首页 > 最新文献

Acta Pharmacologica Sinica最新文献

英文 中文
Krüppel-like factor 9 alleviates Alzheimer's disease via IDE-mediated Aβ degradation.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-02-17 DOI: 10.1038/s41401-025-01491-0
Yue-Yao Feng, Jing-Ran Hao, Yu-Jie Zhang, Tong-Tong Qiu, Meng-Lin Zhang, Wei Qiao, Jin-Jin Wu, Ping Qiu, Chao-Fan Xu, Yin-Liang Zhang, Chun-Yuan Du, Zhe Pan, Yong-Sheng Chang

The deposition of β-amyloid (Aβ) in the brain is a crucial factor in the pathogenesis of Alzheimer's disease (AD). Insulin-degrading enzyme (IDE) plays a critical role in the balance between Aβ production and degradation. However, the regulatory mechanisms of IDE are not yet fully understood. Therefore, uncovering additional IDE regulatory mechanisms will help elucidate the pathogenesis of AD and identify key therapeutic targets for this disease. This study revealed that global Krüppel-like factor 9-mutant (Klf9-/-) mice exhibited impaired cognitive function. Additionally, we found that Klf9 expression in hippocampal tissue was reduced in APPswe/PS1dE9 (APP/PS1) mice. This study also showed that Klf9 stimulates IDE expression and promotes the Aβ degradation process by directly binding to IDE and activating its transcription. Silencing IDE blocked the Klf9-induced Aβ degradation process. We stereotactically injected an adeno-associated virus to selectively overexpress IDE (AAV-IDE) in the hippocampal neurons of Klf9-/- mice and found that the overexpression of IDE in hippocampal neurons ameliorated cognitive deficits and reduced the Aβ content in Klf9-/- mice. Additionally, we also stereotactically injected AAV-Klf9 into the hippocampal neurons of APP/PS1 mice and found that overexpression of Klf9 in hippocampal neurons ameliorated cognitive deficits and reduced Aβ levels in APP/PS1 mice. These findings suggest that downregulation of Klf9 may be a key factor in AD progression, as it reduces Aβ clearance by decreasing IDE expression. Overexpression or activation of Klf9 may be a potential strategy for preventing the pathogenesis of AD.

{"title":"Krüppel-like factor 9 alleviates Alzheimer's disease via IDE-mediated Aβ degradation.","authors":"Yue-Yao Feng, Jing-Ran Hao, Yu-Jie Zhang, Tong-Tong Qiu, Meng-Lin Zhang, Wei Qiao, Jin-Jin Wu, Ping Qiu, Chao-Fan Xu, Yin-Liang Zhang, Chun-Yuan Du, Zhe Pan, Yong-Sheng Chang","doi":"10.1038/s41401-025-01491-0","DOIUrl":"https://doi.org/10.1038/s41401-025-01491-0","url":null,"abstract":"<p><p>The deposition of β-amyloid (Aβ) in the brain is a crucial factor in the pathogenesis of Alzheimer's disease (AD). Insulin-degrading enzyme (IDE) plays a critical role in the balance between Aβ production and degradation. However, the regulatory mechanisms of IDE are not yet fully understood. Therefore, uncovering additional IDE regulatory mechanisms will help elucidate the pathogenesis of AD and identify key therapeutic targets for this disease. This study revealed that global Krüppel-like factor 9-mutant (Klf9<sup>-/-</sup>) mice exhibited impaired cognitive function. Additionally, we found that Klf9 expression in hippocampal tissue was reduced in APPswe/PS1dE9 (APP/PS1) mice. This study also showed that Klf9 stimulates IDE expression and promotes the Aβ degradation process by directly binding to IDE and activating its transcription. Silencing IDE blocked the Klf9-induced Aβ degradation process. We stereotactically injected an adeno-associated virus to selectively overexpress IDE (AAV-IDE) in the hippocampal neurons of Klf9<sup>-/-</sup> mice and found that the overexpression of IDE in hippocampal neurons ameliorated cognitive deficits and reduced the Aβ content in Klf9<sup>-/-</sup> mice. Additionally, we also stereotactically injected AAV-Klf9 into the hippocampal neurons of APP/PS1 mice and found that overexpression of Klf9 in hippocampal neurons ameliorated cognitive deficits and reduced Aβ levels in APP/PS1 mice. These findings suggest that downregulation of Klf9 may be a key factor in AD progression, as it reduces Aβ clearance by decreasing IDE expression. Overexpression or activation of Klf9 may be a potential strategy for preventing the pathogenesis of AD.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Circular RNA hsa_circ_0000288 protects against epilepsy in mice by binding to and stabilizing caprin1 protein.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-02-17 DOI: 10.1038/s41401-025-01486-x
Lin Guo, Na Lv, Jian-Lun Ji, Ce Gao, Si-Yu Liu, Zi-Yu Liu, Xin-Ting Lin, Zhi-Dong Liu, Yun Wang

