Pub Date : 2020-11-01Epub Date: 2020-09-17DOI: 10.1111/jcmm.15871
Bo Wang, Zhuowang Ge, Yan Wu, Yafang Zha, Xuan Zhang, Yexiang Yan, Yuquan Xie
Endothelial-mesenchymal transition (EndMT) is a major source of transformed cardiac fibroblasts, which is reported to play a key role in cardiac fibrosis (CF), a pathogenesis of cardiovascular diseases such as heart failure, myocardial infarction and atrial fibrillation. Nonetheless, the specific mechanism underlying the progression of EndMT to CF is still largely unknown. In this study, we aimed to investigate the role of milk fat globule-EGF factor 8 (MFGE8), a kind of soluble glycoprotein, in TGF-β1-induced EndMT. In animal experiments, the expression of MFGE8 was found down-regulated in the left ventricle and aorta of rats after transverse aortic constriction (TAC) compared with the sham group, especially in endothelial cells (ECs). In in vitro cultured ECs, silencing MFGE8 with small interfering RNA (siRNA) was found to promote the process of TGF-β1-induced EndMT, whereas administration of recombinant human MFGE8 (rh-MFGE8) attenuated the process. Moreover, activated Smad2/3 signalling pathway after TGF-β1 treatment and EndMT-related transcription factors, such as Snail, Twist and Slug, was potentiated by MFGE8 knock-down but inhibited by rh-MFGE8. In conclusion, our experiments indicate that MFGE8 might play a protective role in TGF-β1-induced EndMT and might be a potential therapeutic target for cardiac fibrosis.
{"title":"MFGE8 is down-regulated in cardiac fibrosis and attenuates endothelial-mesenchymal transition through Smad2/3-Snail signalling pathway.","authors":"Bo Wang, Zhuowang Ge, Yan Wu, Yafang Zha, Xuan Zhang, Yexiang Yan, Yuquan Xie","doi":"10.1111/jcmm.15871","DOIUrl":"https://doi.org/10.1111/jcmm.15871","url":null,"abstract":"<p><p>Endothelial-mesenchymal transition (EndMT) is a major source of transformed cardiac fibroblasts, which is reported to play a key role in cardiac fibrosis (CF), a pathogenesis of cardiovascular diseases such as heart failure, myocardial infarction and atrial fibrillation. Nonetheless, the specific mechanism underlying the progression of EndMT to CF is still largely unknown. In this study, we aimed to investigate the role of milk fat globule-EGF factor 8 (MFGE8), a kind of soluble glycoprotein, in TGF-β1-induced EndMT. In animal experiments, the expression of MFGE8 was found down-regulated in the left ventricle and aorta of rats after transverse aortic constriction (TAC) compared with the sham group, especially in endothelial cells (ECs). In in vitro cultured ECs, silencing MFGE8 with small interfering RNA (siRNA) was found to promote the process of TGF-β1-induced EndMT, whereas administration of recombinant human MFGE8 (rh-MFGE8) attenuated the process. Moreover, activated Smad2/3 signalling pathway after TGF-β1 treatment and EndMT-related transcription factors, such as Snail, Twist and Slug, was potentiated by MFGE8 knock-down but inhibited by rh-MFGE8. In conclusion, our experiments indicate that MFGE8 might play a protective role in TGF-β1-induced EndMT and might be a potential therapeutic target for cardiac fibrosis.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15871","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38393706","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 : 2020-11-01Epub Date: 2020-09-22DOI: 10.1111/jcmm.15833
Lan Dong, Lu Zhang, Hua Liu, Meiting Xie, Jing Gao, Xiaoyan Zhou, Qinghong Zhao, Silin Zhang, Jing Yang
Endometriosis is considered a benign gynaecological disease with cancer-like characterizations, which has a high incidence among women of reproductive age. However, this disease has so far lacked timely diagnosis and effective treatment owing to its unclear aetiology. In this study, we identified aberrant high expression of circ_0007331 in ectopic endometrial cells by comparing the endometrial samples from patients with and without endometriosis. Further functional experiments revealed that circ_0007331 knock-down effectively suppressed the viability, proliferation and invasive capacity of ectopic endometrial cells. Additionally, we attempted to define the molecular mechanism of circ_0007331 in the initiation and progression of endometriosis. Circ_0007331 acted as a miRNA sponge for miR-200c-3p to indirectly regulate the function of HIF-1α, which plays a key role in the local angiogenesis and hypoxic mechanisms of ectopic endometrium. A final in vivo experiment confirmed that circ_0007331 knock-down could suppress the development of endometriosis through down-regulating the expression of HIF-1α. Collectively, we preliminarily characterized the role and possible insights of circ_0007331/miR-200c-3p/HIF-1α axis in the proliferation and invasion of ectopic endometrial cells. We hope that by exploring the potential function and molecular mechanism of circ_0007331, we can increase our biological insight into the pathogenesis of endometriosis, which will bring the new ways for the diagnosis and therapy of this disease.
