective, but not at 12 or 24 hr. CRF, injected 28 micrograms/kg i.v. 0, 10 or 20 min after heat exposure, inhibited the progressive development of swelling immediately. Histological examination of skin showed that CRF, given before or after heat, reduced vesication, edema, epidermal necrosis and the disruption of tissue architecture produced by thermal injury. The alpha-helical CRF(9-41) antagonist administered alone, 92 micrograms/kg i.v., before or after heat did not affect heat injury. The antagonist, however, both prevented and reversed the inhibitory effects of CRF on the swelling produced by heat. The antagonist-induced reversal occurred as late as 2 hr after CRF, 28 micrograms/kg s.c. Overall, these results suggested that CRF is a potent and efficacious agent in protecting skin against experimental thermal injury.