Current anti-epileptic drugs remain to be unsatisfactory, new therapeutic approaches are needed. Circular RNA is a promising class of therapeutic RNAs. Recent studies have shown the role of circRNA in the pathologic process of epilepsy. In this study, we identified the circRNA in epileptic patients in remission that inhibited the epileptic course. By comparing the profiles of differentially expressed circRNAs in peripheral serum between patients in remission and those not in remission, we found that the level of hsa_circ_0000288 (circ288) was markedly elevated in the epileptic patients in remission. We established a kainic acid-induced status epilepticus model in mice. Overexpression of Circ288 by injecting adeno-associated virus (AAV)-circ288-overexpression vector into hippocampi significantly ameliorated epilepsy-induced neuronal injury, promoted hippocampus neurogenesis, and inhibited abnormal migration of newborn neurons into the dentate hilus. Moreover, circ288 overexpression significantly decreased the epileptiform discharges and the spontaneous seizures in the chronic phase of epileptogenesis and alleviated mood disorders (anxiety, depression), and cognitive deficits in epileptic mice. We revealed that circ288 directly bound to an RNA-binding protein caprin1 and inhibited its degradation. The protective action of circ288 was reversed by the knockdown of caprin1 in an in vitro epileptic model and lost in the neuron-specific caprin1 knockout mice (CaMK2α-Cre:Caprin1f/f). Overexpression of circ288 or caprin1 raised the mRNA level of NMDA receptor 3B, a negative modulator of NMDA receptors, suggesting the involvement of the carpin1-NMDA receptor 3B pathway in the role of circ288. Given the disadvantages of circ288 overexpression by a virus, we constructed exosomes-encapsulated circ288 (EXO-circ288) and demonstrated that tail vein injection of EXO-circ288 exerted robust protective effects. This study provides a new avenue for developing anti-epileptic therapeutic RNAs.