{"title":"Circ_0007331 knock-down suppresses the progression of endometriosis via miR-200c-3p/HiF-1α axis.","authors":"Lan Dong, Lu Zhang, Hua Liu, Meiting Xie, Jing Gao, Xiaoyan Zhou, Qinghong Zhao, Silin Zhang, Jing Yang","doi":"10.1111/jcmm.15833","DOIUrl":"10.1111/jcmm.15833","url":null,"abstract":"<p><p>Endometriosis is considered a benign gynaecological disease with cancer-like characterizations, which has a high incidence among women of reproductive age. However, this disease has so far lacked timely diagnosis and effective treatment owing to its unclear aetiology. In this study, we identified aberrant high expression of circ_0007331 in ectopic endometrial cells by comparing the endometrial samples from patients with and without endometriosis. Further functional experiments revealed that circ_0007331 knock-down effectively suppressed the viability, proliferation and invasive capacity of ectopic endometrial cells. Additionally, we attempted to define the molecular mechanism of circ_0007331 in the initiation and progression of endometriosis. Circ_0007331 acted as a miRNA sponge for miR-200c-3p to indirectly regulate the function of HIF-1α, which plays a key role in the local angiogenesis and hypoxic mechanisms of ectopic endometrium. A final in vivo experiment confirmed that circ_0007331 knock-down could suppress the development of endometriosis through down-regulating the expression of HIF-1α. Collectively, we preliminarily characterized the role and possible insights of circ_0007331/miR-200c-3p/HIF-1α axis in the proliferation and invasion of ectopic endometrial cells. We hope that by exploring the potential function and molecular mechanism of circ_0007331, we can increase our biological insight into the pathogenesis of endometriosis, which will bring the new ways for the diagnosis and therapy of this disease.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38406789","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 : 2020-11-01Epub Date: 2020-09-28DOI: 10.1111/jcmm.15870
Kaihua Zhong, Shuxin Fan, Shujun Yao, Haibin Xu, Suping Bai
In this study, a new water and alkaline-soluble polysaccharide (ALP), with an average molecular weight of 6.63 × 104 Da, was successfully purified from the rhizomes of Atractylodes lancea. GC analysis demonstrated that ALP was a kind of glucan. The effect of the ALP on the interaction between E-selectin and sialyl Lewis X (sLex ) was examined in human osteosarcoma U-2 OS cells. It was obvious that the expression of sLex antigen on the surface of U-2 OS cells was visible under fluorescence microscopy. The addition of ALP (0.5, 1 and 2 mg/mL) resulted in a marked inhibition on the adhesion, migration and invasion of U-2 OS cells to human umbilical vein endothelial cells (HUVECs), which was achieved by the decreased sLex expression on U-2 OS cells. Additionally, the induction of apoptosis can be observed in U-2 OS cells following ALP treatment using TUNEL staining and Annexin V-FITC/PI double-staining analysis on flow cytometry. In conclusion, these results indicated that ALP exerted anti-metastatic activity towards osteosarcoma cells via inhibition of sLex /E-selectin binding, which suggested that ALP could be a potent agent for human osteosarcoma intervention.
本研究成功地从苍术根茎中分离得到了一种平均分子量为6.63 × 104 Da的水碱溶多糖(ALP)。GC分析表明ALP是葡聚糖的一种。在人骨肉瘤U-2 OS细胞中检测了ALP对e -选择素与唾液Lewis X (sLex)相互作用的影响。荧光显微镜下可见U-2 OS细胞表面有明显的sLex抗原表达。添加ALP(0.5、1和2 mg/mL)可显著抑制U-2 OS细胞对人脐静脉内皮细胞(HUVECs)的粘附、迁移和侵袭,这是通过降低U-2 OS细胞上sLex的表达实现的。流式细胞术TUNEL染色和Annexin V-FITC/PI双染色分析表明,ALP对U-2 OS细胞有诱导凋亡作用。综上所述,这些结果表明ALP通过抑制sLex / e -选择素的结合对骨肉瘤细胞具有抗转移活性,这表明ALP可能是一种有效的骨肉瘤干预药物。
{"title":"A Atractylodes lancea polysaccharide inhibits metastasis of human osteosarcoma U-2 OS cells by blocking sialyl Lewis X (sLe<sup>x</sup> )/E-selectin binding.","authors":"Kaihua Zhong, Shuxin Fan, Shujun Yao, Haibin Xu, Suping Bai","doi":"10.1111/jcmm.15870","DOIUrl":"https://doi.org/10.1111/jcmm.15870","url":null,"abstract":"<p><p>In this study, a new water and alkaline-soluble polysaccharide (ALP), with an average molecular weight of 6.63 × 10<sup>4</sup> Da, was successfully purified from the rhizomes of Atractylodes lancea. GC analysis demonstrated that ALP was a kind of glucan. The effect of the ALP on the interaction between E-selectin and sialyl Lewis X (sLe<sup>x</sup> ) was examined in human osteosarcoma U-2 OS cells. It was obvious that the expression of sLe<sup>x</sup> antigen on the surface of U-2 OS cells was visible under fluorescence microscopy. The addition of ALP (0.5, 1 and 2 mg/mL) resulted in a marked inhibition on the adhesion, migration and invasion of U-2 OS cells to human umbilical vein endothelial cells (HUVECs), which was achieved by the decreased sLe<sup>x</sup> expression on U-2 OS cells. Additionally, the induction of apoptosis can be observed in U-2 OS cells following ALP treatment using TUNEL staining and Annexin V-FITC/PI double-staining analysis on flow cytometry. In conclusion, these results indicated that ALP exerted anti-metastatic activity towards osteosarcoma cells via inhibition of sLe<sup>x</sup> /E-selectin binding, which suggested that ALP could be a potent agent for human osteosarcoma intervention.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15870","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38427305","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 : 2020-11-01Epub Date: 2020-10-06DOI: 10.1111/jcmm.15856
