Journal of Advanced Research最新文献_第10页

Moscatilin inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating the WNT3/β-catenin signalling pathway Moscatilin 通过激活 IL13RA2 依赖性抑制 STAT3 和削弱 WNT3/β-catenin 信号通路来抑制血管钙化。

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2025-02-01 DOI: 10.1016/j.jare.2024.02.020

Tingting Zhang , Mengmeng Zhu , Jialing Ma , Zhenghong Liu , Zhidan Zhang , Meijie Chen , Yaping Zhao , Huaxin Li , Shengnan Wang , Xiaoning Wei , Wenwen Zhang , Xiaoxiao Yang , Peter J. Little , Danielle Kamato , Hao Hu , Yajun Duan , Baotong Zhang , Jianbo Xiao , Suowen Xu , Yuanli Chen

Introduction

Vascular calcification, a devastating vascular complication accompanying atherosclerotic cardiovascular disease and chronic kidney disease, increases the incidence of adverse cardiovascular events and compromises the efficacy of vascular interventions. However, effective therapeutic drugs and treatments to delay or prevent vascular calcification are lacking.

Objectives

This study was designed to test the therapeutic effects and mechanism of Moscatilin (also known as dendrophenol) from Dendrobium huoshanense (an eminent traditional Chinese medicine) in suppressing vascular calcification in vitro, ex vivo and in vivo.

Methods

Male C57BL/6J mice (25-week-old) were subjected to nicotine and vitamin D₃ (VD₃) treatment to induce vascular calcification. In vitro, we established the cellular model of osteogenesis of human aortic smooth muscle cells (HASMCs) under phosphate conditions.

Results

By utilizing an in-house drug screening strategy, we identified Moscatilin as a new naturally-occurring chemical entity to reduce HASMC calcium accumulation. The protective effects of Moscatilin against vascular calcification were verified in cultured HASMCs. Unbiased transcriptional profiling analysis and cellular thermal shift assay suggested that Moscatilin suppresses vascular calcification via binding to interleukin 13 receptor subunit A2 (IL13RA2) and augmenting its expression. Furthermore, IL13RA2 was reduced during HASMC osteogenesis, thus promoting the secretion of inflammatory factors via STAT3. We further validated the participation of Moscatilin-inhibited vascular calcification by the classical WNT/β-catenin pathway, among which WNT3 played a key role in this process. Moscatilin mitigated the crosstalk between WNT3/β-catenin and IL13RA2/STAT3 to reduce osteogenic differentiation of HASMCs.

Conclusion

This study supports the potential of Moscatilin as a new naturally-occurring candidate drug for treating vascular calcification via regulating the IL13RA2/STAT3 and WNT3/β-catenin signalling pathways.

导言：血管钙化是伴随动脉粥样硬化性心血管疾病和慢性肾脏病的一种破坏性血管并发症，会增加不良心血管事件的发生率，并损害血管干预的效果。然而，目前还缺乏有效的治疗药物和疗法来延缓或预防血管钙化：本研究旨在检测霍山石斛（一种著名中药）中的莫斯卡替林在体外、体内和体外抑制血管钙化的疗效和机制：方法：雄性C57BL/6J小鼠（25周龄）经尼古丁和维生素D3（VD3）处理后诱导血管钙化。在体外，我们建立了磷酸条件下人主动脉平滑肌细胞（HASMC）成骨的细胞模型：通过使用内部药物筛选方案，我们发现了一种新的天然化学实体 Moscatilin，它可以减少 HASMC 的钙积累。在培养的 HASMCs 中验证了 Moscatilin 对血管钙化的保护作用。无偏见的转录谱分析和细胞热转移分析表明，莫斯卡替林通过与白细胞介素13受体亚基A2（IL13RA2）结合并增强其表达来抑制血管钙化。此外，IL13RA2在HASMC成骨过程中减少，从而通过STAT3促进了炎症因子的分泌。我们进一步验证了莫斯卡替林抑制血管钙化的经典WNT/β-catenin通路的参与，其中WNT3在这一过程中起着关键作用。莫斯卡替林减轻了WNT3/β-catenin和IL13RA2/STAT3之间的串扰，从而减少了HASMCs的成骨分化：本研究支持莫斯卡替林作为一种新的天然候选药物，通过调节 IL13RA2/STAT3 和 WNT3/β -catenin 信号通路来治疗血管钙化。

