The maladaptive drug memory developed between the drug-rewarding effect and environmental cues contributes to difficulty in preventing drug relapse. Established reward memories can be disrupted by pharmacologic interventions following their reactivation. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) kinase, has been proved to be involved in various memory consolidation. However, it is less well characterized in drug memory reconsolidation. Using a conditioned place preference (CPP) procedure, we examined the effects of systemically administered rapamycin on reconsolidation of drug memory in rats. We found that systemically administered rapamycin (0.1 or 10 mg/kg, i.p.) after re-exposure to drug-paired environment, dose dependently decreased the expression of CPP 1 d later, and the effect lasted for up to 14 d and could not be reversed by a priming injection of morphine. The effect of rapamycin on morphine-associated memory was specific to drug-paired context, and rapamycin had no effect on subsequent CPP expression when rats were exposed to saline-paired context or homecage. These results indicated that systemic administration of rapamycin after memory reactivation can persistently inhibit the drug seeking behaviour via disruption of morphine memory reconsolidation in rats. Additionally, the effect of rapamycin on memory reconsolidation was reproduced in cocaine CPP and alcohol CPP. Furthermore, rapamycin did not induce conditioned place aversion and had no effect on locomotor activity and anxiety behaviour. These findings suggest that rapamycin could erase the acquired drug CPP in rats, and that mTOR activity plays an important role in drug reconsolidation and is required for drug relapse.
Although miR-193a-3p has been found to be dysregulated in variety of human tumors, little is known about its role in renal cell carcinoma. This study was designed to investigate the function and underlying mechanism of miR-193a-3p in human renal cell carcinoma tissues and cell lines. Here, we demonstrated that the expression of miR-193-3p was increased in renal cell carcinoma tissues and cell lines. In addition, knockdown of miR-193a-3p significantly inhibited cell proliferation and colony formation and induced cells into G1 phase arrest. Meanwhile, the migration potential of 786-O cells was also decreased compared to control group. Furthermore, we identified PTEN as a direct and functional target of miR-193a-3p, at least partly responsible for promoting tumor effect of miR-193a-3p in renal cell carcinoma. Taken together, the findings indicated for the first time that miR-193a-3p functions as a tumor-promoting microRNA by directly targeting PTEN in renal cell carcinoma.
The aim of the present study was to investigate the changes of the bladder epithelial barrier in the pathogenesis of ketamine-induced cystitis (KIC). A total of 60 female mice were randomly allocated into control and ketamine groups, which received daily intraperitoneal injections of saline and ketamine, respectively. Micturition behavior was recorded in 2-h intervals at the end of 4, 8 and 12 weeks, and bladders were harvested for subsequent analyses. Routine hematoxylin and eosin staining was performed on the bladders and histopathological changes were analyzed using light microscopy. The distribution of zonula occludens-1 (ZO-1) protein was determined by immunohistochemical analysis. The ultrastructure of umbrella cells was observed using a transmission electron microscope (TEM). Ketamine-addicted mice exhibited a significantly increased frequency of micturitions following 8 and 12 weeks of ketamine treatment (P<0.05 and P<0.01, respectively). Suburothelial congestion and infiltration of mononuclear cells was observed in ketamine-addicted mice following 8 and 12 weeks of treatment. Immunohistochemical examination demonstrated that there was an increased abnormal distribution of ZO-1 in the bladders of ketamine-treated mice compared with control mice. TEM analysis demonstrated that the surface of bladder urothelium became flattened, the tight junctions between umbrella cells became thinner and the endothelial cells exhibited cell body shrinkage, chromatin condensation and layer denudation in mice treated with ketamine. The present study indicated that the structural and functional changes to the bladder epithelial barrier caused by long-term use of ketamine may be key mechanisms in the development of KIC.
Background-ELL plays an important role in tumorigenesis and animal development. HIF-1 is a transcriptional factor that functions as a master regulator of O 2 homeostasis. Our previous studies showed that a binding partner of ELL, U19/Eaf2, can modulate HIF-1α activity and hypoxia response, suggesting that ELL may also influence HIF-1α pathway and hypoxia response.
Clinically, autologous gastrointestinal segments are traditionally used for urinary diversion. However, this procedure often causes many serious complications. Tissue engineering may provide an alternative treatment method in urinary diversion. This research aims to produce tissue-engineered tubular substitutions by using homologous adipose-derived stem cells, smooth muscle cells, and bladder acellular matrix in developing urinary diversion in a rabbit model. Adipose-derived stem cells and smooth muscle cells of rabbit were obtained and cultured in vitro. These cultured adipose-derived stem cells and smooth muscle cells were seeded onto the two sides of the bladder acellular matrix and then incubated for seven days. The cell-seeded matrix was used to build tissue-engineered tubular substitutions, which were then implanted and wrapped into the omentum in vivo for two weeks to promote angiogenesis. In the experimental group, the bladder of 20 rabbits was totally resected, and the above tissue-engineered tubular substitutions were used for urinary diversion. In the control group, bladder acellular matrix tubular substitutions with unseeded cells were implanted into the omentum and were used as urinary diversion on another five rabbits with the same process. The implants were harvested, and histological examination was conducted at 2, 4, 8, and 16 weeks after operation. Intravenous urography assessment was performed at 16 weeks postoperatively. All the rabbits were alive in the experimental group until they were sacrificed. Histological analysis of the construct displayed the presence of multilayer urothelial cells on the luminal side and organized smooth muscle tissue on the other side, and different diameters of neovascularization were clearly identified in the substitutions obtained. No leakage, stricture, or obstructions were noted with intravenous urography assessment. All the animals in the control group died within two weeks, and urine leakage, scar formation, and inflammation were detected through autopsy. This study demonstrates the feasibility of tissue-engineered tubular substitutions constructed using homologous adipose-derived stem cells, smooth muscle cells, and bladder acellular matrix for urinary diversion in a rabbit model.
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