Junyi Gao, Mengyi Wang, Tong Li, Qiaofei Liu, Lei You, Quan Liao
CDHR5 has been reported to play key roles in carcinogenesis of various cancers, but its roles in pancreatic cancer have not been reported. The present study was designed to investigate its clinical value in pancreatic ductal adenocarcinoma (PDAC). Tissue microarray-based immunohistochemistry was performed to analyse the correlation between CDHR5 expression and clinical and pathological features of PDAC, as well as the CDHR5 expression during tumour progression. Cell function assays were performed to investigate CDHR5's effects on PDAC cells. Moreover, qRT-PCR was applied to investigate the expression of CDHR5 isoforms in PDAC cells. Expression of CDHR5 was higher on the membrane of PDAC cells. This high expression level was associated with shorter overall survival of PDAC patients and was identified as an independent prognostic factor for overall survival by multivariate Cox regression analysis. In addition, expression level of CDHR5 presented an increased trend in the occurrence and progression of PDAC. Cell experiment suggested that CDHR5 could notably promote invasion and migration of PDAC cells. Moreover, analysis of CDHR5 isoforms indicated CDHR5-L was the major isoform expressed in PDAC cell lines. CDHR5 appears to be a promising and novel prognostic factor for PDAC, and its promotion in PDAC metastasis might be ascribed to the isoform CDHR5-L.
{"title":"Up-regulation of CDHR5 expression promotes malignant phenotype of pancreatic ductal adenocarcinoma.","authors":"Junyi Gao, Mengyi Wang, Tong Li, Qiaofei Liu, Lei You, Quan Liao","doi":"10.1111/jcmm.15856","DOIUrl":"10.1111/jcmm.15856","url":null,"abstract":"<p><p>CDHR5 has been reported to play key roles in carcinogenesis of various cancers, but its roles in pancreatic cancer have not been reported. The present study was designed to investigate its clinical value in pancreatic ductal adenocarcinoma (PDAC). Tissue microarray-based immunohistochemistry was performed to analyse the correlation between CDHR5 expression and clinical and pathological features of PDAC, as well as the CDHR5 expression during tumour progression. Cell function assays were performed to investigate CDHR5's effects on PDAC cells. Moreover, qRT-PCR was applied to investigate the expression of CDHR5 isoforms in PDAC cells. Expression of CDHR5 was higher on the membrane of PDAC cells. This high expression level was associated with shorter overall survival of PDAC patients and was identified as an independent prognostic factor for overall survival by multivariate Cox regression analysis. In addition, expression level of CDHR5 presented an increased trend in the occurrence and progression of PDAC. Cell experiment suggested that CDHR5 could notably promote invasion and migration of PDAC cells. Moreover, analysis of CDHR5 isoforms indicated CDHR5-L was the major isoform expressed in PDAC cell lines. CDHR5 appears to be a promising and novel prognostic factor for PDAC, and its promotion in PDAC metastasis might be ascribed to the isoform CDHR5-L.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15856","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38462323","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 : 2020-11-01Epub Date: 2020-09-19DOI: 10.1111/jcmm.15791
Marcela Hortová-Kohoutková, Petra Lázničková, Kamila Bendíčková, Marco De Zuani, Ivana Andrejčinová, Veronika Tomášková, Pavel Suk, Vladimír Šrámek, Martin Helán, Jan Frič
Sepsis is characterized by dynamic changes of the immune system resulting in deregulated inflammation and failure of homoeostasis and can escalate to septic shock. Circulating monocytes and other innate immune cells are among the first ones to recognize and clear pathogens. Monocytes have an important role in sepsis and septic shock and have been studied as potential diagnostic markers. In total, forty-two patients with septic shock were recruited and blood samples obtained within first 12 hours of ICU admission. We showed that frequency of classical and intermediate monocytes assessed at the time of admission to the intensive care unit are significantly distinct in patients with septic shock who survived longer that five days from those who died. These parameters correlate significantly with differences in serum levels of inflammatory cytokines MCP-1, IL-6, IL-8, IL-10, and IL-18, and with the proportion of helper and cytotoxic T cells. The described changes in frequency of monocyte subsets and their activation status may predict short-term septic shock survival and help with fast identification of the group of vulnerable patients, who may profit from tailored therapy.