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引用次数: 0

Sonic hedgehog restrains the ubiquitin-dependent degradation of SP1 to inhibit neuronal/glial senescence associated phenotypes in chemotherapy-induced peripheral neuropathy via the TRIM25-CXCL13 axis 音速刺猬通过TRIM25-CXCL13轴抑制泛素依赖性降解SP1，从而抑制化疗诱导的周围神经病变中与神经元/胶质细胞衰老相关的表型

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2025-02-01 DOI: 10.1016/j.jare.2024.03.006

Ying Zou , Shu Wu , Qian Hu , Haoxian Zhou , Yuanlong Ge , Zhenyu Ju , Shengkang Luo

Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication that affects an increasing number of cancer survivors. However, the current treatment options for CIPN are limited. Paclitaxel (PTX) is a widely used chemotherapeutic drug that induces senescence in cancer cells. While previous studies have demonstrated that Sonic hedgehog (Shh) can counteract cellular dysfunction during aging, its role in CIPN remains unknown.

Objectives

Herein, the aim of this study was to investigate whether Shh activation could inhibits neuronal/glial senescence and alleviates CIPN.

Methods

We treated ND7/23 neuronal cells and RSC96 Schwann cells with two selective Shh activators (purmorphamine [PUR] and smoothened agonist [SAG]) in the presence of PTX. Additionally, we utilized a CIPN mouse model induced by PTX injection. To assess cellular senescence, we performed a senescence-associated β-galactosidase (SA-β-gal) assay, measured reactive oxygen species (ROS) levels, and examined the expression of P16, P21, and γH2AX. To understand the underlying mechanisms, we conducted ubiquitin assays, LC-MS/MS, H&E staining, and assessed protein expression through Western blotting and immunofluorescence staining.

Results

In vitro, we observed that Shh activation significantly alleviated the senescence-related decline in multiple functions included SA-β-gal activity, expression of P16 and P21, cell viability, and ROS accumulation in DRG sensory neurons and Schwann cells after PTX exposure. Furthermore, our in vivo experiments demonstrated that Shh activation significantly reduced axonal degeneration, demyelination, and improved nerve conduction. Mechanistically, we discovered that PTX reduced the protein level of SP1, which was ubiquitinated by the E3 ligase TRIM25 at the lysine 694 (K694), leading to increased CXCL13 expression, and we found that Shh activation inhibited PTX-induced neuronal/glial senescence and CIPN through the TRIM25-SP1-CXCL13 axis.

Conclusion

These findings provide evidence for the role of PTX-induced senescence in DRG sensory neurons and Schwann cells, suggesting that Shh could be a potential therapeutic target for CIPN.

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引用次数: 0

Collecting duct NCOR1 controls blood pressure by regulating mineralocorticoid receptor 集合管 NCOR1 通过调节矿质皮质激素受体控制血压

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2025-02-01 DOI: 10.1016/j.jare.2024.02.003

Ke Sun , Yong-Li Wang , Chen-Chen Hou , Da Shang , Lin-Juan Du , Lan Bai , Xing-Yu Zhang , Chuan-Ming Hao , Sheng-Zhong Duan

Introduction

Nuclear receptor corepressor 1(NCOR1) is reported to play crucial roles in cardiovascular diseases, but its function in the kidney has remained obscure.

Objective

We aim to elucidate the role of collecting duct NCOR1 in blood pressure (BP) regulation.

Methods and Results

Collecting duct NCOR1 knockout (KO) mice manifested increased BP and aggravated vascular and renal injury in an angiotensin II (Ang II)-induced hypertensive model. KO mice also showed significantly higher BP than littermate control (LC) mice in deoxycorticosterone acetate (DOCA)-salt model. Further study showed that collecting duct NCOR1 deficiency aggravated volume and sodium retention after saline challenge. Among the sodium transporter in the collecting duct, the expression of the three epithelial sodium channel (ENaC) subunits was markedly increased in the renal medulla of KO mice. Consistently, BP in Ang II-infused KO mice decreased significantly to the similar level as those in LC mice after amiloride treatment. ChIP analysis revealed that NCOR1 deficiency increased the enrichment of mineralocorticoid receptor (MR) on the promoters of the three ENaC genes in primary inner medulla collecting duct (IMCD) cells. Co-IP results showed interaction between NCOR1 and MR, and luciferase reporter results demonstrated that NCOR1 inhibited the transcriptional activity of MR. Knockdown of MR eliminated the increased ENaC expression in primary IMCD cells isolated from KO mice. Finally, BP was significantly decreased in Ang II-infused KO mice after treatment of MR antagonist spironolactone and the difference between LC and KO mice was abolished.

