Pub Date : 2020-09-01Epub Date: 2020-08-07DOI: 10.1111/jcmm.15709
Huan Li, Anjara Rabearivony, Wenxiang Zhang, Siyu Chen, Xiaofei An, Chang Liu
The chronopharmacology refers to the utilization of physiological circadian rhythms to optimize the administration time of drugs, thus increasing their efficacy and safety, or reducing adverse effects. Simvastatin is one of the most widely prescribed drugs for the treatment of hypercholesterolaemia, hyperlipidemia and coronary artery disease. There are conflicting statements regarding the timing of simvastatin administration, and convincing experimental evidence remains unavailable. Thus, we aimed to examine whether different administration times would influence the efficacy of simvastatin. High-fat diet-fed mice were treated with simvastatin at zeitgeber time 1 (ZT1) or ZT13, respectively, for nine weeks. Simvastatin showed robust anti-hypercholesterolaemia and anti-hyperlipidemia effects on these obese mice, regardless of administration time. However, simvastatin administrated at ZT13, compared to ZT1, was more functional for decreasing serum levels of total cholesterol, triglycerides, non-esterified free fatty acids and LDL cholesterol, as well as improving liver pathological characteristics. In terms of possible mechanisms, we found that simvastatin did not alter the expression of hepatic circadian clock gene in vivo, although it failed to change the period, phase and amplitude of oscillation patterns in Per2::Luc U2OS and Bmal1::Luc U2OS cells in vitro. In contrast, simvastatin regulated the expression of Hmgcr, Mdr1 and Slco2b1 in a circadian manner, which potentially contributed to the chronopharmacological function of the drug. Taken together, we provide solid evidence to suggest that different administration times affect the lipid-lowering effects of simvastatin.
{"title":"Chronopharmacology of simvastatin on hyperlipidaemia in high-fat diet-fed obese mice.","authors":"Huan Li, Anjara Rabearivony, Wenxiang Zhang, Siyu Chen, Xiaofei An, Chang Liu","doi":"10.1111/jcmm.15709","DOIUrl":"https://doi.org/10.1111/jcmm.15709","url":null,"abstract":"<p><p>The chronopharmacology refers to the utilization of physiological circadian rhythms to optimize the administration time of drugs, thus increasing their efficacy and safety, or reducing adverse effects. Simvastatin is one of the most widely prescribed drugs for the treatment of hypercholesterolaemia, hyperlipidemia and coronary artery disease. There are conflicting statements regarding the timing of simvastatin administration, and convincing experimental evidence remains unavailable. Thus, we aimed to examine whether different administration times would influence the efficacy of simvastatin. High-fat diet-fed mice were treated with simvastatin at zeitgeber time 1 (ZT1) or ZT13, respectively, for nine weeks. Simvastatin showed robust anti-hypercholesterolaemia and anti-hyperlipidemia effects on these obese mice, regardless of administration time. However, simvastatin administrated at ZT13, compared to ZT1, was more functional for decreasing serum levels of total cholesterol, triglycerides, non-esterified free fatty acids and LDL cholesterol, as well as improving liver pathological characteristics. In terms of possible mechanisms, we found that simvastatin did not alter the expression of hepatic circadian clock gene in vivo, although it failed to change the period, phase and amplitude of oscillation patterns in Per2::Luc U2OS and Bmal1::Luc U2OS cells in vitro. In contrast, simvastatin regulated the expression of Hmgcr, Mdr1 and Slco2b1 in a circadian manner, which potentially contributed to the chronopharmacological function of the drug. Taken together, we provide solid evidence to suggest that different administration times affect the lipid-lowering effects of simvastatin.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15709","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38250629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-09-01Epub Date: 2020-08-17DOI: 10.1111/jcmm.15747
Jun Liu, Jinli Ding, Bing Qu, Jiuying Liu, Xiaojie Song, Qingli Suo, Aifen Zhou, Jing Yang
Polycystic ovary syndrome (PCOS), the most common female endocrine disease that causes anovulatory infertility, still lacks promising strategy for the accurate diagnosis and effective therapeutics of PCOS attributed to its unclear aetiology. In this study, we determined the abnormal reduction in circPSMC3 expression by comparing the ovarian tissue samples of PCOS patients and normal individuals. The symptom relief caused by up-regulation of circPSMC3 in PCOS model mice suggested the potential for further study. In vitro functional experiments confirmed that circPSMC3 can inhibit cell proliferation and promote apoptosis by blocking the cell cycle in human-like granular tumour cell lines. Mechanism study revealed that circPSMC3 may play its role through sponging miR-296-3p to regulate PTEN expression. Collectively, we preliminarily characterized the role and possible insights of circPSMC3/miR-296-3p/PTEN axis in the proliferation and apoptosis of KGN cells. We hope that this work provides some original and valuable information for the research of circRNAs in PCOS, not only to better understand the pathogenesis but also to help provide new clues for seeking for the future therapeutic target of PCOS.