{"title":"Differences in monocyte subsets are associated with short-term survival in patients with septic shock.","authors":"Marcela Hortová-Kohoutková, Petra Lázničková, Kamila Bendíčková, Marco De Zuani, Ivana Andrejčinová, Veronika Tomášková, Pavel Suk, Vladimír Šrámek, Martin Helán, Jan Frič","doi":"10.1111/jcmm.15791","DOIUrl":"https://doi.org/10.1111/jcmm.15791","url":null,"abstract":"<p><p>Sepsis is characterized by dynamic changes of the immune system resulting in deregulated inflammation and failure of homoeostasis and can escalate to septic shock. Circulating monocytes and other innate immune cells are among the first ones to recognize and clear pathogens. Monocytes have an important role in sepsis and septic shock and have been studied as potential diagnostic markers. In total, forty-two patients with septic shock were recruited and blood samples obtained within first 12 hours of ICU admission. We showed that frequency of classical and intermediate monocytes assessed at the time of admission to the intensive care unit are significantly distinct in patients with septic shock who survived longer that five days from those who died. These parameters correlate significantly with differences in serum levels of inflammatory cytokines MCP-1, IL-6, IL-8, IL-10, and IL-18, and with the proportion of helper and cytotoxic T cells. The described changes in frequency of monocyte subsets and their activation status may predict short-term septic shock survival and help with fast identification of the group of vulnerable patients, who may profit from tailored therapy.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15791","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38493627","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 : 2020-11-01Epub Date: 2020-09-05DOI: 10.1111/jcmm.15798
Xiaofei Qu, Lei Cheng, Liqin Zhao, Lixin Qiu, Weijian Guo
The solute carrier family 52 member 3 (SLC52A3) gene encodes riboflavin transporter protein which is essential to maintain mitochondrial function in cells. In our research, we found that SLC52A3 rs13042395 C > T variation was significantly associated with poor survival in a 926 Chinese gastric cancer (GCa) patients cohort (CC/CT genotype versus TT genotype, HR = 0.57, 95%CI (0.40-0.82), log-rank P = 0.015). The SLC52A3 rs13042395 C > T change led to its increased mRNA expression according to expression quantitative trait loci analysis (P = 0.0029). In vitro, it was revealed that rs13042395 C allele had higher binding affinity to inhibitory transcription factor Meis homeobox 1 (MEIS1) compared with T allele, knock-down of MEIS1 could up-regulate SLC52A3, and overexpression of SLC52A3 contributed to the increased ability of proliferation, colony formation, migration and invasion in GCa cells. Subsequently, the bioinformatics analysis combined with experiments in vitro suggested that Gap junction protein alpha 1 (GJA1) was the downstream effector of SLC52A3, SLC52A3 may promote the GCa cells aggressiveness by down-regulating the GJA1 expression. Overall, SLC52A3 genetic variant rs13042395 C > T change was associated with poorer survival in Chinese GCa patients and increased SLC52A3 expression by interaction with MEIS1. SLC52A3 promoted the GCa cells aggressiveness by down-regulating the GJA1 expression.