{"title":"Circular RNA hsa_circ_0000288 protects against epilepsy in mice by binding to and stabilizing caprin1 protein.","authors":"Lin Guo, Na Lv, Jian-Lun Ji, Ce Gao, Si-Yu Liu, Zi-Yu Liu, Xin-Ting Lin, Zhi-Dong Liu, Yun Wang","doi":"10.1038/s41401-025-01486-x","DOIUrl":"https://doi.org/10.1038/s41401-025-01486-x","url":null,"abstract":"<p><p>Current anti-epileptic drugs remain to be unsatisfactory, new therapeutic approaches are needed. Circular RNA is a promising class of therapeutic RNAs. Recent studies have shown the role of circRNA in the pathologic process of epilepsy. In this study, we identified the circRNA in epileptic patients in remission that inhibited the epileptic course. By comparing the profiles of differentially expressed circRNAs in peripheral serum between patients in remission and those not in remission, we found that the level of hsa_circ_0000288 (circ288) was markedly elevated in the epileptic patients in remission. We established a kainic acid-induced status epilepticus model in mice. Overexpression of Circ288 by injecting adeno-associated virus (AAV)-circ288-overexpression vector into hippocampi significantly ameliorated epilepsy-induced neuronal injury, promoted hippocampus neurogenesis, and inhibited abnormal migration of newborn neurons into the dentate hilus. Moreover, circ288 overexpression significantly decreased the epileptiform discharges and the spontaneous seizures in the chronic phase of epileptogenesis and alleviated mood disorders (anxiety, depression), and cognitive deficits in epileptic mice. We revealed that circ288 directly bound to an RNA-binding protein caprin1 and inhibited its degradation. The protective action of circ288 was reversed by the knockdown of caprin1 in an in vitro epileptic model and lost in the neuron-specific caprin1 knockout mice (CaMK2α-Cre:Caprin1<sup>f/f</sup>). Overexpression of circ288 or caprin1 raised the mRNA level of NMDA receptor 3B, a negative modulator of NMDA receptors, suggesting the involvement of the carpin1-NMDA receptor 3B pathway in the role of circ288. Given the disadvantages of circ288 overexpression by a virus, we constructed exosomes-encapsulated circ288 (EXO-circ288) and demonstrated that tail vein injection of EXO-circ288 exerted robust protective effects. This study provides a new avenue for developing anti-epileptic therapeutic RNAs.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Co-inhibition of RAGE and TLR4 sensitizes pancreatic cancer to irreversible electroporation in mice by disrupting autophagy.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-02-14 DOI: 10.1038/s41401-025-01487-w
Cui-Fang Ye, Jia-di Wu, Lin-Rong Li, Shu-Guo Sun, Yu-Gang Wang, Tian-An Jiang, Xin Long, Jun Zhao

Irreversible electroporation (IRE) is a local ablative treatment for patients with pancreatic cancer. During the IRE procedure, high-intensity electric pulses are released intratumorally to disrupt plasma membranes and induce cell death. Since the intensity of the pulsed electric field (PEF) can be decreased by the tumor microenvironment, some cancer cells are subjected to a sublethal PEF and may survive to cause tumor recurrence later. Autophagy activation induced by anticancer therapies is known to promote treatment resistance. In this study, we investigated whether autophagy is activated in residual cancer cells after IRE and assessed the roles it plays during tumor recurrence. Subcutaneous KPC-A548 or Panc02 murine pancreatic cancer cell line xenograft mouse models were established; once the tumors reached 7 mm in one dimension, the tumor-bearing mice were subjected to IRE. For in vitro sublethal PEF treatment, the pancreatic cancer cell suspension was in direct contact with the electrodes and pulsed at room temperature. We showed that autophagy was activated in surviving residual cells, as evidenced by increased expression of LC3 and p62. Suppression of autophagy with hydroxychloroquine (60 mg/kg, daily intraperitoneal injection) markedly increased the efficacy of IRE. We demonstrated that autophagy activation can be attributed to increased expression of high-mobility group box 1 (HMGB1); co-inhibition of two HMGB1 receptors, receptor for advanced glycosylation end products (RAGE) and Toll-like receptor 4 (TLR4), suppressed autophagy activation by upregulating the PI3K/AKT/p70 ribosomal S6 protein kinase (p70S6K) axis and sensitized pancreatic cancer cells to PEF. We prepared a polymeric micelle formulation (M-R/T) encapsulating inhibitors of both RAGE and TLR4. The combination of IRE and M-R/T (equivalent to RAGE inhibitor at 10.4 mg/kg and TLR4 inhibitor at 5.7 mg/kg, intravenous or intraperitoneal injection every other day) significantly promoted tumor apoptosis, suppressed cell cycle progression, and prolonged animal survival in pancreatic tumor models. This study suggests that disruption of HMGB1-mediated autophagy with nanomedicine is a promising strategy to enhance the response of pancreatic cancer to IRE.