Conclusions

NCOR1 interacts with MR to control ENaC activity in the collecting duct and to regulate sodium reabsorption and ultimately BP. Targeting NCOR1 might be a promising tactic to interrupt the volume and sodium retention of the collecting duct in hypertension.

引言据报道，核受体核心抑制因子 1（NCOR1）在心血管疾病中发挥着重要作用，但其在肾脏中的功能仍不明确：目的：我们旨在阐明集合管 NCOR1 在血压（BP）调节中的作用：收集管 NCOR1 基因敲除（KO）小鼠在血管紧张素 II（Ang II）诱导的高血压模型中表现出血压升高，血管和肾脏损伤加重。在醋酸脱氧皮质酮（DOCA）-盐模型中，KO小鼠的血压也明显高于同卵对照（LC）小鼠。进一步的研究表明，集合管 NCOR1 缺乏会加重生理盐水挑战后的血容量和钠潴留。在集合管钠转运体中，三个上皮钠通道（ENaC）亚基在 KO 小鼠肾髓质中的表达明显增加。同样，在阿米洛利处理后，Ang II 注入 KO 小鼠的血压显著下降至与 LC 小鼠相似的水平。ChIP 分析显示，NCOR1 缺乏会增加原代内髓集合管（IMCD）细胞中三个 ENaC 基因启动子上的矿质皮质激素受体（MR）的富集。Co-IP 结果显示了 NCOR1 与 MR 之间的相互作用，荧光素酶报告结果表明 NCOR1 抑制了 MR 的转录活性。敲除 MR 可消除从 KO 小鼠分离的原代 IMCD 细胞中增加的 ENaC 表达。最后，MR拮抗剂螺内酯治疗后，注入Ang II的KO小鼠血压明显下降，LC和KO小鼠之间的差异消失：结论：NCOR1与MR相互作用，控制集合管中ENaC的活性，调节钠重吸收，最终调节血压。结论：NCOR1与MR相互作用，控制集合管中ENaC的活性，调节钠的重吸收，最终调节血压。以NCOR1为靶点可能是阻断高血压患者集合管容量和钠潴留的一种有前途的策略。

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引用次数: 0

HnRNPR-mediated UPF3B mRNA splicing drives hepatocellular carcinoma metastasis HnRNPR 介导的 UPF3B mRNA 剪接驱动肝细胞癌转移。

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2025-02-01 DOI: 10.1016/j.jare.2024.02.010

Hong Wang , Dong Qian , Jiabei Wang , Yao Liu , Wenguang Luo , Hongyan Zhang , Jingjing Cheng , Heng Li , Yang Wu , Wuhan Li , Jing Wang , Xia Yang , Tianzhi Zhang , Dong Han , Qinyao Wang , Chris Zhiyi Zhang , Lianxin Liu

Introduction

Abnormal alternative splicing (AS) contributes to aggressive intrahepatic invasion and metastatic spread, leading to the high lethality of hepatocellular carcinoma (HCC).

Objectives

This study aims to investigate the functional implications of UPF3B-S (a truncated oncogenic splice variant) in HCC metastasis.

Methods

Basescope assay was performed to analyze the expression of UPF3B-S mRNA in tissues and cells. RNA immunoprecipitation, and in vitro and in vivo models were used to explore the role of UPF3B-S and the underlying mechanisms.

Results

We show that splicing factor HnRNPR binds to the pre-mRNA of UPF3B via its RRM2 domain to generate an exon 8 exclusion truncated splice variant UPF3B-S. High expression of UPF3B-S is correlated with tumor metastasis and unfavorable overall survival in patients with HCC. The knockdown of UPF3B-S markedly suppresses the invasive and migratory capacities of HCC cells in vitro and in vivo. Mechanistically, UPF3B-S protein targets the 3′-UTR of CDH1 mRNA to enhance the degradation of CDH1 mRNA, which results in the downregulation of E-cadherin and the activation of epithelial–mesenchymal transition. Overexpression of UPF3B-S enhances the dephosphorylation of LATS1 and the nuclear accumulation of YAP1 to trigger the Hippo signaling pathway.

Conclusion

Our findings suggest that HnRNPR-induced UPF3B-S promotes HCC invasion and metastasis by exhausting CDH1 mRNA and modulating YAP1-Hippo signaling. UPF3B-S could potentially serve as a promising biomarker for the clinical management of invasive HCC.