溶质载体家族52成员3 (SLC52A3)基因编码核黄素转运蛋白,该蛋白对维持细胞线粒体功能至关重要。在我们的研究中,我们发现SLC52A3 rs13042395 C > T变异与926例中国胃癌(GCa)患者的不良生存率显著相关(CC/CT基因型与TT基因型,HR = 0.57, 95%CI (0.40-0.82), log-rank P = 0.015)。表达数量性状位点分析显示,SLC52A3 rs13042395 C > T的改变导致其mRNA表达量增加(P = 0.0029)。体外研究发现,与T等位基因相比,rs13042395 C等位基因对抑制转录因子Meis同源盒1 (MEIS1)具有更高的结合亲和力,敲低MEIS1可上调SLC52A3,过表达SLC52A3有助于提高GCa细胞的增殖、集落形成、迁移和侵袭能力。随后,生物信息学分析结合体外实验表明,缝隙连接蛋白α 1 (GJA1)是SLC52A3的下游效应蛋白,SLC52A3可能通过下调GJA1的表达来促进GCa细胞的侵袭性。总体而言,SLC52A3基因变异rs13042395 C > T改变与中国GCa患者较差的生存率相关,并通过与MEIS1相互作用增加SLC52A3的表达。SLC52A3通过下调GJA1的表达来促进GCa细胞的侵袭性。
{"title":"Functional variation of SLC52A3 rs13042395 predicts survival of Chinese gastric cancer patients.","authors":"Xiaofei Qu, Lei Cheng, Liqin Zhao, Lixin Qiu, Weijian Guo","doi":"10.1111/jcmm.15798","DOIUrl":"https://doi.org/10.1111/jcmm.15798","url":null,"abstract":"<p><p>The solute carrier family 52 member 3 (SLC52A3) gene encodes riboflavin transporter protein which is essential to maintain mitochondrial function in cells. In our research, we found that SLC52A3 rs13042395 C > T variation was significantly associated with poor survival in a 926 Chinese gastric cancer (GCa) patients cohort (CC/CT genotype versus TT genotype, HR = 0.57, 95%CI (0.40-0.82), log-rank P = 0.015). The SLC52A3 rs13042395 C > T change led to its increased mRNA expression according to expression quantitative trait loci analysis (P = 0.0029). In vitro, it was revealed that rs13042395 C allele had higher binding affinity to inhibitory transcription factor Meis homeobox 1 (MEIS1) compared with T allele, knock-down of MEIS1 could up-regulate SLC52A3, and overexpression of SLC52A3 contributed to the increased ability of proliferation, colony formation, migration and invasion in GCa cells. Subsequently, the bioinformatics analysis combined with experiments in vitro suggested that Gap junction protein alpha 1 (GJA1) was the downstream effector of SLC52A3, SLC52A3 may promote the GCa cells aggressiveness by down-regulating the GJA1 expression. Overall, SLC52A3 genetic variant rs13042395 C > T change was associated with poorer survival in Chinese GCa patients and increased SLC52A3 expression by interaction with MEIS1. SLC52A3 promoted the GCa cells aggressiveness by down-regulating the GJA1 expression.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15798","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38347551","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 : 2020-11-01Epub Date: 2020-10-15DOI: 10.1111/jcmm.15883
Évila Lopes Salles, Hesam Khodadadi, Abbas Jarrahi, Meenakshi Ahluwalia, Valdemar Antonio Paffaro, Vincenzo Costigliola, Jack C Yu, David C Hess, Krishnan M Dhandapani, Babak Baban
Considering lack of target-specific antiviral treatment and vaccination for COVID-19, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve COVID-19-infected patient outcomes. In a follow-up study to our recent findings indicating the potential of Cannabidiol (CBD) in the treatment of acute respiratory distress syndrome (ARDS), here we show for the first time that CBD may ameliorate the symptoms of ARDS through up-regulation of apelin, a peptide with significant role in the central and peripheral regulation of immunity, CNS, metabolic and cardiovascular system. By administering intranasal Poly (I:C), a synthetic viral dsRNA, while we were able to mimic the symptoms of ARDS in a murine model, interestingly, there was a significant decrease in the expression of apelin in both blood and lung tissues. CBD treatment was able to reverse the symptoms of ARDS towards a normal level. Importantly, CBD treatment increased the apelin expression significantly, suggesting a potential crosstalk between apelinergic system and CBD may be the therapeutic target in the treatment of inflammatory diseases such as COVID-19 and many other pathologic conditions.