{"title":"Co-inhibition of RAGE and TLR4 sensitizes pancreatic cancer to irreversible electroporation in mice by disrupting autophagy.","authors":"Cui-Fang Ye, Jia-di Wu, Lin-Rong Li, Shu-Guo Sun, Yu-Gang Wang, Tian-An Jiang, Xin Long, Jun Zhao","doi":"10.1038/s41401-025-01487-w","DOIUrl":"https://doi.org/10.1038/s41401-025-01487-w","url":null,"abstract":"<p><p>Irreversible electroporation (IRE) is a local ablative treatment for patients with pancreatic cancer. During the IRE procedure, high-intensity electric pulses are released intratumorally to disrupt plasma membranes and induce cell death. Since the intensity of the pulsed electric field (PEF) can be decreased by the tumor microenvironment, some cancer cells are subjected to a sublethal PEF and may survive to cause tumor recurrence later. Autophagy activation induced by anticancer therapies is known to promote treatment resistance. In this study, we investigated whether autophagy is activated in residual cancer cells after IRE and assessed the roles it plays during tumor recurrence. Subcutaneous KPC-A548 or Panc02 murine pancreatic cancer cell line xenograft mouse models were established; once the tumors reached 7 mm in one dimension, the tumor-bearing mice were subjected to IRE. For in vitro sublethal PEF treatment, the pancreatic cancer cell suspension was in direct contact with the electrodes and pulsed at room temperature. We showed that autophagy was activated in surviving residual cells, as evidenced by increased expression of LC3 and p62. Suppression of autophagy with hydroxychloroquine (60 mg/kg, daily intraperitoneal injection) markedly increased the efficacy of IRE. We demonstrated that autophagy activation can be attributed to increased expression of high-mobility group box 1 (HMGB1); co-inhibition of two HMGB1 receptors, receptor for advanced glycosylation end products (RAGE) and Toll-like receptor 4 (TLR4), suppressed autophagy activation by upregulating the PI3K/AKT/p70 ribosomal S6 protein kinase (p70S6K) axis and sensitized pancreatic cancer cells to PEF. We prepared a polymeric micelle formulation (M-R/T) encapsulating inhibitors of both RAGE and TLR4. The combination of IRE and M-R/T (equivalent to RAGE inhibitor at 10.4 mg/kg and TLR4 inhibitor at 5.7 mg/kg, intravenous or intraperitoneal injection every other day) significantly promoted tumor apoptosis, suppressed cell cycle progression, and prolonged animal survival in pancreatic tumor models. This study suggests that disruption of HMGB1-mediated autophagy with nanomedicine is a promising strategy to enhance the response of pancreatic cancer to IRE.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Author Correction: Bicyclol protects HepG2 cells against D-galactosamine-induced apoptosis through inducing heat shock protein 27 and mitochondria associated pathway.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-02-13 DOI: 10.1038/s41401-025-01482-1
Xiu-Qi Bao, Geng-Tao Liu
{"title":"Author Correction: Bicyclol protects HepG2 cells against D-galactosamine-induced apoptosis through inducing heat shock protein 27 and mitochondria associated pathway.","authors":"Xiu-Qi Bao, Geng-Tao Liu","doi":"10.1038/s41401-025-01482-1","DOIUrl":"https://doi.org/10.1038/s41401-025-01482-1","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Correction: A novel annexin dimer targets microglial phagocytosis of astrocytes to protect the brain-blood barrier after cerebral ischemia.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-02-12 DOI: 10.1038/s41401-025-01480-3
Wei Tang, Rong Cheng, Meng-Yue Gao, Min-Jin Hu, Lu Zhang, Qiang Wang, Xin-Yu Li, Wei Yan, Xiao-Ying Wang, Hai-Mei Yang, Jian Cheng, Zi-Chun Hua
{"title":"Correction: A novel annexin dimer targets microglial phagocytosis of astrocytes to protect the brain-blood barrier after cerebral ischemia.","authors":"Wei Tang, Rong Cheng, Meng-Yue Gao, Min-Jin Hu, Lu Zhang, Qiang Wang, Xin-Yu Li, Wei Yan, Xiao-Ying Wang, Hai-Mei Yang, Jian Cheng, Zi-Chun Hua","doi":"10.1038/s41401-025-01480-3","DOIUrl":"10.1038/s41401-025-01480-3","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Acyl-CoA thioesterase 8 induces gemcitabine resistance via regulation of lipid metabolism and antiferroptotic activity in pancreatic ductal adenocarcinoma.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-02-12 DOI: 10.1038/s41401-025-01477-y
Bo-Rui Li, Ting Wang, Hai-Feng Hu, Di Wu, Chen-Jie Zhou, Shun-Rong Ji, Qi-Feng Zhuo, Zheng Li, Zhi-Liang Wang, Gui-Xiong Fan, De-Sheng Jing, Chong-Yuan Yu, Yi Qin, Xue-Min Chen, Jun-Feng Xu, Xiao-Wu Xu