简介：异常替代剪接（AS）会导致肝细胞癌（HCC）的侵袭和转移扩散：异常替代剪接（AS）有助于肝内侵袭和转移扩散，导致肝细胞癌（HCC）的高致死率：本研究旨在探讨UPF3B-S（一种截短的致癌剪接变体）在HCC转移中的功能影响：方法：采用Basescope法分析UPF3B-S mRNA在组织和细胞中的表达。结果：我们发现，剪接因子 Hnn 在 HCC 转移过程中起着重要作用：结果：我们发现剪接因子HnRNPR通过其RRM2结构域与UPF3B的前mRNA结合，生成外显子8排斥截短的剪接变体UPF3B-S。UPF3B-S的高表达与HCC患者的肿瘤转移和不利的总生存率相关。敲除UPF3B-S可显著抑制HCC细胞在体外和体内的侵袭和迁移能力。从机理上讲，UPF3B-S蛋白靶向CDH1 mRNA的3'-UTR，增强CDH1 mRNA的降解，从而导致E-cadherin下调，激活上皮-间质转化。UPF3B-S的过表达增强了LATS1的去磷酸化和YAP1的核聚集，从而触发了Hippo信号通路：我们的研究结果表明，HnRNPR诱导的UPF3B-S通过耗尽CDH1 mRNA和激活YAP1-Hippo信号通路促进了HCC的侵袭和转移。UPF3B-S有可能成为临床治疗侵袭性HCC的一种有前景的生物标志物。

{"title":"HnRNPR-mediated UPF3B mRNA splicing drives hepatocellular carcinoma metastasis","authors":"Hong Wang , Dong Qian , Jiabei Wang , Yao Liu , Wenguang Luo , Hongyan Zhang , Jingjing Cheng , Heng Li , Yang Wu , Wuhan Li , Jing Wang , Xia Yang , Tianzhi Zhang , Dong Han , Qinyao Wang , Chris Zhiyi Zhang , Lianxin Liu","doi":"10.1016/j.jare.2024.02.010","DOIUrl":"10.1016/j.jare.2024.02.010","url":null,"abstract":"<div><h3>Introduction</h3><div>Abnormal alternative splicing (AS) contributes to aggressive intrahepatic invasion and metastatic spread, leading to the high lethality of hepatocellular carcinoma (HCC).</div></div><div><h3>Objectives</h3><div>This study aims to investigate the functional implications of UPF3B-S (a truncated oncogenic splice variant) in HCC metastasis.</div></div><div><h3>Methods</h3><div>Basescope assay was performed to analyze the expression of UPF3B-S mRNA in tissues and cells. RNA immunoprecipitation, and in vitro and in vivo models were used to explore the role of UPF3B-S and the underlying mechanisms.</div></div><div><h3>Results</h3><div>We show that splicing factor HnRNPR binds to the pre-mRNA of UPF3B via its RRM2 domain to generate an exon 8 exclusion truncated splice variant UPF3B-S. High expression of UPF3B-S is correlated with tumor metastasis and unfavorable overall survival in patients with HCC. The knockdown of UPF3B-S markedly suppresses the invasive and migratory capacities of HCC cells in vitro and in vivo. Mechanistically, UPF3B-S protein targets the 3′-UTR of CDH1 mRNA to enhance the degradation of CDH1 mRNA, which results in the downregulation of E-cadherin and the activation of epithelial–mesenchymal transition. Overexpression of UPF3B-S enhances the dephosphorylation of LATS1 and the nuclear accumulation of YAP1 to trigger the Hippo signaling pathway.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that HnRNPR-induced UPF3B-S promotes HCC invasion and metastasis by exhausting CDH1 mRNA and modulating YAP1-Hippo signaling. UPF3B-S could potentially serve as a promising biomarker for the clinical management of invasive HCC.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"68 ","pages":"Pages 257-270"},"PeriodicalIF":11.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Achieving healthy aging through gut microbiota-directed dietary intervention: Focusing on microbial biomarkers and host mechanisms 通过以肠道微生物为导向的饮食干预实现健康老龄化：关注微生物生物标志物和宿主机制。

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2025-02-01 DOI: 10.1016/j.jare.2024.03.005

Yue Xiao , Yingxuan Feng , Jianxin Zhao , Wei Chen , Wenwei Lu

Background

Population aging has become a primary global public health issue, and the prevention of age-associated diseases and prolonging healthy life expectancies are of particular importance. Gut microbiota has emerged as a novel target in various host physiological disorders including aging. Comprehensive understanding on changes of gut microbiota during aging, in particular gut microbiota characteristics of centenarians, can provide us possibility to achieving healthy aging or intervene pathological aging through gut microbiota-directed strategies.