{"title":"Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome.","authors":"Évila Lopes Salles, Hesam Khodadadi, Abbas Jarrahi, Meenakshi Ahluwalia, Valdemar Antonio Paffaro, Vincenzo Costigliola, Jack C Yu, David C Hess, Krishnan M Dhandapani, Babak Baban","doi":"10.1111/jcmm.15883","DOIUrl":"https://doi.org/10.1111/jcmm.15883","url":null,"abstract":"<p><p>Considering lack of target-specific antiviral treatment and vaccination for COVID-19, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve COVID-19-infected patient outcomes. In a follow-up study to our recent findings indicating the potential of Cannabidiol (CBD) in the treatment of acute respiratory distress syndrome (ARDS), here we show for the first time that CBD may ameliorate the symptoms of ARDS through up-regulation of apelin, a peptide with significant role in the central and peripheral regulation of immunity, CNS, metabolic and cardiovascular system. By administering intranasal Poly (I:C), a synthetic viral dsRNA, while we were able to mimic the symptoms of ARDS in a murine model, interestingly, there was a significant decrease in the expression of apelin in both blood and lung tissues. CBD treatment was able to reverse the symptoms of ARDS towards a normal level. Importantly, CBD treatment increased the apelin expression significantly, suggesting a potential crosstalk between apelinergic system and CBD may be the therapeutic target in the treatment of inflammatory diseases such as COVID-19 and many other pathologic conditions.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/jcmm.15883","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38491172","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: 2020-08-14DOI: 10.1111/jcmm.15729
Katarzyna Iżykowska, Karolina Rassek, Magdalena Żurawek, Karina Nowicka, Julia Paczkowska, Iwona Ziółkowska-Suchanek, Marta Podralska, Agnieszka Dzikiewicz-Krawczyk, Monika Joks, Karolina Olek-Hrab, Maciej Giefing, Grzegorz K Przybylski
Sézary syndrome (SS) is an aggressive form of cutaneous T-cell lymphoma (CTCL) characterized by the presence of circulating malignant CD4+ T cells (Sézary cells) with many complex changes in the genome, transcriptome and epigenome. Epigenetic dysregulation seems to have an important role in the development and progression of SS as it was shown that SS cells are characterized by widespread changes in DNA methylation. In this study, we show that the transmembrane protein coding gene TMEM244 is ectopically expressed in all SS patients and SS-derived cell lines and, to a lower extent, in mycosis fungoides and in a fraction of T-cell lymphomas, but not in B-cell malignancies and mononuclear cells of healthy individuals. We show that in patient samples and in the T-cell lines TMEM244 expression is negatively correlated with the methylation level of its promoter. Furthermore, we demonstrate that TMEM244 expression can be activated in vitro by the CRISPR-dCas9-induced specific demethylation of TMEM244 promoter region. Since both, TMEM244 expression and its promoter demethylation, are not detected in normal lymphoid cells, they can be potentially used as markers in Sézary syndrome and some other T-cell lymphomas.
{"title":"Hypomethylation of the promoter region drives ectopic expression of TMEM244 in Sézary cells.","authors":"Katarzyna Iżykowska, Karolina Rassek, Magdalena Żurawek, Karina Nowicka, Julia Paczkowska, Iwona Ziółkowska-Suchanek, Marta Podralska, Agnieszka Dzikiewicz-Krawczyk, Monika Joks, Karolina Olek-Hrab, Maciej Giefing, Grzegorz K Przybylski","doi":"10.1111/jcmm.15729","DOIUrl":"https://doi.org/10.1111/jcmm.15729","url":null,"abstract":"<p><p>Sézary syndrome (SS) is an aggressive form of cutaneous T-cell lymphoma (CTCL) characterized by the presence of circulating malignant CD4+ T cells (Sézary cells) with many complex changes in the genome, transcriptome and epigenome. Epigenetic dysregulation seems to have an important role in the development and progression of SS as it was shown that SS cells are characterized by widespread changes in DNA methylation. In this study, we show that the transmembrane protein coding gene TMEM244 is ectopically expressed in all SS patients and SS-derived cell lines and, to a lower extent, in mycosis fungoides and in a fraction of T-cell lymphomas, but not in B-cell malignancies and mononuclear cells of healthy individuals. We show that in patient samples and in the T-cell lines TMEM244 expression is negatively correlated with the methylation level of its promoter. Furthermore, we demonstrate that TMEM244 expression can be activated in vitro by the CRISPR-dCas9-induced specific demethylation of TMEM244 promoter region. Since both, TMEM244 expression and its promoter demethylation, are not detected in normal lymphoid cells, they can be potentially used as markers in Sézary syndrome and some other T-cell lymphomas.</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.15729","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38272552","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: 2020-08-14DOI: 10.1111/jcmm.15724
Rujia Miao, Yao Lu, Xue He, Xuelian Liu, Zhiheng Chen, Jiangang Wang
Ubiquitin-specific protease 19 (USP19) belongs to USP family and is involved in promoting skeletal muscle atrophy. Although USP19 is expressed in the heart, the role of USP19 in the heart disease remains unknown. The present study provides in vivo and in vitro data to reveal the role of USP19 in preventing pathological cardiac hypertrophy. We generated USP19-knockout mice and isolated neonatal rat cardiomyocytes (NRCMs) that overexpressed or were deficient in USP19 to investigate the effect of USP19 on transverse aortic constriction (TAC) or phenylephrine (PE)-mediated cardiac hypertrophy. Echocardiography, pathological and molecular analysis were used to determine the extent of cardiac hypertrophy, fibrosis, dysfunction and inflammation. USP19 expression was markedly increased in rodent hypertrophic heart or cardiomyocytes underwent TAC or PE culturing, the increase was mediated by the reduction of Seven In Absentia Homolog-2. The extent of TAC-induced cardiac hypertrophy, fibrosis, dysfunction and inflammation in USP19-knockout mice was exacerbated. Consistently, gain-of-function and loss-of-function approaches that involved USP19 in cardiomyocytes suggested that the down-regulation of USP19 promoted the hypertrophic phenotype, while the up-regulation of USP19 improved the worsened phenotype. Mechanistically, the USP19-elicited cardiac hypertrophy improvement was attributed to the abrogation of the transforming growth factor beta-activated kinase 1 (TAK1)-p38/JNK1/2 transduction. Furthermore, the inhibition of TAK1 abolished the aggravated hypertrophy induced by the loss of USP19. In conclusion, the present study revealed that USP19 and the downstream of TAK1-p38/JNK1/2 signalling pathway might be a potential target to attenuate pathological cardiac hypertrophy.