{"title":"CircPSMC3 alleviates the symptoms of PCOS by sponging miR-296-3p and regulating PTEN expression.","authors":"Jun Liu, Jinli Ding, Bing Qu, Jiuying Liu, Xiaojie Song, Qingli Suo, Aifen Zhou, Jing Yang","doi":"10.1111/jcmm.15747","DOIUrl":"https://doi.org/10.1111/jcmm.15747","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS), the most common female endocrine disease that causes anovulatory infertility, still lacks promising strategy for the accurate diagnosis and effective therapeutics of PCOS attributed to its unclear aetiology. In this study, we determined the abnormal reduction in circPSMC3 expression by comparing the ovarian tissue samples of PCOS patients and normal individuals. The symptom relief caused by up-regulation of circPSMC3 in PCOS model mice suggested the potential for further study. In vitro functional experiments confirmed that circPSMC3 can inhibit cell proliferation and promote apoptosis by blocking the cell cycle in human-like granular tumour cell lines. Mechanism study revealed that circPSMC3 may play its role through sponging miR-296-3p to regulate PTEN expression. Collectively, we preliminarily characterized the role and possible insights of circPSMC3/miR-296-3p/PTEN axis in the proliferation and apoptosis of KGN cells. We hope that this work provides some original and valuable information for the research of circRNAs in PCOS, not only to better understand the pathogenesis but also to help provide new clues for seeking for the future therapeutic target of PCOS.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15747","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38274261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MicroRNAs (miRNAs) have already been proposed to be implicated in the development of ischaemic stroke. We aim to investigate the role of miR-130a in the neurological deficit and angiogenesis in rats with ischaemic stroke by regulating X-linked inhibitor of apoptosis protein (XIAP). Middle cerebral artery occlusion (MCAO) models were established by suture-occluded method, and MCAO rats were then treated with miR-130a mimics/inhibitors or/and altered XIAP for detection of changes of rats' neurological function, nerve damage and angiogenesis in MCAO rats. The oxygen-glucose deprivation (OGD) cellular models were established and respectively treated to determine the roles of miR-130a and XIAP in neuronal viability and apoptosis. The expression levels of miR-130a and XIAP in brain tissues of MCAO rats and OGD-treated neurons were detected. The binding site between miR-130a and XIAP was verified by luciferase activity assay. MiR-130a was overexpressed while XIAP was down-regulated in MCAO rats and OGD-treated neurons. In animal models, suppressed miR-130a improved neurological function, alleviated nerve damage and increased new vessels in brain tissues of rats with MCAO. In cellular models, miR-130a inhibition promoted neuronal viability and suppressed apoptosis. Inhibited XIAP reversed the effect of inhibited miR-130a in both MCAO rats and OGD-treated neurons. XIAP was identified as a target of miR-130a. Our study reveals that miR-130a regulates neurological deficit and angiogenesis in rats with MCAO by targeting XIAP.
