首页 > 最新文献

FASEB Journal最新文献

英文 中文
Spatially restricted ecto-5′-nucleotidase expression promotes the growth of uterine leiomyomas by modulating Akt activity 空间受限的外-5'-核苷酸酶表达通过调节 Akt 活性促进子宫肌瘤生长
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 DOI: 10.1096/fj.202401432R
Xiaofang Guo, Maja Okuka, Brittney Short, Asli Ozmen, Nihan Semerci Gunay, Jake Rymer, Burak Un, Ozlem Guzeloglu-Kayisli, Thomas J. Rutherford, Umit Kayisli, Matthew L. Anderson

Found in as many as 80% of women, uterine leiomyomas are a frequent cause of abnormal uterine bleeding, pelvic pain, and infertility. Despite their significant clinical impact, the mechanisms responsible for driving leiomyoma growth remain poorly understood. After obtaining IRB permission, expression of ecto-5′-nucleotidase (NT5E, CD73) was assessed in matched specimens of myometrium and leiomyoma by real-time qPCR, Western blot, and immunohistochemistry (IHC). Adenosine concentrations were measured by enzyme-linked assay. Primary cultures were used to assess the impact of adenosine and/or adenosine receptor agonists on proliferation, apoptosis, and patterns of intracellular signaling in vitro. When compared to matched specimens of healthy myometrium, uterine leiomyomas were characterized by reduced CD73 expression. Largely limited to thin-walled vascular structures and the pseudocapsule of leiomyomas despite diffuse myometrial distribution. Restricted intra-tumoral CD73 expression was accompanied by decreased levels of intra-tumoral adenosine. In vitro, incubation of primary leiomyoma cultures with adenosine or its hydrolysis-resistant analog 2-chloro-adenosine (2-CL-AD) inhibited proliferation, induced apoptosis, and reduced proportion of myocytes in S- and G2-M phases of the cell cycle. Decreased proliferation was accompanied by reduced expression of phospho-Akt, phospho-Cdk2-Tyr15, and phospho-Histone H3. Enforced expression of the A2B adenosine receptor (ADORA2B) and ADORA2B-selective agonists similarly suppressed proliferation and inhibited Akt phosphorylation. Collectively, these observations broadly implicate CD73 and reduced extracellular concentrations of adenosine as key regulators of leiomyoma growth and potentially identify novel strategies for clinically managing these common tumors.

多达 80% 的女性体内都存在子宫纵膈肌瘤,它是导致异常子宫出血、盆腔疼痛和不孕症的常见原因。尽管它们对临床有重大影响,但人们对驱动子宫肌瘤生长的机制仍然知之甚少。在获得 IRB 许可后,我们通过实时 qPCR、Western 印迹和免疫组织化学(IHC)评估了匹配的子宫肌层和子宫肌瘤标本中外向-5'-核苷酸酶(NT5E,CD73)的表达。腺苷浓度通过酶联检测法进行测量。使用原代培养物评估腺苷和/或腺苷受体激动剂对体外增殖、凋亡和细胞内信号转导模式的影响。与匹配的健康子宫肌瘤标本相比,子宫肌瘤的特点是 CD73 表达减少。尽管子宫肌瘤呈弥漫性分布,但主要局限于薄壁血管结构和假包膜。瘤内 CD73 表达受限的同时,瘤内腺苷水平降低。在体外,用腺苷或其抗水解类似物 2-氯腺苷(2-CL-AD)培养原发性子宫肌瘤可抑制增殖、诱导凋亡并降低细胞周期 S 期和 G2-M 期的肌细胞比例。伴随增殖减少的是磷酸-Akt、磷酸-Cdk2-Tyr15 和磷酸组蛋白 H3 表达的减少。A2B腺苷受体(ADORA2B)的强制表达和ADORA2B选择性激动剂同样抑制了增殖并抑制了Akt磷酸化。总之,这些观察结果广泛表明,CD73和腺苷细胞外浓度的降低是子宫肌瘤生长的关键调节因素,并有可能为临床治疗这些常见肿瘤找到新的策略。
{"title":"Spatially restricted ecto-5′-nucleotidase expression promotes the growth of uterine leiomyomas by modulating Akt activity","authors":"Xiaofang Guo,&nbsp;Maja Okuka,&nbsp;Brittney Short,&nbsp;Asli Ozmen,&nbsp;Nihan Semerci Gunay,&nbsp;Jake Rymer,&nbsp;Burak Un,&nbsp;Ozlem Guzeloglu-Kayisli,&nbsp;Thomas J. Rutherford,&nbsp;Umit Kayisli,&nbsp;Matthew L. Anderson","doi":"10.1096/fj.202401432R","DOIUrl":"10.1096/fj.202401432R","url":null,"abstract":"<p>Found in as many as 80% of women, uterine leiomyomas are a frequent cause of abnormal uterine bleeding, pelvic pain, and infertility. Despite their significant clinical impact, the mechanisms responsible for driving leiomyoma growth remain poorly understood. After obtaining IRB permission, expression of ecto-5′-nucleotidase (<i>NT5E,</i> CD73<i>)</i> was assessed in matched specimens of myometrium and leiomyoma by real-time qPCR, Western blot, and immunohistochemistry (IHC). Adenosine concentrations were measured by enzyme-linked assay. Primary cultures were used to assess the impact of adenosine and/or adenosine receptor agonists on proliferation, apoptosis, and patterns of intracellular signaling in vitro. When compared to matched specimens of healthy myometrium, uterine leiomyomas were characterized by reduced CD73 expression. Largely limited to thin-walled vascular structures and the pseudocapsule of leiomyomas despite diffuse myometrial distribution. Restricted intra-tumoral CD73 expression was accompanied by decreased levels of intra-tumoral adenosine. In vitro, incubation of primary leiomyoma cultures with adenosine or its hydrolysis-resistant analog 2-chloro-adenosine (2-CL-AD) inhibited proliferation, induced apoptosis, and reduced proportion of myocytes in S- and G2-M phases of the cell cycle. Decreased proliferation was accompanied by reduced expression of phospho-Akt, phospho-Cdk2-Tyr15, and phospho-Histone H3. Enforced expression of the A2B adenosine receptor (ADORA2B) and ADORA2B-selective agonists similarly suppressed proliferation and inhibited Akt phosphorylation. Collectively, these observations broadly implicate CD73 and reduced extracellular concentrations of adenosine as key regulators of leiomyoma growth and potentially identify novel strategies for clinically managing these common tumors.</p>","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exosomal let-7b-5p deriving from parietal epithelial cells attenuate renal fibrosis through suppression of TGFβR1 and ARID3a in obstructive kidney disease 来自顶叶上皮细胞的外泌体let-7b-5p通过抑制TGFβR1和ARID3a减轻梗阻性肾病患者的肾脏纤维化。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-01 DOI: 10.1096/fj.202400802RR
Ahui Song, Minzhou Wang, Kewei Xie, Jiayue Lu, Bingru Zhao, Wangshu Wu, Cheng Qian, Wenkai Hong, Leyi Gu