Aim of Review

This review aims to summarize the characteristics of the gut microbiota associated with aging, explore potential biomarkers of aging and address microbiota-associated mechanisms of host aging focusing on intestinal barrier and immune status. By summarizing the existing effective dietary strategies in aging interventions, the probability of developing a diet targeting the gut microbiota in future is provided.

Key Scientific Concepts of Review

This review is focused on three key notions: Firstly, gut microbiota has become a new target for regulating health status and lifespan, and its changes are closely related to age. Thus, we summarized aging-associated gut microbiota features at the levels of key genus/species and important metabolites through comparing the microbiota differences among centenarians, elderly people and younger people. Secondly, exploring microbiota biomarkers related to aging and discussing future possibility using dietary regime/components targeted to aging-related microbiota biomarkers promote human healthy lifespan. Thirdly, dietary intervention can effectively improve the imbalance of gut microbiota related to aging, such as probiotics, prebiotics, and postbiotics, but their effects vary among.

背景：人口老龄化已成为全球公共卫生的首要问题，预防老年相关疾病和延长健康预期寿命尤为重要。肠道微生物群已成为包括衰老在内的各种宿主生理紊乱的新靶点。全面了解衰老过程中肠道微生物群的变化，尤其是百岁老人的肠道微生物群特征，可为我们通过肠道微生物群导向策略实现健康衰老或干预病理衰老提供可能：本综述旨在总结与衰老相关的肠道微生物群的特征，探索衰老的潜在生物标志物，并以肠道屏障和免疫状态为重点，探讨与微生物群相关的宿主衰老机制。通过总结衰老干预方面现有的有效膳食策略，为未来开发针对肠道微生物群的膳食提供了可能性：本综述主要围绕三个关键概念展开：首先，肠道微生物群已成为调节健康状况和寿命的新目标，其变化与年龄密切相关。因此，我们通过比较百岁老人、老年人和年轻人的微生物群差异，从关键属/种和重要代谢物的层面总结了与衰老相关的肠道微生物群特征。其次，探索与衰老相关的微生物群生物标志物，并探讨未来针对衰老相关微生物群生物标志物使用膳食制度/成分促进人类健康寿命的可能性。第三，膳食干预能有效改善与衰老相关的肠道微生物群失衡，如益生菌、益生元和后益生元，但其效果因人而异。

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引用次数: 0

Metformin blocks BIK1-mediated CPK28 phosphorylation and enhances plant immunity 二甲双胍可阻断 BIK1 介导的 CPK28 磷酸化，增强植物免疫力。

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2025-02-01 DOI: 10.1016/j.jare.2024.02.025

Yazhou Bao , Qian Zhang , Hai Zhu , Yong Pei , Yaning Zhao , Yixin Li , Peiyun Ji , Dandan Du , Hao Peng , Guangyuan Xu , Xiaodan Wang , Zhiyuan Yin , Gan Ai , Xiangxiu Liang , Daolong Dou

Introduction

Metformin (MET), derived from Galega officinalis, stands as the primary first-line medication for the treatment of type 2 diabetes (T2D). Despite its well-documented benefits in mammalian cellular processes, its functions and underlying mechanisms in plants remain unclear.

Objectives

This study aimed to elucidate MET’s role in inducing plant immunity and investigate the associated mechanisms.

Methods

To investigate the impact of MET on enhancing plant immune responses, we conducted assays measuring defense gene expression, reactive oxygen species (ROS) accumulation, mitogen-activated protein kinase (MAPK) phosphorylation, and pathogen infection. Additionally, surface plasmon resonance (SPR) and microscale thermophoresis (MST) techniques were employed to identify MET targets. Protein-protein interactions were analyzed using a luciferase complementation assay and a co-immunoprecipitation assay.

Results

Our findings revealed that MET boosts plant disease resistance by activating MAPKs, upregulating the expression of downstream defense genes, and fortifying the ROS burst. CALCIUM-DEPENDENT PROTEIN KINASE 28 (CPK28) was identified as a target of MET. It inhibited the interaction between BOTRYTIS-INDUCED KINASE 1 (BIK1) and CPK28, blocking CPK28 threonine 76 (T76) transphosphorylation by BIK1, and alleviating the negative regulation of immune responses by CPK28. Moreover, MET enhanced disease resistance in tomato, pepper, and soybean plants.

