Objective To review the role of mTOR signal pathway in chemo-resistance of gastric cancer. Methods Domestic and international publications related mTOR signal pathway in chemo-resistance of gastric cancer in recent years were collected and reviewed. Results mTOR was a central signaling molecule of mTOR signal pathway， which regulated key cellular processes such as cell growth， cell proliferation， cell metabolism， and angiogenesis. Signaling molecules of mTOR signal pathway were overexpressed in gastric cancer. Moreover， mTOR signal pathway might play an important role in chemo-resistance of gastric cancer， and tumor stem cells were involved in it too. Conclusion As mTOR signal pathway plays an important role in chemo-resistance of gastric cancer， the combination of mTOR inhibitors and chemotherapy drugs may overcome the chemo-resistance of gastric cancer.
Objective To study the p-mammalian target of rapamyein(p-roTOR)expression and its prognostic significance in non-small cell lung cancer(NSCLC)．Methods Immunohistochemical staining of EnVision was applied to investigate the expression of p-roTOR in lung specimens from 59 cases with NSCLC and 10 cases with benign pulmonary diseases(3 pulmonary tuberculosises and 7 inflammatory pseudotumors 1．Results The positive rate of p-mTOR was 40．7％ in NSCLC which was significantly higher than that in the benign pulmonary diseases(x =6．237，P=0．013)．The expression of p-mTOR was closely correlated with age，sex and pTNM stage．Kaplan-Meire survival analysis revealed that the expression of p-mTOR was not correlated significantly with survival days(Log rank test P =0．055)．Conclusion P-mTOR might be a biomark for differential diagnosis of malignant lung disease，but has poor prognostic value．
Objective To review the possible mechanisms of the mammal ian target of rapamycin (mTOR) in theneuronal restoration process after nervous system injury. Methods The related l iterature on mTOR in the restoration ofnervous system injury was extensively reviewed and comprehensively analyzed. Results mTOR can integrate signals fromextracellular stress and then plays a critical role in the regulation of various cell biological processes, thus contributes to therestoration of nervous system injury. Conclusion Regulating the activity of mTOR signaling pathway in different aspects cancontribute to the restoration of nervous system injury via different mechanisms, especially in the stress-induced brain injury.mTOR may be a potential target for neuronal restoration mechanism after nervous system injury.
Objective To investigate the mechanism of adenosine-tri phosphate (ATP) activated mammal ian target of rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT3) signal pathway in the physiology and pathology of spinal cord injury (SCI). Methods Ninety-six adult healthy female Sprague-Dawley rats were randomly divided into 4 groups (groups A, B, C and D, n=24). In groups A, B and C, the rats were made the SCI models at T8-10 levels by using a modified Allen’ s stall, and in group D, rats were given laminectomy without SCI. The rats were subjected to the administration of ATP (40 mg/kg) for 7 days in group A, to the administration of physiological sal ine (equal-volume) for 7 days in group B, to the administration of ATP (40 mg/kg) and rapamycin (3 mg/kg) for 7 days in group C, and to the administration of physiological sal ine (equal-volume) for 7 days in group D. Locomotor activity was evaluated using the Basso-Beattie-Bresnahan rating scale at the postoperative 1st, 2nd, 3rd, and 4th weeks. Then, the expressions of spinal cord cell marker [Nestin, neuron-specific enolase (NSE), gl ial fibrillary acidic protein (GFAP)] and the mTOR/STAT3 pathway factors (mTOR, STAT3) were detected at the postoperative 1st, 2nd, 3rd, and 4th weeks by immunohistochemistry analysis, Western blot assay, and real-time fluorescence PCR analysis. Results The BBB scores in group A showed a steady increase in the postoperative 1st-4th weeks and were significantly higher than those in groups B and C (P lt; 0.01), but were lower than that in group D (P lt; 0.01). Real-time fluorescence PCR results showed that the mRNA expressions of mTOR, STAT3, NSE of group A steadily increased, however, the Nestin mRNA expression gradually decreased in the postoperative 1st-4th weeks, which were all significantly higher than those of groups B, C, and D (P lt; 0.01). The mRNA expression of GFAP showed a steady increase in group A and was significantly less than those of groups B and C, but was higher than that of group D (P lt; 0.01). There were significant differences (Plt; 0.01) in all markers between groups B, C, and group D; there were significant differences in mTOR, P-mTOR, STAT3, and P-STAT3 mRNA between groups B and C at 1st-4th weeks (P lt; 0.05). The similar changes were found by Western blot assay. Conclusion ATP can activate the mTOR/STAT3 pathway to induce endogenic NSCs to prol iferate and differentiate into neurons in rats, it enhances the heal ing of SCI.