As renal progenitor cells, parietal epithelial cells (PECs) have demonstrated multilineage differentiation potential in response to kidney injury. However, the function of exosomes derived from PECs has not been extensively explored. Immunofluorescent staining of Claudin-1 was used to identify primary PECs isolated from mouse glomeruli. Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of PECs-derived exosomes (PEC-Exo). The therapeutic role of PEC-Exo in tubulointerstitial fibrosis was investigated in the unilateral ureteral obstruction (UUO) mouse model and TGF-β1-stimulated HK-2 cells. High-throughput miRNA sequencing was employed to profile PEC-Exo miRNAs. One of the most enriched miRNAs in PEC-Exo was knocked down by transfecting miRNA inhibitor, and then we investigated whether this candidate miRNA was involved in PEC-Exo-mediated tubular repair. The primary PECs expressed Claudin-1, PEC-Exo was homing to obstructed kidney, and TGF-β1 induced HK-2 cells. PEC-Exo significantly alleviated renal inflammation and ameliorated tubular fibrosis both in vivo and in vitro. Mechanistically, let-7b-5p, highly enriched in PEC-Exo, downregulated the protein levels of transforming growth factor beta receptor 1(TGFβR1) and AT-Rich Interaction Domain 3A(ARID3a) in tubular epithelial cells (TECs), leading to the inhibition of p21 and p27 to restoring cell cycle. Furthermore, administration of let-7b-5p agomir mitigated renal fibrosis in vivo. Our findings demonstrated that PEC-derived exosomes significantly repressed the expression of TGFβR1 and ARID3a by delivering let-7b-5p, thereby alleviating renal fibrosis. This study provides novel insights into the role of PEC-Exo in the repair of kidney injury and new ideas for renal fibrosis intervention.

作为肾脏祖细胞,顶叶上皮细胞(PECs)在应对肾脏损伤时具有多线分化潜力。然而,人们尚未广泛探究从顶叶上皮细胞提取的外泌体的功能。研究人员利用Claudin-1的免疫荧光染色来识别从小鼠肾小球中分离出来的原发性PECs。透射电子显微镜、纳米颗粒追踪分析和免疫印迹法被用来描述 PECs 衍生的外泌体(PEC-Exo)的特性。在单侧输尿管梗阻(UUO)小鼠模型和TGF-β1刺激的HK-2细胞中研究了PEC-Exo在输尿管间质纤维化中的治疗作用。研究人员采用高通量 miRNA 测序技术分析了 PEC-Exo miRNAs。通过转染 miRNA 抑制剂,我们敲除了 PEC-Exo 中含量最高的一种 miRNA,然后研究了这种候选 miRNA 是否参与了 PEC-Exo 介导的肾小管修复。原代PECs表达Claudin-1,PEC-Exo向梗阻肾脏归巢,TGF-β1诱导HK-2细胞。PEC-Exo 在体内和体外都能明显缓解肾脏炎症并改善肾小管纤维化。从机理上讲,PEC-Exo中高度富集的let-7b-5p可下调肾小管上皮细胞(TECs)中转化生长因子β受体1(TGFβR1)和AT-Rich Interaction Domain 3A(ARID3a)的蛋白水平,从而抑制p21和p27,恢复细胞周期。此外,服用 let-7b-5p 激动剂可减轻体内肾脏纤维化。我们的研究结果表明,PEC衍生的外泌体通过递送let-7b-5p,显著抑制了TGFβR1和ARID3a的表达,从而缓解了肾脏纤维化。这项研究为PEC外泌体在肾损伤修复中的作用提供了新的见解,也为肾纤维化干预提供了新的思路。
{"title":"Exosomal let-7b-5p deriving from parietal epithelial cells attenuate renal fibrosis through suppression of TGFβR1 and ARID3a in obstructive kidney disease","authors":"Ahui Song,&nbsp;Minzhou Wang,&nbsp;Kewei Xie,&nbsp;Jiayue Lu,&nbsp;Bingru Zhao,&nbsp;Wangshu Wu,&nbsp;Cheng Qian,&nbsp;Wenkai Hong,&nbsp;Leyi Gu","doi":"10.1096/fj.202400802RR","DOIUrl":"10.1096/fj.202400802RR","url":null,"abstract":"<p>As renal progenitor cells, parietal epithelial cells (PECs) have demonstrated multilineage differentiation potential in response to kidney injury. However, the function of exosomes derived from PECs has not been extensively explored. Immunofluorescent staining of Claudin-1 was used to identify primary PECs isolated from mouse glomeruli. Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of PECs-derived exosomes (PEC-Exo). The therapeutic role of PEC-Exo in tubulointerstitial fibrosis was investigated in the unilateral ureteral obstruction (UUO) mouse model and TGF-β1-stimulated HK-2 cells. High-throughput miRNA sequencing was employed to profile PEC-Exo miRNAs. One of the most enriched miRNAs in PEC-Exo was knocked down by transfecting miRNA inhibitor, and then we investigated whether this candidate miRNA was involved in PEC-Exo-mediated tubular repair. The primary PECs expressed Claudin-1, PEC-Exo was homing to obstructed kidney, and TGF-β1 induced HK-2 cells. PEC-Exo significantly alleviated renal inflammation and ameliorated tubular fibrosis both in vivo and in vitro. Mechanistically, let-7b-5p, highly enriched in PEC-Exo, downregulated the protein levels of transforming growth factor beta receptor 1(TGFβR1) and AT-Rich Interaction Domain 3A(ARID3a) in tubular epithelial cells (TECs), leading to the inhibition of p21 and p27 to restoring cell cycle. Furthermore, administration of let-7b-5p agomir mitigated renal fibrosis in vivo. Our findings demonstrated that PEC-derived exosomes significantly repressed the expression of TGFβR1 and ARID3a by delivering let-7b-5p, thereby alleviating renal fibrosis. This study provides novel insights into the role of PEC-Exo in the repair of kidney injury and new ideas for renal fibrosis intervention.</p>","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Effects of unilateral nasal obstruction on mandibular condyle in mice of different ages: An exploration based on H-type angiogenesis coupling osteogenesis 单侧鼻阻塞对不同年龄小鼠下颌骨髁状突的影响:基于H型血管生成耦合成骨的探索
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-30 DOI: 10.1096/fj.202401273R
Yun Hu, Hegang Li

Nasal obstruction leads to a hypoxia condition throughout the entire body. In this study, the unilateral nasal obstruction (UNO) mouse model was established by blocking the left nostril of mice. The aim of this study was to investigate the effects of UNO-induced hypoxia on mandibular condyle in juvenile (3-week-old), adolescent (6-week-old) and adult (12-week-old) male C57BL/6J mice from the perspective of H-type angiogenesis coupling osteogenesis. Firstly, UNO exerted a significant inhibitory effect on weight gain in mice of all ages. However, only in adolescent mice did UNO have an obvious detrimental effect on femoral bone mass accrual. Subsequently, micro-computed tomography (CT) analysis of mandibular condylar bone mass revealed that UNO significantly retarded condylar head volume gain but increased condylar head trabecular number (Tb.N) in juvenile and adolescent mice. Furthermore, UNO promoted the ratio of proliferative layer to cartilage layer in condylar cartilage and facilitated the chondrocyte-to-osteoblast transformation in juvenile and adolescent mice. Moreover, although UNO enhanced the positive expression of hypoxia-inducible factor (HIF)-1α in the condylar subchondral bone of mice in all ages, an increase in H-type vessels and Osterix+ cells was only detected in juvenile and adolescent mice. In summary, on the one hand, in terms of condylar morphology, UNO has a negative effect on condylar growth, hindering the increase in condylar head volume in juvenile and adolescent mice. However, on the other hand, in terms of condylar microstructure, UNO has a positive effect on condylar osteogenesis, promoting the increase of condylar Tb.N, chondrocyte-to-osteoblast transformation, HIF-1α expression, H-type angiogenesis and Osterix+ cells in juvenile and adolescent mice. Although the changes in condylar morphology and microstructure caused by UNO have not yet been fully elucidated, these findings improve our current understanding of the effects of UNO on condylar bone homeostasis.