Conclusion

Collectively, our data suggest that MET enhances plant immunity by blocking BIK1-mediated CPK28 phosphorylation.

简介二甲双胍（MET）提取自 Galega officinalis，是治疗 2 型糖尿病（T2D）的主要一线药物。尽管二甲双胍在哺乳动物细胞过程中的益处有据可查，但其在植物中的功能和潜在机制仍不清楚：本研究旨在阐明 MET 在诱导植物免疫中的作用，并研究其相关机制：为了研究 MET 对增强植物免疫反应的影响，我们进行了防御基因表达、活性氧（ROS）积累、丝裂原活化蛋白激酶（MAPK）磷酸化和病原体感染的测定。此外，我们还采用了表面等离子体共振（SPR）和微尺度热泳（MST）技术来识别 MET 靶标。利用荧光素酶互补试验和共免疫沉淀试验分析了蛋白质与蛋白质之间的相互作用：结果：我们的研究结果表明，MET通过激活MAPKs、上调下游防御基因的表达以及增强ROS爆发来提高植物的抗病性。钙独立蛋白激酶 28（CPK28）被确定为 MET 的靶标。MET抑制了BOTRYTIS-INDUCED KINASE 1（BIK1）和CPK28之间的相互作用，阻止了CPK28苏氨酸76（T76）被BIK1转磷酸化，减轻了CPK28对免疫反应的负调控。此外，MET 还能增强番茄、辣椒和大豆植株的抗病性：总之，我们的数据表明，MET 可通过阻断 BIK1 介导的 CPK28 磷酸化增强植物免疫力。

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引用次数: 0

The epidermal lipid-microbiome loop and immunity: Important players in atopic dermatitis 表皮脂质-微生物组环路与免疫：特应性皮炎的重要角色。

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2025-02-01 DOI: 10.1016/j.jare.2024.03.001

Junchao Wu , Lisha Li , Tingrui Zhang , Jiaye Lu , Zongguang Tai , Quangang Zhu , Zhongjian Chen

Background

The promotion of epidermal barrier dysfunction is attributed to abnormalities in the lipid-microbiome positive feedback loop which significantly influences the imbalance of the epithelial immune microenvironment (EIME) in atopic dermatitis (AD). This imbalance encompasses impaired lamellar membrane integrity, heightened exposure to epidermal pathogens, and the regulation of innate and adaptive immunity. The lipid-microbiome loop is substantially influenced by intense adaptive immunity which is triggered by abnormal loop activity and affects the loop's integrity through the induction of atypical lipid composition and responses to dysregulated epidermal microbes. Immune responses participate in lipid abnormalities within the EIME by downregulating barrier gene expression and are further cascade-amplified by microbial dysregulation which is instigated by barrier impairment.

Aim of review

This review examines the relationship between abnormal lipid composition, microbiome disturbances, and immune responses in AD while progressively substantiating the crosstalk mechanism among these factors. Based on this analysis, the “lipid-microbiome” positive feedback loop, regulated by immune responses, is proposed.

Key scientific concepts of review

The review delves into the impact of adaptive immune responses that regulate the EIME, driving AD, and investigates potential mechanisms by which lipid supplementation and probiotics may alleviate AD through the up-regulation of the epidermal barrier and modulation of immune signaling. This exploration offers support for targeting the EIME to attenuate AD.

背景：促进表皮屏障功能障碍的原因是脂质-微生物组正反馈环路的异常，它极大地影响了特应性皮炎（AD）中上皮免疫微环境（EIME）的失衡。这种失衡包括薄层膜完整性受损、表皮病原体暴露增加以及先天性免疫和适应性免疫的调节。脂质-微生物组环路受到强烈的适应性免疫的重大影响，适应性免疫由异常环路活动引发，并通过诱导非典型脂质组成和对失调表皮微生物的反应影响环路的完整性。免疫反应通过下调屏障基因表达参与表皮内脂质异常，并通过屏障受损引发的微生物失调进一步级联放大：本综述探讨了 AD 中异常脂质组成、微生物组紊乱和免疫反应之间的关系，同时逐步证实了这些因素之间的串联机制。在此分析基础上，提出了由免疫反应调控的 "脂质-微生物组 "正反馈循环：综述深入探讨了调节表皮屏障的适应性免疫反应的影响，以及驱动 AD 的因素，并研究了补充脂质和益生菌可通过上调表皮屏障和调节免疫信号转导来缓解 AD 的潜在机制。这一探索为靶向 EIME 以减轻 AD 提供了支持。