MicroRNAs (miRNAs)已经被认为与缺血性卒中的发展有关。我们旨在研究miR-130a通过调节X-linked inhibitor of apoptosis protein (XIAP)在缺血性脑卒中大鼠神经功能缺损和血管生成中的作用。采用缝合闭塞法建立大脑中动脉闭塞(MCAO)模型,然后用miR-130a模拟物/抑制剂或/和改变的XIAP处理MCAO大鼠,检测MCAO大鼠神经功能、神经损伤和血管生成的变化。建立氧糖剥夺(OGD)细胞模型,分别处理miR-130a和XIAP在神经元活力和凋亡中的作用。检测miR-130a和XIAP在MCAO大鼠脑组织和ogd处理神经元中的表达水平。通过荧光素酶活性测定验证miR-130a与XIAP的结合位点。在MCAO大鼠和ogd处理的神经元中,MiR-130a过表达,而XIAP下调。在动物模型中,抑制miR-130a可改善MCAO大鼠的神经功能,减轻神经损伤,增加脑组织新生血管。在细胞模型中,miR-130a抑制可促进神经元活力并抑制细胞凋亡。抑制XIAP逆转了MCAO大鼠和ogd处理神经元中抑制miR-130a的作用。XIAP被确定为miR-130a的靶标。我们的研究表明,miR-130a通过靶向XIAP调节MCAO大鼠的神经功能缺损和血管生成。
{"title":"MicroRNA-130a regulates neurological deficit and angiogenesis in rats with ischaemic stroke by targeting XIAP.","authors":"Wenjing Deng, Chenghe Fan, Yanan Zhao, Yuewei Mao, Jiajia Li, Yonggan Zhang, Junfang Teng","doi":"10.1111/jcmm.15732","DOIUrl":"https://doi.org/10.1111/jcmm.15732","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) have already been proposed to be implicated in the development of ischaemic stroke. We aim to investigate the role of miR-130a in the neurological deficit and angiogenesis in rats with ischaemic stroke by regulating X-linked inhibitor of apoptosis protein (XIAP). Middle cerebral artery occlusion (MCAO) models were established by suture-occluded method, and MCAO rats were then treated with miR-130a mimics/inhibitors or/and altered XIAP for detection of changes of rats' neurological function, nerve damage and angiogenesis in MCAO rats. The oxygen-glucose deprivation (OGD) cellular models were established and respectively treated to determine the roles of miR-130a and XIAP in neuronal viability and apoptosis. The expression levels of miR-130a and XIAP in brain tissues of MCAO rats and OGD-treated neurons were detected. The binding site between miR-130a and XIAP was verified by luciferase activity assay. MiR-130a was overexpressed while XIAP was down-regulated in MCAO rats and OGD-treated neurons. In animal models, suppressed miR-130a improved neurological function, alleviated nerve damage and increased new vessels in brain tissues of rats with MCAO. In cellular models, miR-130a inhibition promoted neuronal viability and suppressed apoptosis. Inhibited XIAP reversed the effect of inhibited miR-130a in both MCAO rats and OGD-treated neurons. XIAP was identified as a target of miR-130a. Our study reveals that miR-130a regulates neurological deficit and angiogenesis in rats with MCAO by targeting XIAP.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15732","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38260720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Superparamagnetic iron oxide nanoparticles (SPION) have been widely used in the diagnosis and treatment for cardiovascular diseases.1-6 Correspondingly, the myocardial tissue safety of SPION is becoming a bottleneck to seriously restrict its clinical translation. In recent years, in vitro and in vivo experiments have confirmed that SPION-induced oxidative stress of normal myocardium in mice, leading to myocardial cell injury, apoptosis or necrosis.7-9 More alarmingly, SPION applied to ischemic myocardium could accumulate in the target sites for a long time with high concentration,5,6,10 thereby probably further aggravating oxidative stress injury and cardiomyocytes death.11,12 So far, however, the specific molecular mechanism of cardiotoxicity of SPION remains unclear. Previous studies have reported that SPION-induced apoptosis of murine macrophage (J774) cells 13 and necrosis of human endothelial cells.14 SPION can selectively induce autophagy-mediated cell death of human cancer cells (A549).15 After SPION pre-treatment, H9C2 cardiomyocytes were exposed to acrolein or H2O2, leading to reactive oxygen species (ROS) dependent cell necrosis.7 Our in vitro experiment showed that SPION significantly increased oxidative stress damage to overactivate autophagy and endoplasmic reticulum stress, eventually resulting in cardiomyocyte apoptosis.12 Furthermore, SPION could elicit IL-1βrelease and pyroptosis in macrophages, especially with the octapod and plate morphology.16 Notably, it has been recently reported that sorafenib or cisplatin assembled into nano-devices