鼻阻塞会导致全身缺氧。本研究通过阻塞小鼠的左鼻孔建立了单侧鼻阻塞(UNO)小鼠模型。本研究的目的是从H型血管生成耦联成骨的角度研究UNO诱导的缺氧对幼年(3周龄)、青少年(6周龄)和成年(12周龄)雄性C57BL/6J小鼠下颌骨髁状突的影响。首先,UNO 对各年龄段小鼠的体重增加都有显著的抑制作用。然而,只有在青春期小鼠中,UNO 才对股骨骨量的增加有明显的不利影响。随后,对下颌骨髁状突骨质进行的显微计算机断层扫描(CT)分析表明,在幼年和青春期小鼠中,UNO明显延缓了髁状突头体积的增加,但增加了髁状突头骨小梁数量(Tb.N)。此外,UNO 还能提高髁状突软骨中增殖层与软骨层的比例,促进幼年和青春期小鼠软骨细胞向成骨细胞的转化。此外,虽然 UNO 增强了各年龄段小鼠髁突软骨下骨中缺氧诱导因子(HIF)-1α 的阳性表达,但只有在幼年和青春期小鼠中才能检测到 H 型血管和 Osterix+ 细胞的增加。总之,一方面,在髁状突形态方面,UNO 对髁状突的生长有负面影响,阻碍了幼年和青春期小鼠髁状突头体积的增加。但另一方面,在髁状突微结构方面,UNO 对髁状突的成骨具有积极作用,可促进幼年和青春期小鼠髁状突 Tb.N、软骨细胞向成骨细胞转化、HIF-1α 表达、H 型血管生成和 Osterix+ 细胞的增加。尽管 UNO 引起的髁状突形态和微观结构的变化尚未完全阐明,但这些发现提高了我们目前对 UNO 对髁状突骨稳态影响的认识。
{"title":"Effects of unilateral nasal obstruction on mandibular condyle in mice of different ages: An exploration based on H-type angiogenesis coupling osteogenesis","authors":"Yun Hu,&nbsp;Hegang Li","doi":"10.1096/fj.202401273R","DOIUrl":"10.1096/fj.202401273R","url":null,"abstract":"<p>Nasal obstruction leads to a hypoxia condition throughout the entire body. In this study, the unilateral nasal obstruction (UNO) mouse model was established by blocking the left nostril of mice. The aim of this study was to investigate the effects of UNO-induced hypoxia on mandibular condyle in juvenile (3-week-old), adolescent (6-week-old) and adult (12-week-old) male C57BL/6J mice from the perspective of H-type angiogenesis coupling osteogenesis. Firstly, UNO exerted a significant inhibitory effect on weight gain in mice of all ages. However, only in adolescent mice did UNO have an obvious detrimental effect on femoral bone mass accrual. Subsequently, micro-computed tomography (CT) analysis of mandibular condylar bone mass revealed that UNO significantly retarded condylar head volume gain but increased condylar head trabecular number (Tb.N) in juvenile and adolescent mice. Furthermore, UNO promoted the ratio of proliferative layer to cartilage layer in condylar cartilage and facilitated the chondrocyte-to-osteoblast transformation in juvenile and adolescent mice. Moreover, although UNO enhanced the positive expression of hypoxia-inducible factor (HIF)-1α in the condylar subchondral bone of mice in all ages, an increase in H-type vessels and Osterix<sup>+</sup> cells was only detected in juvenile and adolescent mice. In summary, on the one hand, in terms of condylar morphology, UNO has a negative effect on condylar growth, hindering the increase in condylar head volume in juvenile and adolescent mice. However, on the other hand, in terms of condylar microstructure, UNO has a positive effect on condylar osteogenesis, promoting the increase of condylar Tb.N, chondrocyte-to-osteoblast transformation, HIF-1α expression, H-type angiogenesis and Osterix<sup>+</sup> cells in juvenile and adolescent mice. Although the changes in condylar morphology and microstructure caused by UNO have not yet been fully elucidated, these findings improve our current understanding of the effects of UNO on condylar bone homeostasis.</p>","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Jawbone periosteum-derived cells with high osteogenic potential controlled by R-spondin 3 由 R-spondin 3 控制的具有高成骨细胞潜能的颌骨骨膜衍生细胞。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-28 DOI: 10.1096/fj.202400988RR
Shu Zhang, Jingxian Zhu, Siyu Jin, Wei Sun, Wei Ji, Zhi Chen

The jawbone periosteum, the easily accessible tissue responding to bone repair, has been overlooked in the recent development of cell therapy for jawbone defect reconstruction. Therefore, this study aimed to elucidate the in vitro and in vivo biological characteristics of jawbone periosteum-derived cells (jb-PDCs). For this purpose, we harvested the jb-PDCs from 8-week-old C57BL/6 mice. The in vitro cultured jb-PDCs (passages 1 and 3) contained skeletal stem/progenitor cells and exhibited clonogenicity and tri-lineage differentiation capacity. When implanted in vivo, the jb-PDCs (passage 3) showed evident ectopic bone formation after 4-week subcutaneous implantation, and active contribution to repair the critical-size jawbone defects in mice. Molecular profiling suggested that R-spondin 3 was strongly associated with the superior in vitro and in vivo osteogenic potentials of jb-PDCs. Overall, our study highlights the significance of comprehending the biological characteristics of the jawbone periosteum, which could pave the way for innovative cell-based therapies for the reconstruction of jawbone defects.

颚骨骨膜是易于获取的骨修复组织,但在近年来用于颚骨缺损重建的细胞疗法发展中却被忽视了。因此,本研究旨在阐明颌骨骨膜衍生细胞(jb-PDCs)的体外和体内生物学特性。为此,我们从8周大的C57BL/6小鼠身上采集了jb-PDCs。体外培养的jb-PDCs(第1和第3传代)含有骨骼干细胞/祖细胞,具有克隆性和三系分化能力。在体内植入时,jb-PDCs(第 3 代)在皮下植入 4 周后显示出明显的异位骨形成,并对修复小鼠临界大小的颌骨缺损做出了积极贡献。分子分析表明,R-spondin 3 与 jb-PDCs 的体外和体内成骨潜能密切相关。总之,我们的研究强调了了解颌骨骨膜生物学特性的重要性,这将为重建颌骨缺损的创新细胞疗法铺平道路。
{"title":"Jawbone periosteum-derived cells with high osteogenic potential controlled by R-spondin 3","authors":"Shu Zhang,&nbsp;Jingxian Zhu,&nbsp;Siyu Jin,&nbsp;Wei Sun,&nbsp;Wei Ji,&nbsp;Zhi Chen","doi":"10.1096/fj.202400988RR","DOIUrl":"10.1096/fj.202400988RR","url":null,"abstract":"<p>The jawbone periosteum, the easily accessible tissue responding to bone repair, has been overlooked in the recent development of cell therapy for jawbone defect reconstruction. Therefore, this study aimed to elucidate the in vitro and in vivo biological characteristics of jawbone periosteum-derived cells (jb-PDCs). For this purpose, we harvested the jb-PDCs from 8-week-old C57BL/6 mice. The in vitro cultured jb-PDCs (passages 1 and 3) contained skeletal stem/progenitor cells and exhibited clonogenicity and tri-lineage differentiation capacity. When implanted in vivo, the jb-PDCs (passage 3) showed evident ectopic bone formation after 4-week subcutaneous implantation, and active contribution to repair the critical-size jawbone defects in mice. Molecular profiling suggested that <i>R-spondin 3</i> was strongly associated with the superior in vitro and in vivo osteogenic potentials of jb-PDCs. Overall, our study highlights the significance of comprehending the biological characteristics of the jawbone periosteum, which could pave the way for innovative cell-based therapies for the reconstruction of jawbone defects.</p>","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Understanding the relationship between inflammation, apoptosis, and diabetes osteoporosis: A bioinformatics approach and experimental verification 了解炎症、细胞凋亡与糖尿病骨质疏松症之间的关系:生物信息学方法与实验验证。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-28 DOI: 10.1096/fj.202401452R
Jun Quan Li, Bo Li, Zhang Qing Fei, Shan Shan Lei