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引用次数: 0

Metal-free production of natural blue colorants through anthocyanin–protein interactions 通过花青素与蛋白质的相互作用生产无金属的天然蓝色着色剂。

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2025-02-01 DOI: 10.1016/j.jare.2024.02.018

Wenxin Wang , Peiqing Yang , Fuqing Gao , Yongtao Wang , Zhenzhen Xu , Xiaojun Liao

Introduction

The scarcity of naturally available sources for blue colorants has driven reliance on synthetic alternatives. Nevertheless, growing health concerns have prompted the development of naturally derived blue colorants, which remains challenging with limited success thus far. Anthocyanins (ACNs) are known for providing blue colors in plants, and metal complexation with acylated ACNs remains the primary strategy to generate stable blue hues. However, this approach can be costly and raise concerns regarding potential metal consumption risks.

Objectives

Our study aims to introduce a metal-free approach to achieve blue coloration in commonly distributed non-acylated 3-glucoside ACNs by exploring their interactions with proteins and unveiling the underlying mechanisms.

Methods

Using human serum albumin (HSA) as a model protein, we investigated the structural influences of ACNs on their blue color generation using visible absorption spectroscopy, fluorescence quenching, and molecular simulations. Additionally, we examined the bluing effects of six proteins derived from milk and egg and identified the remarkable roles of bovine serum albumin (BSA) and lysozyme (LYS).

Results

Our findings highlighted the importance of two or more hydroxyl or methoxyl substituents in the B-ring of ACNs for generating blue colors. Cyanidin-, delphinidin- and petunidin-3-glucoside, featuring two neighboring hydroxyl groups in the B-ring, exhibited blue coloration when interacting with HSA or LYS, driven primarily by favorable enthalpy changes. In contrast, malvidin-3-glucoside, with two methoxyl substituents, achieved blue coloration through interactions with HSA or BSA, where entropy change played significant roles.

Conclusion

Our work, for the first time, demonstrates the remarkable capability of widely distributed 3-glucoside ACNs to generate diverse blue shades through interactions with certain proteins. This offers a promising and straightforward strategy for the production of ACN-based blue colorants, stimulating further research in this field.

简介：由于天然蓝色着色剂来源稀缺，人们不得不依赖合成替代品。然而，人们对健康的日益关注促使人们开发天然提取的蓝色着色剂，但迄今为止，这项工作仍然充满挑战，取得的成功也很有限。众所周知，花青素（ACNs）可为植物提供蓝色，与酰化 ACNs 进行金属络合仍是生成稳定蓝色色调的主要策略。然而，这种方法成本高昂，而且会引发潜在的金属消耗风险：我们的研究旨在引入一种无金属方法，通过探索非酰化 3-葡萄糖苷 ACN 与蛋白质的相互作用并揭示其潜在机理，从而在常见的非酰化 3-葡萄糖苷 ACN 中实现蓝色着色：方法：我们以人血清白蛋白（HSA）为模型蛋白质，利用可见吸收光谱、荧光淬灭和分子模拟研究了ACN对其蓝色生成的结构影响。此外，我们还研究了从牛奶和鸡蛋中提取的六种蛋白质的蓝化效应，并确定了牛血清白蛋白（BSA）和溶菌酶（LYS）的显著作用：结果：我们的研究结果突显了乙腈 B 环中两个或两个以上羟基或甲氧基取代基对产生蓝色的重要性。B环中有两个相邻羟基的矢车菊素、花翠素和矮牵牛素-3-葡萄糖苷在与 HSA 或 LYS 作用时呈现蓝色，这主要是由有利的焓变驱动的。相比之下，具有两个甲氧基取代基的麦饭石黄素-3-葡萄糖苷则通过与 HSA 或 BSA 的相互作用呈现蓝色，其中熵的变化发挥了重要作用：我们的研究工作首次证明了广泛分布的 3-葡萄糖苷 ACN 通过与某些蛋白质相互作用产生不同蓝色色调的卓越能力。这为生产基于 ACN 的蓝色着色剂提供了一种前景广阔且简单易行的策略，从而推动了这一领域的进一步研究。