Objective To evaluate the short and long term effectiveness and safety of rapamycin-based immunosuppression regimes with CsA preserving versus CsA withdrawal. Methods We searched MEDLINE, EMBASE, The Cochrane Library and CNKI from Jan. 1995 to Dec. 2005. We identified randomized controlled trials of rapamycin-hased immunosuppression regimes with CsA preserving versus CsA withdrawal for renal transplantation patients. The quality of included trials was evaluated by two reviewers. Meta-analysis was conducted on homogeneous studies. Results Ten studies （1 121 patients） undergoing renal transplantation were included. All included studies were graded in term of randomization, allocation concealment and bhnding. Six studies were graded A and the other 4 were graded B. Meta-analysis results showed CsA withdrawal in sirolimus-based therapy in renal transplantation patients survival rate OR.（95% CI ） values were 0,77（0.17, 3.52）, 1.24（0.48, 3.16）, 1.32（0.57, 3.08）, 1.21（0.60, 2.41） at the end of 6, 12, 24, 36 months respectively; renal allografts survival rate OR. （95% CI） values were 1.79 （0.63, 5.06）, 1.15 （ 0.56, 2.36） , 1.39 （0.68, 2.85）, 1.80（0.99, 3.29）, 2. 13（1.16, 3.89）, 2.01（1.15, 3.51） at the end of 6, 12, 24, 36, 48, 54 months respectively; and acute rejection OP,（95% CI） values were 0.92（0.48, 1.78）, 1.90（1.25, 2.89）, 2. 01 （0.94,4.27）, 1.93（0.93, 4.00）, 1.52（0.77, 3.02） at the end of6, 12, 24, 36, 48 months respectively. Conclusions Available evidence shows that compared with CsA preserving, CsA withdrawal in rapamycin-based immunosuppression regimes can lead to higher incidence rates of acute rejection at the end of one year while there is no statistical difference to survival rate of patients/renal allograft in cases with stabilized renal function post-transplantation. And CsA withdrawal is of benefit to allografts for long term survival rate and is helpful to recovery of renal function. Owing to high possibility of selection bias and measurement bias in included studies, there must be a negative impact on evidence intensity of our results. We expect best evidence from with high quality double blind randomized control trials.
Objective To investigate the cell growth inhibition and apoptosis induced by rapamycin on human hepatocellular carcinoma Bel-7402 cells and to study the role of mitochondrium membrane potential in the process of apoptosis. Methods Bel-7402 cells in vitro were given 5, 10, 20, 30, 40 and 50 nmol/L different concentrations of rapamycin, and the cell growth inhibiting ratio of Bel-7402 was assessed by MTT assay. The changes of morphology of Bel-7402 were observed by Hoechst 33258 staining and flow cytometry (FCM), respectively; The cell mitochondrial membrane potential was detected by using JC-1 staining method. Results Rapamycin could inhibit the growth of Bel-7402 cells significantly by inducing apoptosis, and the growth suppression and the cell apoptosis both presented time-effect relationship and were also dose-dependent. The rates of inhibiting and cell apoptosis after 72 h exposure to 50 nmol/L rapamycin were significantly higher that those of other groups (P＜0.01). Typical morphological changes of cell apoptosis were observed very clearly after the Bel-7402 cells had been exposed to rapamycin for 48 hours using Hoechst 33258 staining method, and it was also observed that the mitochondrial membrane potential decreased when apoptosis occured (P＜0.01). Conclusion Rapamycin could inhibit the growth of Bel-7402 cells by inducing cell apoptosis, and the descent of mitochondrial membrane potential may play an important role in the process of cell apoptosis.
ObjectiveTo investigate the effect of dexamethasone on mammalian target of rapamycin (mTOR) expression of astrocytes in hippocampus of rats with sepsis associated encephalopathy (SAE). MethodsTotally, 90 cases of 30-day-old male Wistar rats were randomly divided into sham-operation group (n=10) and cecal ligation and puncture (CLP) group (n=80). Models of rats with sepsis were established by CLP. At 12 hours after CLP, if rats appeared lower neurobehavioral scores, abnormal electroencephalogram (EEG) and somatosensory evoked potential (SEP), they were diagnosed with SAE. And then, they were randomly divided into non-treated group and dexamethasone group. Rats in the dexamethasone group were injected with dexamethasone (1 mg/kg) via tail vein every other day for a total of 3 times. The same dose of saline was used in the non-treated group. The neurobehavioral score was measured, SEP and EEG were examined in the age of 40 days, and then the rats were killed and the hippocampus was taken. Expressions of mTOR protein were measured by Western blot. The glial fibrillary acidic protein (GFAP) and mTOR were detected by immunofluorescence assay, and the number of positive cells was calculated by image analysis system software. ResultsSix of 80 CLP rats died in 12 hours after operation, and 28 of 74 rats were diagnosed as SAE because they appeared lower neurobehavioral scores, abnormal EEG and SEP at 12 hours after CLP. The incidence of SAE was 37.84% (28/74). In the age of 40 days, compared with non-treated group, neurobehavioral score of rats in the dexamethasone group was low, the amount of alpha waves in EEG reduced, delta waves increased, the amplitude of P1 waves in SEP was decreased, and the latencies of P1 and N1 waves were prolonged (P＜0.05). GFAP immunofluorescence staining showed astrocytic body and processes were small in the sham operation group. However, astrocytes in the non-treated group had large body and hypertrophic processes, and compared with the sham operation group, the number of these cells increased significantly (P＜0.05). Astrocytic body and processes were small in the dexamethasone group compared with the non-treated group, and the number of cells also decreased (P＜0.05). The mTOR positive astrocytes in the non-treated group were more than those in the sham operation group (P＜0.05). But mTOR positive astrocytes in the dexamethasone group were fewer than those in the non-treated group (P＜0.05). ConclusionsAstrocytes are activated in the hippocampus of rats with SAE. They show features of reactive hyperplasia, and the expression of mTOR is up-regulated, while dexamethasone can inhibit effects on these.