containing SPION, which are phagocytized by tumour cells and degraded into free divalent iron to accelerate Fenton reaction, leading to the lipid peroxidation burst to promote ferroptosis of tumour cells.17,18 Taken together, SPION can induce apoptosis, necrosis, autophagy, pyroptosis or ferroptosis in vitro and in vivo studies. The discrepancy may be attributed to distinct cell types and experiments design. It has already been well documented that the toxicity of SPION is mainly due to its degradation and release of free iron to catalyse Fenton reaction, leading to oxidative stress by a large number of ROS generation.19,20 Then, what is the downstream molecular mechanism of SPION mediated cardiotoxicity? Ferroptosis is a novel form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides to lethal levels, which is morphologically, biochemically, and genetically distinct from apoptosis, necroptosis and autophagy.21 Recent studies found that ferroptosis is not only an important pathological mechanism in the case of circulating iron overload of hemochromatosis,22 but also a key molecular mechanism of cellular iron overload in doxorubicin (DOX) induced cardiomyopathy.23 DOX induced mitochondria iron overload by down-regulating ABCB8,24 a mitochondrial protein that facilitates iron export, to elicit lipid peroxidation and mitochondria dysfunction, eventually causi
{"title":"Superparamagnetic iron oxide nanoparticles promote ferroptosis of ischemic cardiomyocytes.","authors":"Hao Zheng, Jieyun You, Xiaobo Yao, Qizheng Lu, Wei Guo, Yunli Shen","doi":"10.1111/jcmm.15722","DOIUrl":"https://doi.org/10.1111/jcmm.15722","url":null,"abstract":"Superparamagnetic iron oxide nanoparticles (SPION) have been widely used in the diagnosis and treatment for cardiovascular diseases.1-6 Correspondingly, the myocardial tissue safety of SPION is becoming a bottleneck to seriously restrict its clinical translation. In recent years, in vitro and in vivo experiments have confirmed that SPION-induced oxidative stress of normal myocardium in mice, leading to myocardial cell injury, apoptosis or necrosis.7-9 More alarmingly, SPION applied to ischemic myocardium could accumulate in the target sites for a long time with high concentration,5,6,10 thereby probably further aggravating oxidative stress injury and cardiomyocytes death.11,12 So far, however, the specific molecular mechanism of cardiotoxicity of SPION remains unclear. Previous studies have reported that SPION-induced apoptosis of murine macrophage (J774) cells 13 and necrosis of human endothelial cells.14 SPION can selectively induce autophagy-mediated cell death of human cancer cells (A549).15 After SPION pre-treatment, H9C2 cardiomyocytes were exposed to acrolein or H2O2, leading to reactive oxygen species (ROS) dependent cell necrosis.7 Our in vitro experiment showed that SPION significantly increased oxidative stress damage to overactivate autophagy and endoplasmic reticulum stress, eventually resulting in cardiomyocyte apoptosis.12 Furthermore, SPION could elicit IL-1βrelease and pyroptosis in macrophages, especially with the octapod and plate morphology.16 Notably, it has been recently reported that sorafenib or cisplatin assembled into nano-devices containing SPION, which are phagocytized by tumour cells and degraded into free divalent iron to accelerate Fenton reaction, leading to the lipid peroxidation burst to promote ferroptosis of tumour cells.17,18 Taken together, SPION can induce apoptosis, necrosis, autophagy, pyroptosis or ferroptosis in vitro and in vivo studies. The discrepancy may be attributed to distinct cell types and experiments design. It has already been well documented that the toxicity of SPION is mainly due to its degradation and release of free iron to catalyse Fenton reaction, leading to oxidative stress by a large number of ROS generation.19,20 Then, what is the downstream molecular mechanism of SPION mediated cardiotoxicity? Ferroptosis is a novel form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides to lethal levels, which is morphologically, biochemically, and genetically distinct from apoptosis, necroptosis and autophagy.21 Recent