Diabetes osteoporosis (DOP) is a chronic metabolic bone disease. This study aimed to identify potential biomarkers of DOP and explore their underlying mechanisms through bioinformatics methods and experimental verification. Bioinformatics methods were used to identify differentially expressed genes (DEGs) for DOP based on GEO data and the GeneCards database. GO and KEGG enrichment analyses were used to search the key pathways. The STRING website was used to construct a protein–protein interaction (PPI) network and identify key genes. Then, 50 mg/mL glucose was used to interveneosteoblasts (OBs).CCK-8 and Alizarin Red staining were used to investigate the proliferation and differentiation changes in OBs. Flowcytometry was used to investigate apoptosis. The membrane protein chip, WB, and RT-PCR were used to verify the expression of key targets or pathways about DOP. Forty-two common genes were screened between DOP-related targets and DEGs. GO and KEGG enrichment analysis showed that DOP was mainly associated with cytokine-cytokine receptor interactions, and apoptosis. PPI network analysis showed that TNF, IL1A, IL6, IL1B, IL2RA, Fas ligand (FASLG), and Fas cell surface death receptor (FAS) were key up-regulated genes in the occurrence of DOP. The experiment results show that 50 mg/mL glucose significantly inhibited OBs proliferation but presented an increase in apoptosis. Membrane protein chip, WB, and RT-PCR-verified a significantly active in the expression of TNF/FASLG/FAS pathway. High glucose activated the TNF-α/FAS/FASLG pathway and induced the inflammatory microenvironment and apoptosis, then impaired osteogenic differentiation of OBs. These may be an important mechanism for the occurrence and development of DOP.

糖尿病骨质疏松症(DOP)是一种慢性代谢性骨病。本研究旨在通过生物信息学方法和实验验证,确定 DOP 的潜在生物标志物并探索其潜在机制。基于 GEO 数据和 GeneCards 数据库,采用生物信息学方法鉴定 DOP 的差异表达基因(DEGs)。GO和KEGG富集分析用于搜索关键通路。STRING 网站用于构建蛋白质-蛋白质相互作用(PPI)网络并识别关键基因。然后,用50毫克/毫升葡萄糖干预成骨细胞(OBs),用CCK-8和茜素红染色研究OBs的增殖和分化变化。流式细胞仪用于研究细胞凋亡。膜蛋白芯片、WB和RT-PCR用于验证DOP关键靶点或通路的表达。在DOP相关靶点和DEGs之间筛选出42个共同基因。GO和KEGG富集分析表明,DOP主要与细胞因子-细胞因子受体相互作用和细胞凋亡有关。PPI网络分析显示,TNF、IL1A、IL6、IL1B、IL2RA、Fas配体(FASLG)和Fas细胞表面死亡受体(FAS)是发生DOP的关键上调基因。实验结果表明,50 毫克/毫升葡萄糖可明显抑制 OBs 增殖,但凋亡增加。膜蛋白芯片、WB和RT-PCR验证了TNF/FASLG/FAS通路的表达明显活跃。高糖激活了TNF-α/FAS/FASLG通路,诱导了炎症微环境和细胞凋亡,进而损害了OB的成骨分化。这些可能是DOP发生和发展的重要机制。
{"title":"Understanding the relationship between inflammation, apoptosis, and diabetes osteoporosis: A bioinformatics approach and experimental verification","authors":"Jun Quan Li,&nbsp;Bo Li,&nbsp;Zhang Qing Fei,&nbsp;Shan Shan Lei","doi":"10.1096/fj.202401452R","DOIUrl":"10.1096/fj.202401452R","url":null,"abstract":"<p>Diabetes osteoporosis (DOP) is a chronic metabolic bone disease. This study aimed to identify potential biomarkers of DOP and explore their underlying mechanisms through bioinformatics methods and experimental verification. Bioinformatics methods were used to identify differentially expressed genes (DEGs) for DOP based on GEO data and the GeneCards database. GO and KEGG enrichment analyses were used to search the key pathways. The STRING website was used to construct a protein–protein interaction (PPI) network and identify key genes. Then, 50 mg/mL glucose was used to interveneosteoblasts (OBs).CCK-8 and Alizarin Red staining were used to investigate the proliferation and differentiation changes in OBs. Flowcytometry was used to investigate apoptosis. The membrane protein chip, WB, and RT-PCR were used to verify the expression of key targets or pathways about DOP. Forty-two common genes were screened between DOP-related targets and DEGs. GO and KEGG enrichment analysis showed that DOP was mainly associated with cytokine-cytokine receptor interactions, and apoptosis. PPI network analysis showed that TNF, IL1A, IL6, IL1B, IL2RA, Fas ligand (FASLG), and Fas cell surface death receptor (FAS) were key up-regulated genes in the occurrence of DOP. The experiment results show that 50 mg/mL glucose significantly inhibited OBs proliferation but presented an increase in apoptosis. Membrane protein chip, WB, and RT-PCR-verified a significantly active in the expression of TNF/FASLG/FAS pathway. High glucose activated the TNF-α/FAS/FASLG pathway and induced the inflammatory microenvironment and apoptosis, then impaired osteogenic differentiation of OBs. These may be an important mechanism for the occurrence and development of DOP.</p>","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
White matter hyperintensity genetic risk factor TRIM47 regulates autophagy in brain endothelial cells 白质高密度遗传风险因子TRIM47调节脑内皮细胞的自噬作用
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-27 DOI: 10.1096/fj.202400689RR
Sunny Hoi-Sang Yeung, Ralph Hon-Sun Lee, Gerald Wai-Yeung Cheng, Iris Wai-Ting Ma, Julia Kofler, Candice Kent, Fulin Ma, Karl Herrup, Myriam Fornage, Ken Arai, Kai-Hei Tse

White matter hyperintensity (WMH) is strongly correlated with age-related dementia and hypertension, but its pathogenesis remains obscure. Genome-wide association studies identified TRIM47 at the 17q25 locus as a top genetic risk factor for WMH formation. TRIM family is a class of E3 ubiquitin ligase with pivotal functions in autophagy, which is critical for brain endothelial cell (ECs) remodeling during hypertension. We hypothesize that TRIM47 regulates autophagy and its loss-of-function disturbs cerebrovasculature. Based on transcriptomics and immunohistochemistry, TRIM47 is found highly expressed by brain ECs in human and mouse, and its transcription is upregulated by artificially induced autophagy while downregulated in hypertension-like conditions. Using in silico simulation, immunocytochemistry and super-resolution microscopy, we predicted a highly conserved binding site between TRIM47 and the LIR (LC3-interacting region) motif of LC3B. Importantly, pharmacological autophagy induction increased Trim47 expression on mouse ECs (b.End3) culture, while silencing Trim47 significantly increased autophagy with ULK1 phosphorylation induction, transcription, and vacuole formation. Together, we demonstrate that TRIM47 is an endogenous inhibitor of autophagy in brain ECs, and such TRIM47-mediated regulation connects genetic and physiological risk factors for WMH formation but warrants further investigation.