Pancreatic ductal adenocarcinoma (PDAC) comprises a group of highly malignant tumors of the pancreas. Metabolic reprogramming in tumors plays a pivotal role in promoting cancer progression. However, little is known about the metabolic alterations in tumors that drive cancer drug resistance in patients with PDAC. Here, we identified acyl-CoA thioesterase 8 (ACOT8) as a key player in driving PDAC gemcitabine (GEM) resistance. The expression of ACOT8 is significantly upregulated in GEM-resistant PDAC tissues and is closely associated with poor survival in patients with PDAC. Gain- and loss-of-function studies have shown that ACOT8 drives PDAC GEM resistance both in vitro and in vivo. Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. The combination of orlistat, an ACOT8 inhibitor, and GEM significantly inhibited tumor growth in PDAC organoid and mouse models. This study reveals the biological importance of ACOT8 and provides a potential combination therapy for treating patients with advanced GEM-resistant PDAC.

{"title":"Acyl-CoA thioesterase 8 induces gemcitabine resistance via regulation of lipid metabolism and antiferroptotic activity in pancreatic ductal adenocarcinoma.","authors":"Bo-Rui Li, Ting Wang, Hai-Feng Hu, Di Wu, Chen-Jie Zhou, Shun-Rong Ji, Qi-Feng Zhuo, Zheng Li, Zhi-Liang Wang, Gui-Xiong Fan, De-Sheng Jing, Chong-Yuan Yu, Yi Qin, Xue-Min Chen, Jun-Feng Xu, Xiao-Wu Xu","doi":"10.1038/s41401-025-01477-y","DOIUrl":"https://doi.org/10.1038/s41401-025-01477-y","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) comprises a group of highly malignant tumors of the pancreas. Metabolic reprogramming in tumors plays a pivotal role in promoting cancer progression. However, little is known about the metabolic alterations in tumors that drive cancer drug resistance in patients with PDAC. Here, we identified acyl-CoA thioesterase 8 (ACOT8) as a key player in driving PDAC gemcitabine (GEM) resistance. The expression of ACOT8 is significantly upregulated in GEM-resistant PDAC tissues and is closely associated with poor survival in patients with PDAC. Gain- and loss-of-function studies have shown that ACOT8 drives PDAC GEM resistance both in vitro and in vivo. Mechanistically, ACOT8 regulates cellular cholesterol ester (CE) levels, decreases the levels of phosphatidylethanolamines (PEs) that bind to polyunsaturated fatty acids and promote peroxisome activation. The knockdown of ACOT8 promotes ferroptosis and increases the chemosensitivity of tumors to GEM by inducing ferroptosis-associated pathway activation in PDAC cell lines. The combination of orlistat, an ACOT8 inhibitor, and GEM significantly inhibited tumor growth in PDAC organoid and mouse models. This study reveals the biological importance of ACOT8 and provides a potential combination therapy for treating patients with advanced GEM-resistant PDAC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Development of orthotopic mouse models for mid-low rectal cancer.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-02-12 DOI: 10.1038/s41401-025-01489-8
Wen Chen, Kun Shi, Dong Mo, Meng Pan, Zhong-Wu Bei, Han-Zhi Deng, Pei-Pei Yang, Qi Tong, Li-Ping Yuan, Yi-Yao Wan, Jia-Feng Liu, Li-Li Pan, Zhi-Yong Qian