studies found that ferroptosis is not only an important pathological mechanism in the case of circulating iron overload of hemochromatosis,22 but also a key molecular mechanism of cellular iron overload in doxorubicin (DOX) induced cardiomyopathy.23 DOX induced mitochondria iron overload by down-regulating ABCB8,24 a mitochondrial protein that facilitates iron export, to elicit lipid peroxidation and mitochondria dysfunction, eventually causi","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15722","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38251492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-09-01Epub Date: 2020-07-22DOI: 10.1111/jcmm.15662
Xiao Lei, Na Ma, Yanjie Liang, Junyan Liu, Pei Zhang, Yanan Han, Wei Chen, Lehui Du, Baolin Qu
Radiotherapy is one of the most important treatments for chest tumours. Although there are plenty of strategies to prevent damage to normal lung tissues, it cannot be avoided with the emergence of radiation-induced lung injury. The purpose of this study was to investigate the potential radioprotective effects of glucosamine, which exerted anti-inflammatory activity in joint inflammation. In this study, we found glucosamine relieved inflammatory response and structural damages in lung tissues after radiation via HE staining. Then, we detected the level of epithelial-mesenchymal transition marker in vitro and in vivo, which we could clearly observe that glucosamine treatment inhibited epithelial-mesenchymal transition. Besides, we found glucosamine could inhibit apoptosis and promote proliferation of normal lung epithelial cells in vitro caused by radiation. In conclusion, our data showed that glucosamine alleviated radiation-induced lung injury via inhibiting epithelial-mesenchymal transition, which indicated glucosamine could be a novel potential radioprotector for radiation-induced lung injury.
{"title":"Glucosamine protects against radiation-induced lung injury via inhibition of epithelial-mesenchymal transition.","authors":"Xiao Lei, Na Ma, Yanjie Liang, Junyan Liu, Pei Zhang, Yanan Han, Wei Chen, Lehui Du, Baolin Qu","doi":"10.1111/jcmm.15662","DOIUrl":"https://doi.org/10.1111/jcmm.15662","url":null,"abstract":"<p><p>Radiotherapy is one of the most important treatments for chest tumours. Although there are plenty of strategies to prevent damage to normal lung tissues, it cannot be avoided with the emergence of radiation-induced lung injury. The purpose of this study was to investigate the potential radioprotective effects of glucosamine, which exerted anti-inflammatory activity in joint inflammation. In this study, we found glucosamine relieved inflammatory response and structural damages in lung tissues after radiation via HE staining. Then, we detected the level of epithelial-mesenchymal transition marker in vitro and in vivo, which we could clearly observe that glucosamine treatment inhibited epithelial-mesenchymal transition. Besides, we found glucosamine could inhibit apoptosis and promote proliferation of normal lung epithelial cells in vitro caused by radiation. In conclusion, our data showed that glucosamine alleviated radiation-induced lung injury via inhibiting epithelial-mesenchymal transition, which indicated glucosamine could be a novel potential radioprotector for radiation-induced lung injury.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15662","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38183596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Traumatic nerve injuries have become a common clinical problem, and axon regeneration is a critical process in the successful functional recovery of the injured nervous system. In this study, we found that peripheral axotomy reduces PTEN expression in adult sensory neurons; however, it did not alter the expression level of PTEN in IB4-positive sensory neurons. Additionally, our results indicate that the artificial inhibition of PTEN markedly promotes adult sensory axon regeneration, including IB4-positive neuronal axon growth. Thus, our results provide strong evidence that PTEN is a prominent repressor of adult sensory axon regeneration, especially in IB4-positive neurons.