泛素特异性蛋白酶19 (USP19)属于USP家族,参与促进骨骼肌萎缩。虽然USP19在心脏中表达,但USP19在心脏病中的作用尚不清楚。本研究提供了体内和体外数据来揭示USP19在预防病理性心肌肥厚中的作用。我们制备了USP19敲除小鼠和分离的USP19过表达或缺乏的新生大鼠心肌细胞(NRCMs),以研究USP19对横断主动脉收缩(TAC)或苯肾上腺素(PE)介导的心脏肥厚的影响。采用超声心动图、病理和分子分析确定心肌肥大、纤维化、功能障碍和炎症的程度。USP19的表达在TAC或PE培养的肥厚心肌细胞中显著增加,其表达增加是由7 in Absentia homologous -2的减少介导的。在usp19基因敲除小鼠中,tac诱导的心肌肥厚、纤维化、功能障碍和炎症程度加重。同样,涉及心肌细胞USP19的功能获得和功能丧失方法表明,USP19的下调促进了肥厚表型,而USP19的上调改善了恶化的表型。从机制上讲,usp19诱导的心肌肥厚改善归因于转化生长因子β活化激酶1 (TAK1)-p38/JNK1/2转导的取消。此外,TAK1的抑制消除了USP19缺失引起的加重肥大。综上所述,本研究揭示USP19和TAK1-p38/JNK1/2信号通路下游可能是减轻病理性心肌肥厚的潜在靶点。
{"title":"Ubiquitin-specific protease 19 blunts pathological cardiac hypertrophy via inhibition of the TAK1-dependent pathway.","authors":"Rujia Miao, Yao Lu, Xue He, Xuelian Liu, Zhiheng Chen, Jiangang Wang","doi":"10.1111/jcmm.15724","DOIUrl":"https://doi.org/10.1111/jcmm.15724","url":null,"abstract":"<p><p>Ubiquitin-specific protease 19 (USP19) belongs to USP family and is involved in promoting skeletal muscle atrophy. Although USP19 is expressed in the heart, the role of USP19 in the heart disease remains unknown. The present study provides in vivo and in vitro data to reveal the role of USP19 in preventing pathological cardiac hypertrophy. We generated USP19-knockout mice and isolated neonatal rat cardiomyocytes (NRCMs) that overexpressed or were deficient in USP19 to investigate the effect of USP19 on transverse aortic constriction (TAC) or phenylephrine (PE)-mediated cardiac hypertrophy. Echocardiography, pathological and molecular analysis were used to determine the extent of cardiac hypertrophy, fibrosis, dysfunction and inflammation. USP19 expression was markedly increased in rodent hypertrophic heart or cardiomyocytes underwent TAC or PE culturing, the increase was mediated by the reduction of Seven In Absentia Homolog-2. The extent of TAC-induced cardiac hypertrophy, fibrosis, dysfunction and inflammation in USP19-knockout mice was exacerbated. Consistently, gain-of-function and loss-of-function approaches that involved USP19 in cardiomyocytes suggested that the down-regulation of USP19 promoted the hypertrophic phenotype, while the up-regulation of USP19 improved the worsened phenotype. Mechanistically, the USP19-elicited cardiac hypertrophy improvement was attributed to the abrogation of the transforming growth factor beta-activated kinase 1 (TAK1)-p38/JNK1/2 transduction. Furthermore, the inhibition of TAK1 abolished the aggravated hypertrophy induced by the loss of USP19. In conclusion, the present study revealed that USP19 and the downstream of TAK1-p38/JNK1/2 signalling pathway might be a potential target to attenuate pathological cardiac hypertrophy.</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.15724","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38266933","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: 2020-08-07DOI: 10.1111/jcmm.15727
Marinela Couselo-Seijas, José N Lopez-Canoa, Ángel L Fernandez, Laila González-Melchor, Luisa M Seoane, Darío Duran-Muñoz, Adriana Rozados-Luis, José Ramón González-Juanatey, Moisés Rodríguez-Mañero, Sonia Eiras
The modulation of acetylcholine (ACh) release by botulinum toxin injection into epicardial fat diminishes atrial fibrillation (AF) recurrence. These results suggest an interaction between autonomic imbalance and epicardial fat as risk factors of AF. Our aim was to study the inflammatory, lipidic and fibroblastic profile of epicardial stroma from patients who underwent open-heart surgery, their regulation by cholinergic activity and its association with AF. We performed in vitro and ex vivo assays from paired subcutaneous and epicardial stromal cells or explants from 33 patients. Acute ACh effects in inflammation and lipid-related genes were analysed by qPCR, in intracellular calcium mobilization were performed by Fluo-4 AM staining and in neutrophil migration by trans-well assays. Chronic ACh effects on lipid accumulation were visualized by AdipoRed. Plasma protein regulation by parasympathetic denervation was studied in vagotomized rats. Our results showed a higher pro-inflammatory profile in epicardial regarding subcutaneous stromal cells. Acute ACh treatment up-regulated monocyte chemoattractant protein 1 levels. Chronic ACh treatment improved lipid accumulation within epicardial stromal cells (60.50% [22.82-85.13] vs 13.85% [6.17-23.16], P < .001). Additionally, patients with AF had higher levels of fatty acid-binding protein 4 (1.54 ± 0.01 vs 1.47 ± 0.01, P = .005). Its plasma levels were pronouncedly declined in vagotomized rats (2.02 ± 0.21 ng/mL vs 0.65 ± 0.23 ng/mL, P < .001). Our findings support the characterization of acute or chronic cholinergic activity on epicardial stroma and its association with AF.