白质高密度(WMH)与老年痴呆症和高血压密切相关,但其发病机制仍不清楚。全基因组关联研究发现,17q25位点上的TRIM47是WMH形成的首要遗传风险因素。TRIM家族是一类E3泛素连接酶,在自噬中具有关键功能,而自噬对高血压期间脑内皮细胞(ECs)的重塑至关重要。我们假设TRIM47调控自噬,其功能缺失会扰乱脑血管。基于转录组学和免疫组化,我们发现TRIM47在人和小鼠的脑EC中高表达,其转录在人工诱导的自噬作用下上调,而在类似高血压的条件下下调。利用硅模拟、免疫细胞化学和超分辨率显微镜,我们预测了 TRIM47 与 LC3B 的 LIR(LC3-interacting region,LC3-相互作用区)基团之间的高度保守结合位点。重要的是,药理自噬诱导增加了 Trim47 在小鼠 ECs(b.End3)培养上的表达,而沉默 Trim47 则显著增加了自噬与 ULK1 磷酸化诱导、转录和空泡形成。总之,我们证明了 TRIM47 是脑 EC 中自噬的内源性抑制剂,这种 TRIM47 介导的调控连接了 WMH 形成的遗传和生理风险因素,但值得进一步研究。
{"title":"White matter hyperintensity genetic risk factor TRIM47 regulates autophagy in brain endothelial cells","authors":"Sunny Hoi-Sang Yeung,&nbsp;Ralph Hon-Sun Lee,&nbsp;Gerald Wai-Yeung Cheng,&nbsp;Iris Wai-Ting Ma,&nbsp;Julia Kofler,&nbsp;Candice Kent,&nbsp;Fulin Ma,&nbsp;Karl Herrup,&nbsp;Myriam Fornage,&nbsp;Ken Arai,&nbsp;Kai-Hei Tse","doi":"10.1096/fj.202400689RR","DOIUrl":"10.1096/fj.202400689RR","url":null,"abstract":"<p>White matter hyperintensity (WMH) is strongly correlated with age-related dementia and hypertension, but its pathogenesis remains obscure. Genome-wide association studies identified TRIM47 at the 17q25 locus as a top genetic risk factor for WMH formation. TRIM family is a class of E3 ubiquitin ligase with pivotal functions in autophagy, which is critical for brain endothelial cell (ECs) remodeling during hypertension. We hypothesize that TRIM47 regulates autophagy and its loss-of-function disturbs cerebrovasculature. Based on transcriptomics and immunohistochemistry, TRIM47 is found highly expressed by brain ECs in human and mouse, and its transcription is upregulated by artificially induced autophagy while downregulated in hypertension-like conditions. Using in silico simulation, immunocytochemistry and super-resolution microscopy, we predicted a highly conserved binding site between TRIM47 and the LIR (LC3-interacting region) motif of LC3B. Importantly, pharmacological autophagy induction increased Trim47 expression on mouse ECs (b.End3) culture, while silencing <i>Trim47</i> significantly increased autophagy with ULK1 phosphorylation induction, transcription, and vacuole formation. Together, we demonstrate that TRIM47 is an endogenous inhibitor of autophagy in brain ECs, and such TRIM47-mediated regulation connects genetic and physiological risk factors for WMH formation but warrants further investigation.</p>","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202400689RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Homocysteine metabolites impair the PHF8/H4K20me1/mTOR/autophagy pathway by upregulating the expression of histone demethylase PHF8-targeting microRNAs in human vascular endothelial cells and mice 高半胱氨酸代谢物通过上调人血管内皮细胞和小鼠体内组蛋白去甲基化酶 PHF8 靶向 microRNA 的表达,损害 PHF8/H4K20me1/mTOR/ 自噬通路
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-26 DOI: 10.1096/fj.202302116R
Łukasz Witucki, Hieronim Jakubowski

The inability to efficiently metabolize homocysteine (Hcy) due to nutritional and genetic deficiencies, leads to hyperhomocysteinemia (HHcy) and endothelial dysfunction, a hallmark of atherosclerosis which underpins cardiovascular disease (CVD). PHF8 is a histone demethylase that demethylates H4K20me1, which affects the mammalian target of rapamycin (mTOR) signaling and autophagy, processes that play important roles in CVD. PHF8 is regulated by microRNA (miR) such as miR-22-3p and miR-1229-3p. Biochemically, HHcy is characterized by elevated levels of Hcy, Hcy-thiolactone and N-Hcy-protein. Here, we examined the effects of these metabolites on miR-22-3p, miR-1229-3p, and their target PHF8, as well as on the downstream consequences of these effects on H4K20me1, mTOR-, and autophagy-related proteins and mRNAs expression in human umbilical vein endothelial cells (HUVEC). We found that treatments with N-Hcy-protein, Hcy-thiolactone, or Hcy upregulated miR-22-3p and miR-1229-3p, attenuated PHF8 expression, upregulated H4K20me1, mTOR, and phospho-mTOR. Autophagy-related proteins (BECN1, ATG5, ATG7, lipidated LC3-II, and LC3-II/LC3-I ratio) were significantly downregulated by at least one of these metabolites. We also found similar changes in the expression of miR-22-3p, Phf8, mTOR- and autophagy-related proteins/mRNAs in vivo in hearts of Cbs−/− mice, which show severe HHcy and endothelial dysfunction. Treatments with inhibitors of miR-22-3p or miR-1229-3p abrogated the effects of Hcy-thiolactone, N-Hcy-protein, and Hcy on miR expression and on PHF8, H4K20me1, mTOR-, and autophagy-related proteins/mRNAs in HUVEC. Taken together, these findings show that Hcy metabolites upregulate miR-22-3p and miR-1229-3p expression, which then dysregulate the PHF8/H4K20me1/mTOR/autophagy pathway, important for vascular homeostasis.