{"title":"Inhibition of PTEN activity promotes IB4-positive sensory neuronal axon growth.","authors":"Li-Yu Zhou, Feng Han, Shi-Bin Qi, Jin-Jin Ma, Yan-Xia Ma, Ji-Le Xie, Hong-Cheng Zhang, Xin-Ya Fu, Jian-Quan Chen, Bin Li, Hui-Lin Yang, Feng Zhou, Saijilafu","doi":"10.1111/jcmm.15648","DOIUrl":"https://doi.org/10.1111/jcmm.15648","url":null,"abstract":"<p><p>Traumatic nerve injuries have become a common clinical problem, and axon regeneration is a critical process in the successful functional recovery of the injured nervous system. In this study, we found that peripheral axotomy reduces PTEN expression in adult sensory neurons; however, it did not alter the expression level of PTEN in IB4-positive sensory neurons. Additionally, our results indicate that the artificial inhibition of PTEN markedly promotes adult sensory axon regeneration, including IB4-positive neuronal axon growth. Thus, our results provide strong evidence that PTEN is a prominent repressor of adult sensory axon regeneration, especially in IB4-positive neurons.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15648","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38220372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-09-01Epub Date: 2020-08-13DOI: 10.1111/jcmm.15730
Jessica Petiti, Marco Lo Iacono, Valentina Rosso, Giacomo Andreani, Aleksandar Jovanovski, Marina Podestà, Dorela Lame, Marco De Gobbi, Carmen Fava, Giuseppe Saglio, Francesco Frassoni, Daniela Cilloni
Myeloproliferative neoplasms are divided into essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Although ruxolitinib was proven to be effective in reducing symptoms, patients rarely achieve complete molecular remission. Therefore, it is relevant to identify new therapeutic targets to improve the clinical outcome of patients. Bcl-xL protein, the long isoform encoded by alternative splicing of the Bcl-x gene, acts as an anti-apoptotic regulator. Our study investigated the role of Bcl-xL as a marker of severity of MPN and the possibility to target Bcl-xL in patients. 129 MPN patients and 21 healthy patients were enrolled in the study. We analysed Bcl-xL expression in leucocytes and in enriched CD34+ and CD235a+ cells. Furthermore, ABT-737, a Bcl-xL inhibitor, was tested in HEL cells and in leucocytes from MPN patients. Bcl-xL was found progressively over-expressed in cells from ET, PV and PMF patients, independently by JAK2 mutational status. Moreover, our data indicated that the combination of ABT-737 and ruxolitinib resulted in a significantly higher apoptotic rate than the individual drug. Our study suggests that Bcl-xL plays an important role in MPN independently from JAK2 V617F mutation. Furthermore, data demonstrate that targeting simultaneously JAK2 and Bcl-xL might represent an interesting new approach.
{"title":"Bcl-xL represents a therapeutic target in Philadelphia negative myeloproliferative neoplasms.","authors":"Jessica Petiti, Marco Lo Iacono, Valentina Rosso, Giacomo Andreani, Aleksandar Jovanovski, Marina Podestà, Dorela Lame, Marco De Gobbi, Carmen Fava, Giuseppe Saglio, Francesco Frassoni, Daniela Cilloni","doi":"10.1111/jcmm.15730","DOIUrl":"https://doi.org/10.1111/jcmm.15730","url":null,"abstract":"<p><p>Myeloproliferative neoplasms are divided into essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Although ruxolitinib was proven to be effective in reducing symptoms, patients rarely achieve complete molecular remission. Therefore, it is relevant to identify new therapeutic targets to improve the clinical outcome of patients. Bcl-xL protein, the long isoform encoded by alternative splicing of the Bcl-x gene, acts as an anti-apoptotic regulator. Our study investigated the role of Bcl-xL as a marker of severity of MPN and the possibility to target Bcl-xL in patients. 