Mid-low rectal cancer is one of the most common types of rectal cancer and has a poor prognosis. Surgery and chemoradiotherapy are the main treatments for early and advanced rectal cancer with an overall 5-year relative survival rate of only 56.9%. Development of novel antitumor agents is needed. Animal models of disease are indispensable for drug development. The most commonly used animal models of rectal cancer are established by inducing tumors by the subcutaneous transplantation, cecum or peritoneal injection, but not injection in the rectum. Their tumor microenvironment differs from that of rectal tumors in situ, which is hard to precisely simulate the occurrence and development process and drug response of human rectal cancer. In this study, we established orthotopic mouse models of mid-low rectal cancer with primary tumors originating from the rectum, including two models that could simulate the early and advanced stages of the disease, respectively. In the first model, the local primary tumor was restricted to the rectal area of the anal verge by rectal submucosal injection, its growth could be monitored with IVIS live imaging and magnetic resonance imaging. Histological analysis confirmed that the tumor originated from the submucosal layer and then invaded the muscular layer without metastatic tumors. This model may be useful for evaluating drugs for early mid-low rectal cancer in the future. The second model featuring a rectal primary tumor accompanied with abdominal metastases was established via rectal serosal injection. In this model, a large tumor formed at the rectal injection site and then metastasized to the abdominal cavity, reproducing the process from occurrence to metastasis of mid-low rectal cancer, and may be a good tool for the evaluation of drugs for advanced-stage disease. The injection methods used in these models do not require the aid of special colonoscopes, are simple and easy to operate, and have high tumor tumorigenicity and reproducibility. These results suggest that our staged modeling can provide targeted choices for preclinical drug research of mid-low rectal cancer at different stages.

{"title":"Development of orthotopic mouse models for mid-low rectal cancer.","authors":"Wen Chen, Kun Shi, Dong Mo, Meng Pan, Zhong-Wu Bei, Han-Zhi Deng, Pei-Pei Yang, Qi Tong, Li-Ping Yuan, Yi-Yao Wan, Jia-Feng Liu, Li-Li Pan, Zhi-Yong Qian","doi":"10.1038/s41401-025-01489-8","DOIUrl":"https://doi.org/10.1038/s41401-025-01489-8","url":null,"abstract":"<p><p>Mid-low rectal cancer is one of the most common types of rectal cancer and has a poor prognosis. Surgery and chemoradiotherapy are the main treatments for early and advanced rectal cancer with an overall 5-year relative survival rate of only 56.9%. Development of novel antitumor agents is needed. Animal models of disease are indispensable for drug development. The most commonly used animal models of rectal cancer are established by inducing tumors by the subcutaneous transplantation, cecum or peritoneal injection, but not injection in the rectum. Their tumor microenvironment differs from that of rectal tumors in situ, which is hard to precisely simulate the occurrence and development process and drug response of human rectal cancer. In this study, we established orthotopic mouse models of mid-low rectal cancer with primary tumors originating from the rectum, including two models that could simulate the early and advanced stages of the disease, respectively. In the first model, the local primary tumor was restricted to the rectal area of the anal verge by rectal submucosal injection, its growth could be monitored with IVIS live imaging and magnetic resonance imaging. Histological analysis confirmed that the tumor originated from the submucosal layer and then invaded the muscular layer without metastatic tumors. This model may be useful for evaluating drugs for early mid-low rectal cancer in the future. The second model featuring a rectal primary tumor accompanied with abdominal metastases was established via rectal serosal injection. In this model, a large tumor formed at the rectal injection site and then metastasized to the abdominal cavity, reproducing the process from occurrence to metastasis of mid-low rectal cancer, and may be a good tool for the evaluation of drugs for advanced-stage disease. The injection methods used in these models do not require the aid of special colonoscopes, are simple and easy to operate, and have high tumor tumorigenicity and reproducibility. These results suggest that our staged modeling can provide targeted choices for preclinical drug research of mid-low rectal cancer at different stages.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Author Correction: Ginsenoside Rg1 mitigates cerebral ischaemia/reperfusion injury in mice by inhibiting autophagy through activation of mTOR signalling.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-02-12 DOI: 10.1038/s41401-025-01502-0
Zhi-Chao Xi, Han-Gui Ren, Lin Ai, Yuan Wang, Meng-Fan Liu, Yu-Fei Qiu, Ji-Ling Feng, Wang Fu, Qian-Qian Bi, Feng Wang, Hong-Xi Xu
{"title":"Author Correction: Ginsenoside Rg1 mitigates cerebral ischaemia/reperfusion injury in mice by inhibiting autophagy through activation of mTOR signalling.","authors":"Zhi-Chao Xi, Han-Gui Ren, Lin Ai, Yuan Wang, Meng-Fan Liu, Yu-Fei Qiu, Ji-Ling Feng, Wang Fu, Qian-Qian Bi, Feng Wang, Hong-Xi Xu","doi":"10.1038/s41401-025-01502-0","DOIUrl":"https://doi.org/10.1038/s41401-025-01502-0","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
METTL14-mediated m6A methylation of pri-miR-5099 to facilitate cardiomyocyte pyroptosis in myocardial infarction.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-02-12 DOI: 10.1038/s41401-025-01485-y
Hang Yu, Qing-Sui Li, Jun-Nan Guo, Zhen Zhang, Xian-Zhi Lang, Yi-Ning Liu, Long Qin, Xu Su, Qing-Wei Zhang, Ya-Dong Xue, Li-Ling Gong, Ning Xu, Ming Li, Wen-Shuang Zhao, Xing-Miao Zhao, Wan-Yu Zhang, Yi-Jing Yao, Xi-Ming Chen, Zhen Zhang, Wei Li, Han-Xiang Wang, Ben-Zhi Cai, Jia-Min Li, Ning Wang