由于营养和遗传缺陷而无法有效代谢同型半胱氨酸(Hcy),会导致高同型半胱氨酸血症(HHcy)和内皮功能障碍,这是动脉粥样硬化的标志,也是心血管疾病(CVD)的基础。PHF8 是一种组蛋白去甲基化酶,能使 H4K20me1 去甲基化,从而影响雷帕霉素哺乳动物靶标(mTOR)信号传导和自噬,这些过程在心血管疾病中发挥着重要作用。PHF8 受 microRNA(miR)如 miR-22-3p 和 miR-1229-3p 的调控。从生物化学角度看,HHcy 的特征是 Hcy、Hcy-硫内酯和 N-Hcy-蛋白水平升高。在此,我们研究了这些代谢物对 miR-22-3p、miR-1229-3p 及其靶标 PHF8 的影响,以及这些影响对人脐静脉内皮细胞(HUVEC)中 H4K20me1、mTOR 和自噬相关蛋白及 mRNA 表达的下游影响。我们发现,N-Hcy-蛋白、Hcy-硫内酯或 Hcy 会上调 miR-22-3p 和 miR-1229-3p,减弱 PHF8 的表达,上调 H4K20me1、mTOR 和磷酸化-mTOR。自噬相关蛋白(BECN1、ATG5、ATG7、脂化 LC3-II、LC3-II/LC3-I 比率)至少被其中一种代谢物显著下调。我们还发现,在 Cbs-/- 小鼠的体内,miR-22-3p、Phf8、mTOR 和自噬相关蛋白/mRNA 的表达也发生了类似的变化,这些小鼠表现出严重的 HHcy 和内皮功能障碍。用 miR-22-3p 或 miR-1229-3p 抑制剂处理 HUVEC,可减弱 Hcy-硫内酯、N-Hcy-蛋白和 Hcy 对 miR 表达以及 PHF8、H4K20me1、mTOR 和自噬相关蛋白/mRNA 的影响。综上所述,这些研究结果表明,Hcy 代谢物会上调 miR-22-3p 和 miR-1229-3p 的表达,进而导致对血管稳态非常重要的 PHF8/H4K20me1/mTOR/ 自噬通路失调。
{"title":"Homocysteine metabolites impair the PHF8/H4K20me1/mTOR/autophagy pathway by upregulating the expression of histone demethylase PHF8-targeting microRNAs in human vascular endothelial cells and mice","authors":"Łukasz Witucki,&nbsp;Hieronim Jakubowski","doi":"10.1096/fj.202302116R","DOIUrl":"https://doi.org/10.1096/fj.202302116R","url":null,"abstract":"<p>The inability to efficiently metabolize homocysteine (Hcy) due to nutritional and genetic deficiencies, leads to hyperhomocysteinemia (HHcy) and endothelial dysfunction, a hallmark of atherosclerosis which underpins cardiovascular disease (CVD). PHF8 is a histone demethylase that demethylates H4K20me1, which affects the mammalian target of rapamycin (mTOR) signaling and autophagy, processes that play important roles in CVD. PHF8 is regulated by microRNA (miR) such as miR-22-3p and miR-1229-3p. Biochemically, HHcy is characterized by elevated levels of Hcy, Hcy-thiolactone and <i>N</i>-Hcy-protein. Here, we examined the effects of these metabolites on miR-22-3p, miR-1229-3p, and their target PHF8, as well as on the downstream consequences of these effects on H4K20me1, mTOR-, and autophagy-related proteins and mRNAs expression in human umbilical vein endothelial cells (HUVEC). We found that treatments with <i>N</i>-Hcy-protein, Hcy-thiolactone, or Hcy upregulated miR-22-3p and miR-1229-3p, attenuated PHF8 expression, upregulated H4K20me1, mTOR, and phospho-mTOR. Autophagy-related proteins (BECN1, ATG5, ATG7, lipidated LC3-II, and LC3-II/LC3-I ratio) were significantly downregulated by at least one of these metabolites. We also found similar changes in the expression of miR-22-3p, Phf8, mTOR- and autophagy-related proteins/mRNAs in vivo in hearts of <i>Cbs</i><sup>−/−</sup> mice, which show severe HHcy and endothelial dysfunction. Treatments with inhibitors of miR-22-3p or miR-1229-3p abrogated the effects of Hcy-thiolactone, <i>N</i>-Hcy-protein, and Hcy on miR expression and on PHF8, H4K20me1, mTOR-, and autophagy-related proteins/mRNAs in HUVEC. Taken together, these findings show that Hcy metabolites upregulate miR-22-3p and miR-1229-3p expression, which then dysregulate the PHF8/H4K20me1/mTOR/autophagy pathway, important for vascular homeostasis.</p>","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202302116R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Resolvin D2/GPR18 signaling enhances monocytic myeloid-derived suppressor cell function to mitigate abdominal aortic aneurysm formation Resolvin D2/GPR18 信号传导可增强单核细胞髓源性抑制细胞的功能,从而缓解腹主动脉瘤的形成
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-25 DOI: 10.1096/fj.202400414RRR
Paolo Bellotti, Zachary Ladd, Victoria Leroy, Gang Su, Shiven Sharma, Joseph B. Hartman, Jonathan Krebs, Chelsea Viscardi, Robert Maile, Lyle L. Moldawer, Phillip A. Efron, Ashish K. Sharma, Gilbert R. Upchurch Jr.

Abdominal aortic aneurysm (AAA) formation is a chronic vascular pathology characterized by inflammation, leukocyte infiltration, and vascular remodeling. The aim of this study was to delineate the protective role of Resolvin D2 (RvD2), a bioactive isoform of specialized pro-resolving lipid mediators, via G-protein-coupled receptor 18 (GPR18) receptor signaling in attenuating AAAs. Importantly, RvD2 and GPR18 levels were significantly decreased in aortic tissue of AAA patients compared with controls. Furthermore, using an established murine model of AAA in C57BL/6 (WT) mice, we observed that treatment with RvD2 significantly attenuated aortic diameter, pro-inflammatory cytokine production, immune cell infiltration (neutrophils and macrophages), elastic fiber disruption, and increased smooth muscle cell α-actin expression as well as increased TGF-β2 and IL-10 expressions compared to untreated mice. Moreover, the RvD2-mediated protection from vascular remodeling and AAA formation was blocked when mice were previously treated with siRNA for GPR18 signifying the importance of RvD2/GPR18 signaling in vascular inflammation. Mechanistically, RvD2-mediated protection significantly enhanced infiltration and activation of monocytic myeloid-derived suppressor cells (M-MDSCs) by increasing TGF-β2 and IL-10 secretions in a GPR18-dependent manner to attenuate aortic inflammation and vascular remodeling. Collectively, this study demonstrates that RvD2 treatment induces an expansion of myeloid-lineage committed progenitors, such as M-MDSCs, activates GPR18-dependent signaling to enhance TGF-β2 and IL-10 secretion, and mitigates SMC activation that contributes to resolution of aortic inflammation and remodeling during AAA formation.