肉毒毒素注入心外膜脂肪对乙酰胆碱(ACh)释放的调节可减少房颤(AF)复发。这些结果表明,自主神经失衡和心外膜脂肪之间的相互作用是房颤的危险因素。我们的目的是研究接受心脏直视手术患者心外膜间质的炎症、脂质和成纤维细胞特征,胆碱能活性对它们的调节及其与房颤的关系。我们对33名患者的配对皮下和心外膜间质细胞或外植体进行了体外和体外实验。用qPCR分析急性乙酰胆碱对炎症和脂质相关基因的影响,用Fluo-4 AM染色分析细胞内钙动员,用trans-well法分析中性粒细胞迁移。通过AdipoRed观察慢性乙酰胆碱对脂质积累的影响。研究了迷走神经切除大鼠副交感神经去神经对血浆蛋白的调节。我们的研究结果显示,与皮下基质细胞相关的心外膜有较高的促炎谱。急性乙酰胆碱处理上调单核细胞趋化蛋白1水平。慢性乙酰胆碱治疗可改善心外膜间质细胞内脂质积累(60.50% [22.82 ~ 85.13]vs 13.85% [6.17 ~ 23.16], P
{"title":"Inflammatory and lipid regulation by cholinergic activity in epicardial stromal cells from patients who underwent open-heart surgery.","authors":"Marinela Couselo-Seijas, José N Lopez-Canoa, Ángel L Fernandez, Laila González-Melchor, Luisa M Seoane, Darío Duran-Muñoz, Adriana Rozados-Luis, José Ramón González-Juanatey, Moisés Rodríguez-Mañero, Sonia Eiras","doi":"10.1111/jcmm.15727","DOIUrl":"https://doi.org/10.1111/jcmm.15727","url":null,"abstract":"<p><p>The modulation of acetylcholine (ACh) release by botulinum toxin injection into epicardial fat diminishes atrial fibrillation (AF) recurrence. These results suggest an interaction between autonomic imbalance and epicardial fat as risk factors of AF. Our aim was to study the inflammatory, lipidic and fibroblastic profile of epicardial stroma from patients who underwent open-heart surgery, their regulation by cholinergic activity and its association with AF. We performed in vitro and ex vivo assays from paired subcutaneous and epicardial stromal cells or explants from 33 patients. Acute ACh effects in inflammation and lipid-related genes were analysed by qPCR, in intracellular calcium mobilization were performed by Fluo-4 AM staining and in neutrophil migration by trans-well assays. Chronic ACh effects on lipid accumulation were visualized by AdipoRed. Plasma protein regulation by parasympathetic denervation was studied in vagotomized rats. Our results showed a higher pro-inflammatory profile in epicardial regarding subcutaneous stromal cells. Acute ACh treatment up-regulated monocyte chemoattractant protein 1 levels. Chronic ACh treatment improved lipid accumulation within epicardial stromal cells (60.50% [22.82-85.13] vs 13.85% [6.17-23.16], P < .001). Additionally, patients with AF had higher levels of fatty acid-binding protein 4 (1.54 ± 0.01 vs 1.47 ± 0.01, P = .005). Its plasma levels were pronouncedly declined in vagotomized rats (2.02 ± 0.21 ng/mL vs 0.65 ± 0.23 ng/mL, P < .001). Our findings support the characterization of acute or chronic cholinergic activity on epicardial stroma and its association with AF.</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.15727","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38241399","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}