N6-methyladenosine (m6A) modification is an important mechanism in microRNA processing and maturation. Previous studies show the involvement of pri-miRNA methylation in regulating the occurrence and development of tumor-related diseases. In this study, we investigated the role of its aberrant regulation in cardiac diseases. Myocardial infarction (MI) mouse were established by ligation of the left anterior descending branch of the coronary artery. We showed that the expression of methyltransferase 14 (METTL14) was significantly increased in myocardium of MI mice. We demonstrated that METTL14 methylated the primary transcript miRNA (pri-miR-5099), promoting the recognition by DiGeorge critical region 8 (DGCR8) and the maturation processing of pri-miR-5099. Mature microRNA-5099-3p (miR-5099-3p) inhibited the expression of E74 like ETS transcription factor 1 (ELF1), which transcriptionally regulated pyroptosis factors such as acysteinyl aspartate-specific proteinase 1 (caspase-1) and gasdermin D (GSDMD), ultimately leading to cardiomyocyte pyroptosis. This study reveals that myocardial infarction-induced miR-5099-3p excessive maturation via m6A modification promotes the development and progression of cardiomyocyte pyroptosis.

{"title":"METTL14-mediated m<sup>6</sup>A methylation of pri-miR-5099 to facilitate cardiomyocyte pyroptosis in myocardial infarction.","authors":"Hang Yu, Qing-Sui Li, Jun-Nan Guo, Zhen Zhang, Xian-Zhi Lang, Yi-Ning Liu, Long Qin, Xu Su, Qing-Wei Zhang, Ya-Dong Xue, Li-Ling Gong, Ning Xu, Ming Li, Wen-Shuang Zhao, Xing-Miao Zhao, Wan-Yu Zhang, Yi-Jing Yao, Xi-Ming Chen, Zhen Zhang, Wei Li, Han-Xiang Wang, Ben-Zhi Cai, Jia-Min Li, Ning Wang","doi":"10.1038/s41401-025-01485-y","DOIUrl":"https://doi.org/10.1038/s41401-025-01485-y","url":null,"abstract":"<p><p>N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification is an important mechanism in microRNA processing and maturation. Previous studies show the involvement of pri-miRNA methylation in regulating the occurrence and development of tumor-related diseases. In this study, we investigated the role of its aberrant regulation in cardiac diseases. Myocardial infarction (MI) mouse were established by ligation of the left anterior descending branch of the coronary artery. We showed that the expression of methyltransferase 14 (METTL14) was significantly increased in myocardium of MI mice. We demonstrated that METTL14 methylated the primary transcript miRNA (pri-miR-5099), promoting the recognition by DiGeorge critical region 8 (DGCR8) and the maturation processing of pri-miR-5099. Mature microRNA-5099-3p (miR-5099-3p) inhibited the expression of E74 like ETS transcription factor 1 (ELF1), which transcriptionally regulated pyroptosis factors such as acysteinyl aspartate-specific proteinase 1 (caspase-1) and gasdermin D (GSDMD), ultimately leading to cardiomyocyte pyroptosis. This study reveals that myocardial infarction-induced miR-5099-3p excessive maturation via m<sup>6</sup>A modification promotes the development and progression of cardiomyocyte pyroptosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bardoxolone displays potent activity against triple negative breast cancer by inhibiting the TRIP13/STAT3 circuit.
IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-02-12 DOI: 10.1038/s41401-025-01481-2
Jun-Hao Deng, Hong-Yue Li, Zi-Yang Liu, Jing-Pei Liang, Ying Ren, Yuan-Ying Zeng, Ya-Li Wang, Xin-Liang Mao