腹主动脉瘤(AAA)的形成是一种以炎症、白细胞浸润和血管重塑为特征的慢性血管病理学。本研究的目的是通过 G 蛋白偶联受体 18(GPR18)受体信号转导,确定 Resolvin D2(RvD2)的保护作用,RvD2 是一种生物活性异构体,专门促进脂质介质的溶解。重要的是,与对照组相比,AAA 患者主动脉组织中的 RvD2 和 GPR18 水平明显下降。此外,利用已建立的 C57BL/6(WT)小鼠 AAA 模型,我们观察到与未治疗的小鼠相比,用 RvD2 治疗可明显减小主动脉直径、促炎细胞因子的产生、免疫细胞浸润(中性粒细胞和巨噬细胞)、弹性纤维破坏、平滑肌细胞 α-actin 表达的增加以及 TGF-β2 和 IL-10 表达的增加。此外,当小鼠之前用GPR18的siRNA处理时,RvD2-介导的保护血管重塑和AAA形成的作用被阻断,这表明RvD2/GPR18信号在血管炎症中的重要性。从机理上讲,RvD2 介导的保护通过增加 TGF-β2 和 IL-10 的分泌,以 GPR18 依赖性的方式显著增强了单核细胞髓源性抑制细胞(M-MDSCs)的浸润和活化,从而减轻了主动脉炎症和血管重塑。总之,这项研究表明,RvD2 治疗可诱导髓系祖细胞(如 M-MDSCs)扩增,激活 GPR18 依赖性信号传导以增强 TGF-β2 和 IL-10 的分泌,并减轻 SMC 的活化,从而有助于解决 AAA 形成过程中的主动脉炎症和重塑问题。
{"title":"Resolvin D2/GPR18 signaling enhances monocytic myeloid-derived suppressor cell function to mitigate abdominal aortic aneurysm formation","authors":"Paolo Bellotti,&nbsp;Zachary Ladd,&nbsp;Victoria Leroy,&nbsp;Gang Su,&nbsp;Shiven Sharma,&nbsp;Joseph B. Hartman,&nbsp;Jonathan Krebs,&nbsp;Chelsea Viscardi,&nbsp;Robert Maile,&nbsp;Lyle L. Moldawer,&nbsp;Phillip A. Efron,&nbsp;Ashish K. Sharma,&nbsp;Gilbert R. Upchurch Jr.","doi":"10.1096/fj.202400414RRR","DOIUrl":"https://doi.org/10.1096/fj.202400414RRR","url":null,"abstract":"<p>Abdominal aortic aneurysm (AAA) formation is a chronic vascular pathology characterized by inflammation, leukocyte infiltration, and vascular remodeling. The aim of this study was to delineate the protective role of Resolvin D2 (RvD2), a bioactive isoform of specialized pro-resolving lipid mediators, via G-protein-coupled receptor 18 (GPR18) receptor signaling in attenuating AAAs. Importantly, RvD2 and GPR18 levels were significantly decreased in aortic tissue of AAA patients compared with controls. Furthermore, using an established murine model of AAA in C57BL/6 (WT) mice, we observed that treatment with RvD2 significantly attenuated aortic diameter, pro-inflammatory cytokine production, immune cell infiltration (neutrophils and macrophages), elastic fiber disruption, and increased smooth muscle cell α-actin expression as well as increased TGF-β2 and IL-10 expressions compared to untreated mice. Moreover, the RvD2-mediated protection from vascular remodeling and AAA formation was blocked when mice were previously treated with siRNA for GPR18 signifying the importance of RvD2/GPR18 signaling in vascular inflammation. Mechanistically, RvD2-mediated protection significantly enhanced infiltration and activation of monocytic myeloid-derived suppressor cells (M-MDSCs) by increasing TGF-β2 and IL-10 secretions in a GPR18-dependent manner to attenuate aortic inflammation and vascular remodeling. Collectively, this study demonstrates that RvD2 treatment induces an expansion of myeloid-lineage committed progenitors, such as M-MDSCs, activates GPR18-dependent signaling to enhance TGF-β2 and IL-10 secretion, and mitigates SMC activation that contributes to resolution of aortic inflammation and remodeling during AAA formation.</p>","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
UA influences the progression of breast cancer via the AhR/p27Kip1/cyclin E pathway UA 通过 AhR/p27Kip1/cyclin E 通路影响乳腺癌的进展
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-25 DOI: 10.1096/fj.202400938R
Zhiying Wang, Yuanqi Zhang, Shengchao Huang, Zhihong Liao, Mingzhang Huang, Wei Lei, Xiaorong Shui

Uric acid (UA) is the end product of purine metabolism. In recent years, UA has been found to be associated with the prognosis of clinical cancer patients. However, the intricate mechanisms by which UA affects the development and prognosis of tumor patients has not been well elucidated. In this study, we explored the role of UA in breast cancer, scrutinizing its impact on breast cancer cell function by treating two types of breast cancer cell lines with UA. The role of UA in the cell cycle and proliferation of tumors and the underlying mechanisms were further investigated. We found that the antioxidant effect of UA facilitated the scavenging of reactive oxygen species (ROS) in breast cancer, thereby reducing aryl hydrocarbon receptor (AhR) expression and affecting the breast cancer cell cycle, driving the proliferation of breast cancer cells through the AhR/p27Kip1/cyclin E1 pathway. Moreover, in breast cancer patients, the expression of AhR and its downstream genes may be closely associated with cancer progression in patients. Therefore, an increase in UA could promote the proliferation of breast cancer cells through the AhR/p27Kip1/cyclin E1 pathway axis.

尿酸(UA)是嘌呤代谢的最终产物。近年来,人们发现尿酸与临床癌症患者的预后有关。然而,尿酸影响肿瘤患者病情发展和预后的复杂机制尚未得到很好的阐明。在这项研究中,我们探讨了 UA 在乳腺癌中的作用,通过用 UA 处理两种乳腺癌细胞系,仔细研究其对乳腺癌细胞功能的影响。我们还进一步研究了 UA 在肿瘤细胞周期和增殖中的作用及其内在机制。我们发现,UA的抗氧化作用有利于清除乳腺癌细胞中的活性氧(ROS),从而降低芳香烃受体(AhR)的表达,影响乳腺癌细胞周期,通过AhR/p27Kip1/细胞周期蛋白E1途径驱动乳腺癌细胞增殖。此外,在乳腺癌患者中,AhR 及其下游基因的表达可能与患者的癌症进展密切相关。因此,UA 的增加可通过 AhR/p27Kip1/cyclin E1 通路轴促进乳腺癌细胞的增殖。
{"title":"UA influences the progression of breast cancer via the AhR/p27Kip1/cyclin E pathway","authors":"Zhiying Wang,&nbsp;Yuanqi Zhang,&nbsp;Shengchao Huang,&nbsp;Zhihong Liao,&nbsp;Mingzhang Huang,&nbsp;Wei Lei,&nbsp;Xiaorong Shui","doi":"10.1096/fj.202400938R","DOIUrl":"https://doi.org/10.1096/fj.202400938R","url":null,"abstract":"<p>Uric acid (UA) is the end product of purine metabolism. In recent years, UA has been found to be associated with the prognosis of clinical cancer patients. However, the intricate mechanisms by which UA affects the development and prognosis of tumor patients has not been well elucidated. In this study, we explored the role of UA in breast cancer, scrutinizing its impact on breast cancer cell function by treating two types of breast cancer cell lines with UA. The role of UA in the cell cycle and proliferation of tumors and the underlying mechanisms were further investigated. We found that the antioxidant effect of UA facilitated the scavenging of reactive oxygen species (ROS) in breast cancer, thereby reducing aryl hydrocarbon receptor (AhR) expression and affecting the breast cancer cell cycle, driving the proliferation of breast cancer cells through the AhR/p27<sup>Kip1</sup>/cyclin E1 pathway. Moreover, in breast cancer patients, the expression of AhR and its downstream genes may be closely associated with cancer progression in patients. Therefore, an increase in UA could promote the proliferation of breast cancer cells through the AhR/p27<sup>Kip1</sup>/cyclin E1 pathway axis.</p>","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202400938R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Electrochemical impedance spectroscopy unmasks high-risk atherosclerotic features in human coronary artery disease 电化学阻抗谱分析揭示了人类冠状动脉疾病的高风险动脉粥样硬化特征。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-24 DOI: 10.1096/fj.202401200R
Michael Chen, Krit Suwannaphoom, Yas Sanaiha, Yuan Luo, Peyman Benharash, Michael C. Fishbein, René R. Sevag Packard