129 MPN patients and 21 healthy patients were enrolled in the study. We analysed Bcl-xL expression in leucocytes and in enriched CD34+ and CD235a+ cells. Furthermore, ABT-737, a Bcl-xL inhibitor, was tested in HEL cells and in leucocytes from MPN patients. Bcl-xL was found progressively over-expressed in cells from ET, PV and PMF patients, independently by JAK2 mutational status. Moreover, our data indicated that the combination of ABT-737 and ruxolitinib resulted in a significantly higher apoptotic rate than the individual drug. Our study suggests that Bcl-xL plays an important role in MPN independently from JAK2 V617F mutation. Furthermore, data demonstrate that targeting simultaneously JAK2 and Bcl-xL might represent an interesting new approach.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15730","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38261031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The authors of the above paper are most grateful to Chris Ricketts of the Peninsula Medical School for alerting them to an error in their paper. The results of the variance component analysis (G-study) in Table 5 (p. 977) were slightly wrong because of a subsequent alteration in the raw data. The authors have provided the corrected results below in case other readers also attempt the analysis themselves and are disappointed to find that their results differ from those in the paper. Any reader who wishes to discuss the implications of this change for interpreting the data is welcome to contact the authors
{"title":"Corrigendum.","authors":"","doi":"10.1111/jcmm.15632","DOIUrl":"https://doi.org/10.1111/jcmm.15632","url":null,"abstract":"The authors of the above paper are most grateful to Chris Ricketts of the Peninsula Medical School for alerting them to an error in their paper. The results of the variance component analysis (G-study) in Table 5 (p. 977) were slightly wrong because of a subsequent alteration in the raw data. The authors have provided the corrected results below in case other readers also attempt the analysis themselves and are disappointed to find that their results differ from those in the paper. Any reader who wishes to discuss the implications of this change for interpreting the data is welcome to contact the authors","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15632","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38567093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-07-01Epub Date: 2020-05-23DOI: 10.1111/jcmm.15412
Xiaoliang Xu, Zechuan Zhang, Yijun Lu, Qikai Sun, Yang Liu, Qiaoyu Liu, Wenfang Tian, Yin Yin, Hailong Yu, Beicheng Sun
Hepatic ischaemia/reperfusion (I/R) injury is a major clinical problem during liver surgical procedures, which usually lead to early transplantation failure and higher organ rejection rate, and current effective therapeutic strategies are still limited. Therefore, in-depth exploring of the molecular mechanisms underlying liver I/R injury is key to the development of new therapeutic methods. β-arrestins are multifunctional proteins serving as important signalling scaffolds in numerous physiopathological processes, including liver-specific diseases. However, the role and underlying mechanism of β-arrestins in hepatic I/R injury remain largely unknown. Here, we showed that only ARRB1, but not ARRB2, was down-regulated during liver I/R injury. Hepatocyte-specific overexpression of ARRB1 significantly ameliorated liver damage, as demonstrated by decreases in serum aminotransferases, hepatocellular necrosis and apoptosis, infiltrating inflammatory cells and secretion of pro-inflammatory cytokines relative to control mice, whereas experiments with ARRB1 knockout mice gotten opposite effects. Mechanistically, ARRB1 directly interacts with ASK1 in hepatocytes and inhibits its TRAF6-mediated Lysine 6-linked polyubiquitination, which then prevents the activation of ASK1 and its downstream signalling pathway during hepatic I/R injury. In addition, inhibition of ASK1 remarkably abolished the disruptive effect result from ARRB1 deficiency in liver I/R injury in vivo, indicating that ASK1 was required for ARRB1 function in hepatic I/R injury. In conclusion, we proposed that ARRB1 is a novel protective regulator during liver I/R injury, and modulation of the regulatory axis between ARRB1 and ASK1 could be a novel therapeutic strategy to prevent this pathological process.