Triple negative breast cancer (TNBC) is difficult to treat and novel therapeutic targets remain to be identified. TRIP13, an AAA+ ATPase, is highly expressed in breast cancer and predicts poor prognosis; however, the specific mechanism is not fully understood. In the present study, we found TRIP13 promotes TNBC cell viability and migration. In a mechanistic study, TRIP13 is found to activate STAT3 but not other STAT members. Out of expectation, TRIP13 is found to be upregulated by STAT3 and STAT3 specifically recognizes and binds to the STAT3-recognition element in the regulatory region of TRIP13. Moreover, we found bardoxolone, a recently approved drug for the treatment of chronic kidney disease, displays potent activity by inhibiting STAT3 activation and downregulating TRIP13. Furthermore, bardoxolone inhibits breast cancer cell proliferation and migration, and induces apoptosis. Consistent with this finding, ectopic expression of TRIP13 ablates bardoxolone-induced breast cancer cell apoptosis. Bardoxolone also exerts great activity to suppress TNBC tumor growth in vivo but does not show toxicity. Therefore, we reveal that the TRIP13/STAT3 circuit promotes TNBC cell proliferation and this circuit is a promising target for the treatment of TNBC.

{"title":"Bardoxolone displays potent activity against triple negative breast cancer by inhibiting the TRIP13/STAT3 circuit.","authors":"Jun-Hao Deng, Hong-Yue Li, Zi-Yang Liu, Jing-Pei Liang, Ying Ren, Yuan-Ying Zeng, Ya-Li Wang, Xin-Liang Mao","doi":"10.1038/s41401-025-01481-2","DOIUrl":"https://doi.org/10.1038/s41401-025-01481-2","url":null,"abstract":"<p><p>Triple negative breast cancer (TNBC) is difficult to treat and novel therapeutic targets remain to be identified. TRIP13, an AAA+ ATPase, is highly expressed in breast cancer and predicts poor prognosis; however, the specific mechanism is not fully understood. In the present study, we found TRIP13 promotes TNBC cell viability and migration. In a mechanistic study, TRIP13 is found to activate STAT3 but not other STAT members. Out of expectation, TRIP13 is found to be upregulated by STAT3 and STAT3 specifically recognizes and binds to the STAT3-recognition element in the regulatory region of TRIP13. Moreover, we found bardoxolone, a recently approved drug for the treatment of chronic kidney disease, displays potent activity by inhibiting STAT3 activation and downregulating TRIP13. Furthermore, bardoxolone inhibits breast cancer cell proliferation and migration, and induces apoptosis. Consistent with this finding, ectopic expression of TRIP13 ablates bardoxolone-induced breast cancer cell apoptosis. Bardoxolone also exerts great activity to suppress TNBC tumor growth in vivo but does not show toxicity. Therefore, we reveal that the TRIP13/STAT3 circuit promotes TNBC cell proliferation and this circuit is a promising target for the treatment of TNBC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Acta Pharmacologica Sinica
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1