Coronary plaque rupture remains the prominent mechanism of myocardial infarction. Accurate identification of rupture-prone plaque may improve clinical management. This study assessed the discriminatory performance of electrochemical impedance spectroscopy (EIS) in human cardiac explants to detect high-risk atherosclerotic features that portend rupture risk. In this single-center, prospective study, n = 26 cardiac explants were collected for EIS interrogation of the three major coronary arteries. Vessels in which advancement of the EIS catheter without iatrogenic plaque disruption was rendered impossible were not assessed. N = 61 vessels underwent EIS measurement and histological analyses. Plaques were dichotomized according to previously established high rupture-risk parameter thresholds. Diagnostic performance was determined via receiver operating characteristic areas-under-the-curve (AUC). Necrotic cores were identified in n = 19 vessels (median area 1.53 mm2) with a median fibrous cap thickness of 62 μm. Impedance was significantly greater in plaques with necrotic core area ≥1.75 mm2 versus <1.75 mm2 (19.8 ± 4.4 kΩ vs. 7.2 ± 1.0 kΩ, p = .019), fibrous cap thickness ≤65 μm versus >65 μm (19.1 ± 3.5 kΩ vs. 6.5 ± 0.9 kΩ, p = .004), and ≥20 macrophages per 0.3 mm-diameter high-power field (HPF) versus <20 macrophages per HPF (19.8 ± 4.1 kΩ vs. 10.2 ± 0.9 kΩ, p = .002). Impedance identified necrotic core area ≥1.75 mm2, fibrous cap thickness ≤65 μm, and ≥20 macrophages per HPF with AUCs of 0.889 (95% CI: 0.716–1.000) (p = .013), 0.852 (0.646–1.000) (p = .025), and 0.835 (0.577–1.000) (p = .028), respectively. Further, phase delay discriminated severe stenosis (≥70%) with an AUC of 0.767 (0.573–0.962) (p = .035). EIS discriminates high-risk atherosclerotic features that portend plaque rupture in human coronary artery disease and may serve as a complementary modality for angiography-guided atherosclerosis evaluation.

冠状动脉斑块破裂仍是心肌梗死的主要机制。准确识别易破裂斑块可改善临床治疗。本研究评估了电化学阻抗谱(EIS)在人体心脏组织中检测预示破裂风险的高危动脉粥样硬化特征的鉴别性能。在这项单中心前瞻性研究中,共收集了 n = 26 个心脏外植体,对三条主要冠状动脉进行了电化学阻抗谱分析。对于无法在不造成斑块破坏的情况下推进 EIS 导管的血管,未进行评估。N = 61 支血管接受了 EIS 测量和组织学分析。根据之前确定的高破裂风险参数阈值对斑块进行二分。诊断性能通过接收者操作特征曲线下面积(AUC)确定。在 n = 19 根血管(中位数面积为 1.53 平方毫米)中确定了坏死核心,中位数纤维帽厚度为 62 微米。坏死核心面积≥1.75 平方毫米的斑块阻抗明显高于面积为 2 平方毫米的斑块(19.8 ± 4.4 kΩ vs. 7.2 ± 1.0 kΩ,p = .019),纤维帽厚度≤65 μm 的斑块阻抗明显高于厚度大于 65 μm 的斑块(19.1 ± 3.5 kΩ vs. 6.5 ± 0.9 kΩ,p = .004)、每 0.3 mm 直径高倍视野(HPF)≥20 个巨噬细胞对 2、纤维帽厚度≤65 μm 和每 HPF ≥20 个巨噬细胞的 AUC 分别为 0.889(95% CI:0.716-1.000)(p = .013)、0.852(0.646-1.000)(p = .025)和 0.835(0.577-1.000)(p = .028)。此外,相位延迟可判别严重狭窄(≥70%),AUC 为 0.767 (0.573-0.962) (p = .035)。EIS 可判别人类冠状动脉疾病中预示斑块破裂的高危动脉粥样硬化特征,可作为血管造影引导下动脉粥样硬化评估的补充模式。
{"title":"Electrochemical impedance spectroscopy unmasks high-risk atherosclerotic features in human coronary artery disease","authors":"Michael Chen,&nbsp;Krit Suwannaphoom,&nbsp;Yas Sanaiha,&nbsp;Yuan Luo,&nbsp;Peyman Benharash,&nbsp;Michael C. Fishbein,&nbsp;René R. Sevag Packard","doi":"10.1096/fj.202401200R","DOIUrl":"10.1096/fj.202401200R","url":null,"abstract":"<p>Coronary plaque rupture remains the prominent mechanism of myocardial infarction. Accurate identification of rupture-prone plaque may improve clinical management. This study assessed the discriminatory performance of electrochemical impedance spectroscopy (EIS) in human cardiac explants to detect high-risk atherosclerotic features that portend rupture risk. In this single-center, prospective study, <i>n</i> = 26 cardiac explants were collected for EIS interrogation of the three major coronary arteries. Vessels in which advancement of the EIS catheter without iatrogenic plaque disruption was rendered impossible were not assessed. <i>N</i> = 61 vessels underwent EIS measurement and histological analyses. Plaques were dichotomized according to previously established high rupture-risk parameter thresholds. Diagnostic performance was determined via receiver operating characteristic areas-under-the-curve (AUC). Necrotic cores were identified in <i>n</i> = 19 vessels (median area 1.53 mm<sup>2</sup>) with a median fibrous cap thickness of 62 μm. Impedance was significantly greater in plaques with necrotic core area ≥1.75 mm<sup>2</sup> versus &lt;1.75 mm<sup>2</sup> (19.8 ± 4.4 kΩ vs. 7.2 ± 1.0 kΩ, <i>p</i> = .019), fibrous cap thickness ≤65 μm versus &gt;65 μm (19.1 ± 3.5 kΩ vs. 6.5 ± 0.9 kΩ, <i>p</i> = .004), and ≥20 macrophages per 0.3 mm-diameter high-power field (HPF) versus &lt;20 macrophages per HPF (19.8 ± 4.1 kΩ vs. 10.2 ± 0.9 kΩ, <i>p</i> = .002). Impedance identified necrotic core area ≥1.75 mm<sup>2</sup>, fibrous cap thickness ≤65 μm, and ≥20 macrophages per HPF with AUCs of 0.889 (95% CI: 0.716–1.000) (<i>p</i> = .013), 0.852 (0.646–1.000) (<i>p</i> = .025), and 0.835 (0.577–1.000) (<i>p</i> = .028), respectively. Further, phase delay discriminated severe stenosis (≥70%) with an AUC of 0.767 (0.573–0.962) (<i>p</i> = .035). EIS discriminates high-risk atherosclerotic features that portend plaque rupture in human coronary artery disease and may serve as a complementary modality for angiography-guided atherosclerosis evaluation.</p>","PeriodicalId":50455,"journal":{"name":"FASEB Journal","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142309016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","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
FASEB Journal
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