Background:μ-opioid receptor agonists(MORAs)are indispensable for analgesia in bladder cancer(BC)patients,both during surgery and for chronic pain treatment.Whether MORAs affect BC progression and metastasis remains ...Background:μ-opioid receptor agonists(MORAs)are indispensable for analgesia in bladder cancer(BC)patients,both during surgery and for chronic pain treatment.Whether MORAs affect BC progression and metastasis remains largely unknown.This study focused on the effects of MORAs on the formation of circulating tumor cells(CTCs)in BC and aimed to provide potential therapeutic targets,which would retain the pain-relieving effects of MORAs in BC patients without sacrificing their long-term prognosis.Methods:Different preclinical models were used to identify the effects of MORAs on the progression of BC.A novel immunocapture microfluidic chip was utilized to analyze whether MORAs affected the number of CTCs in mouse models and clinical BC patients.Bioinformatic analyses,total transcriptome sequencing,and molecular biology methods were then used to investigate the underlying mechanisms in these models and in BC cell lines.Results:Mouse models of hematogenous metastasis and in situ BC demonstrated that tumor metastasis was significantly increased after MORA treatment.A significant increase in the number of mesenchymal and/or epithelial CTCs was detected after MORA treatment in both the mouse models and clinical trial patients.Mechanistically,MORAs facilitated the formation of CTCs by activating the MOR/PI3K/AKT/Slug signaling pathway,hereby promoting the epithelialmesenchymal transition(EMT)of BC cells,as knockdown of MOR,Slug or blockade of PI3K inhibited the EMT process and CTC formation.Conclusion:MORAs promoted BC metastasis by facilitating CTC formation.The EMT-CTC axis could be targeted for preventive measures during MORA treatment to inhibit the associated tumormetastasis or recurrence in BC patients.展开更多
Objective To clarify the role of propofol in controlling incisional pain and its potential effects on the spinal opioid receptor expression. Methods A postoperative model of nociception was established in male Sprague...Objective To clarify the role of propofol in controlling incisional pain and its potential effects on the spinal opioid receptor expression. Methods A postoperative model of nociception was established in male Sprague-Dawley rats weighing 200 -250 g. A total of 96 rats were randomly divided into 8 groups. All drugs were administered intravenously either 5 rain pre-operation or 5 rain post-operation. The analgesic effects of systemic propofol were demonstrated by the measurement of a cumulative pain score （ CPS ）. After that, the lumbar enlargement of the spinal cord was removed to evaluate the mRNA level of the μ-opioid receptor （ MOR ） and δ-opioid receptor （ DOR） by RT-PCR. Results CPS and DOR mRNA expressions significantly increased after the operation. Both propofol post-treatment and propofol pre-treatment groups showed significant suppression of the increased CPS and the expression of DOR mRNA evoked by pain stimulation. Interestingly, propofol pre-treatment had a more pronounced effect in decreasing CPS and the expression of DOR mRNA. Furthermore, these observations were dose-dependent. MOR mRNA expression significantly increased after operation in all animals and propofol treatment had no impact on it. Conclusion Based on these findings, we suggest that propofol can serve as a valuable adjunct in acute postoperative pain management. Systemic propofol induces an analgesic effect on acute incisional pain in a dose-dependant manner, and this effect is mediated in the spinal cord and may be associated with the spinal DOR.展开更多
基金National Natural Science Foundation of China,Grant/Award Numbers:82171177,82173076Shanghai Science and Technology Committee Foundation,Grant/Award Number:19ZR1430600+6 种基金Clinical Research Plan of Shanghai Hospital Development Center,Grant/Award Number:SHDC2020CR4062Key Specialty Construction Project of Pudong Health and Family Planning Commission of Shanghai,Grant/Award Number:PWZxq2017-06Shanghai Municipal Key Clinical Specialty,Grant/Award Number:shslczdzk03601Shanghai Engineering Research Center of Peri-operative Organ Support and Function Preservation,Grant/Award Number:20DZ2254200Shanghai 2021“Science and Technology Innovation Action Plan”domestic science and technology cooperation project,Grant/Award Number:21015801500Innovative research team of high-level local universities in Shanghai,Grant/Award Number:SHSMU-ZLCX20212601STI2030-Major Projects,Grant/Award Number:2022ZD0206200。
文摘Background:μ-opioid receptor agonists(MORAs)are indispensable for analgesia in bladder cancer(BC)patients,both during surgery and for chronic pain treatment.Whether MORAs affect BC progression and metastasis remains largely unknown.This study focused on the effects of MORAs on the formation of circulating tumor cells(CTCs)in BC and aimed to provide potential therapeutic targets,which would retain the pain-relieving effects of MORAs in BC patients without sacrificing their long-term prognosis.Methods:Different preclinical models were used to identify the effects of MORAs on the progression of BC.A novel immunocapture microfluidic chip was utilized to analyze whether MORAs affected the number of CTCs in mouse models and clinical BC patients.Bioinformatic analyses,total transcriptome sequencing,and molecular biology methods were then used to investigate the underlying mechanisms in these models and in BC cell lines.Results:Mouse models of hematogenous metastasis and in situ BC demonstrated that tumor metastasis was significantly increased after MORA treatment.A significant increase in the number of mesenchymal and/or epithelial CTCs was detected after MORA treatment in both the mouse models and clinical trial patients.Mechanistically,MORAs facilitated the formation of CTCs by activating the MOR/PI3K/AKT/Slug signaling pathway,hereby promoting the epithelialmesenchymal transition(EMT)of BC cells,as knockdown of MOR,Slug or blockade of PI3K inhibited the EMT process and CTC formation.Conclusion:MORAs promoted BC metastasis by facilitating CTC formation.The EMT-CTC axis could be targeted for preventive measures during MORA treatment to inhibit the associated tumormetastasis or recurrence in BC patients.
基金Supported by the National Natural Science Foundation of China (No.30672020)
文摘Objective To clarify the role of propofol in controlling incisional pain and its potential effects on the spinal opioid receptor expression. Methods A postoperative model of nociception was established in male Sprague-Dawley rats weighing 200 -250 g. A total of 96 rats were randomly divided into 8 groups. All drugs were administered intravenously either 5 rain pre-operation or 5 rain post-operation. The analgesic effects of systemic propofol were demonstrated by the measurement of a cumulative pain score （ CPS ）. After that, the lumbar enlargement of the spinal cord was removed to evaluate the mRNA level of the μ-opioid receptor （ MOR ） and δ-opioid receptor （ DOR） by RT-PCR. Results CPS and DOR mRNA expressions significantly increased after the operation. Both propofol post-treatment and propofol pre-treatment groups showed significant suppression of the increased CPS and the expression of DOR mRNA evoked by pain stimulation. Interestingly, propofol pre-treatment had a more pronounced effect in decreasing CPS and the expression of DOR mRNA. Furthermore, these observations were dose-dependent. MOR mRNA expression significantly increased after operation in all animals and propofol treatment had no impact on it. Conclusion Based on these findings, we suggest that propofol can serve as a valuable adjunct in acute postoperative pain management. Systemic propofol induces an analgesic effect on acute incisional pain in a dose-dependant manner, and this effect is mediated in the spinal cord and may be associated with the spinal DOR.