{"title":"ARRB1 ameliorates liver ischaemia/reperfusion injury via antagonizing TRAF6-mediated Lysine 6-linked polyubiquitination of ASK1 in hepatocytes.","authors":"Xiaoliang Xu, Zechuan Zhang, Yijun Lu, Qikai Sun, Yang Liu, Qiaoyu Liu, Wenfang Tian, Yin Yin, Hailong Yu, Beicheng Sun","doi":"10.1111/jcmm.15412","DOIUrl":"https://doi.org/10.1111/jcmm.15412","url":null,"abstract":"<p><p>Hepatic ischaemia/reperfusion (I/R) injury is a major clinical problem during liver surgical procedures, which usually lead to early transplantation failure and higher organ rejection rate, and current effective therapeutic strategies are still limited. Therefore, in-depth exploring of the molecular mechanisms underlying liver I/R injury is key to the development of new therapeutic methods. β-arrestins are multifunctional proteins serving as important signalling scaffolds in numerous physiopathological processes, including liver-specific diseases. However, the role and underlying mechanism of β-arrestins in hepatic I/R injury remain largely unknown. Here, we showed that only ARRB1, but not ARRB2, was down-regulated during liver I/R injury. Hepatocyte-specific overexpression of ARRB1 significantly ameliorated liver damage, as demonstrated by decreases in serum aminotransferases, hepatocellular necrosis and apoptosis, infiltrating inflammatory cells and secretion of pro-inflammatory cytokines relative to control mice, whereas experiments with ARRB1 knockout mice gotten opposite effects. Mechanistically, ARRB1 directly interacts with ASK1 in hepatocytes and inhibits its TRAF6-mediated Lysine 6-linked polyubiquitination, which then prevents the activation of ASK1 and its downstream signalling pathway during hepatic I/R injury. In addition, inhibition of ASK1 remarkably abolished the disruptive effect result from ARRB1 deficiency in liver I/R injury in vivo, indicating that ASK1 was required for ARRB1 function in hepatic I/R injury. In conclusion, we proposed that ARRB1 is a novel protective regulator during liver I/R injury, and modulation of the regulatory axis between ARRB1 and ASK1 could be a novel therapeutic strategy to prevent this pathological process.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15412","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37966754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-07-01Epub Date: 2020-05-26DOI: 10.1111/jcmm.15413
Bao Quoc Lam, Sushant K Shrivastava, Anju Shrivastava, Sharmila Shankar, Rakesh K Srivastava
The incidence of obesity and type 2 diabetes (T2DM) in the Western world has increased dramatically during the recent decades. According to the American Cancer Society, pancreatic cancer (PC) is the fourth leading cause of cancer-related death in the United States. The relationship among obesity, T2DM and PC is complex. Due to increase in obesity, diabetes, alcohol consumption and sedentary lifestyle, the mortality due to PC is expected to rise significantly by year 2040. The underlying mechanisms by which diabetes and obesity contribute to pancreatic tumorigenesis are not well understood. Furthermore, metabolism and microenvironment within the pancreas can also modulate pancreatic carcinogenesis. The risk of PC on a population level may be reduced by modifiable lifestyle risk factors. In this review, the interactions of diabetes and obesity to PC development were summarized, and novel strategies for the prevention and treatment of diabetes and PC were discussed.
{"title":"The Impact of obesity and diabetes mellitus on pancreatic cancer: Molecular mechanisms and clinical perspectives.","authors":"Bao Quoc Lam, Sushant K Shrivastava, Anju Shrivastava, Sharmila Shankar, Rakesh K Srivastava","doi":"10.1111/jcmm.15413","DOIUrl":"https://doi.org/10.1111/jcmm.15413","url":null,"abstract":"<p><p>The incidence of obesity and type 2 diabetes (T2DM) in the Western world has increased dramatically during the recent decades. According to the American Cancer Society, pancreatic cancer (PC) is the fourth leading cause of cancer-related death in the United States. The relationship among obesity, T2DM and PC is complex. Due to increase in obesity, diabetes, alcohol consumption and sedentary lifestyle, the mortality due to PC is expected to rise significantly by year 2040. The underlying mechanisms by which diabetes and obesity contribute to pancreatic tumorigenesis are not well understood. Furthermore, metabolism and microenvironment within the pancreas can also modulate pancreatic carcinogenesis. The risk of PC on a population level may be reduced by modifiable lifestyle risk factors. In this review, the interactions of diabetes and obesity to PC development were summarized, and novel strategies for the prevention and treatment of diabetes and PC were discussed.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15413","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37977822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}