{"title":"Metal-free production of natural blue colorants through anthocyanin–protein interactions","authors":"Wenxin Wang , Peiqing Yang , Fuqing Gao , Yongtao Wang , Zhenzhen Xu , Xiaojun Liao","doi":"10.1016/j.jare.2024.02.018","DOIUrl":"10.1016/j.jare.2024.02.018","url":null,"abstract":"<div><h3>Introduction</h3><div>The scarcity of naturally available sources for blue colorants has driven reliance on synthetic alternatives. Nevertheless, growing health concerns have prompted the development of naturally derived blue colorants, which remains challenging with limited success thus far. Anthocyanins (ACNs) are known for providing blue colors in plants, and metal complexation with acylated ACNs remains the primary strategy to generate stable blue hues. However, this approach can be costly and raise concerns regarding potential metal consumption risks.</div></div><div><h3>Objectives</h3><div>Our study aims to introduce a metal-free approach to achieve blue coloration in commonly distributed non-acylated 3-glucoside ACNs by exploring their interactions with proteins and unveiling the underlying mechanisms.</div></div><div><h3>Methods</h3><div>Using human serum albumin (HSA) as a model protein, we investigated the structural influences of ACNs on their blue color generation using visible absorption spectroscopy, fluorescence quenching, and molecular simulations. Additionally, we examined the bluing effects of six proteins derived from milk and egg and identified the remarkable roles of bovine serum albumin (BSA) and lysozyme (LYS).</div></div><div><h3>Results</h3><div>Our findings highlighted the importance of two or more hydroxyl or methoxyl substituents in the B-ring of ACNs for generating blue colors. Cyanidin-, delphinidin- and petunidin-3-glucoside, featuring two neighboring hydroxyl groups in the B-ring, exhibited blue coloration when interacting with HSA or LYS, driven primarily by favorable enthalpy changes. In contrast, malvidin-3-glucoside, with two methoxyl substituents, achieved blue coloration through interactions with HSA or BSA, where entropy change played significant roles.</div></div><div><h3>Conclusion</h3><div>Our work, for the first time, demonstrates the remarkable capability of widely distributed 3-glucoside ACNs to generate diverse blue shades through interactions with certain proteins. This offers a promising and straightforward strategy for the production of ACN-based blue colorants, stimulating further research in this field.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"68 ","pages":"Pages 17-29"},"PeriodicalIF":11.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

NCAPD3 promotes diffuse large B-cell lymphoma progression through modulating SIRT1 expression in an H3K9 monomethylation-dependent manner NCAPD3以H3K9单甲基化依赖性方式调节SIRT1的表达，从而促进弥漫大B细胞淋巴瘤的进展。

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2025-02-01 DOI: 10.1016/j.jare.2024.02.024

Tiange Lu , Juan Yang , Yiqing Cai , Mengfei Ding , Zhuoya Yu , Xiaosheng Fang , Xiangxiang Zhou , Xin Wang

Introduction

Condensin, a family of structural maintenance of chromosome complexes, has been shown to regulate chromosome compaction and segregation during mitosis. NCAPD3, a HEAT-repeat subunit of condensin II, plays a dominant role in condensin-mediated chromosome dynamics but remains unexplored in lymphoma.

Objectives

The study aims to unravel the molecular function and mechanism of NCAPD3 in diffuse large B-cell lymphoma (DLBCL).

Methods

The expression and clinical significance of NCAPD3 were assessed in public database and clinical specimens. Chromosome spreads, co-immunoprecipitation (co-IP), mass spectrometry (MS), and chromatin immunoprecipitation (ChIP) assays were conducted to untangle the role and mechanism of NCAPD3 in DLBCL.

Results

NCAPD3 was highly expressed in DLBCL, correlated with poor prognosis. NCAPD3 deficiency impeded cell proliferation, induced apoptosis and increased the chemosensitivity. Instead, NCAPD3 overexpression facilitated cell proliferation. In vivo experiments further indicated targeting NCAPD3 suppressed tumor growth. Noteworthily, NCAPD3 deficiency disturbed the mitosis, triggering the formation of aneuploids. To reveal the function of NCAPD3 in DLBCL, chromosome spreads were conducted, presenting that chromosomes became compact upon NCAPD3 overexpression, instead, loose, twisted and lacking axial rigidity upon NCAPD3 absence. Meanwhile, the classical transcription-activated marker, H3K4 trimethylation, was found globally upregulated after NCAPD3 knockout, suggesting that NCAPD3 might participate in chromatin remodeling and transcription regulation. MS revealed NCAPD3 could interact with transcription factor, TFII I. Further co-IP and ChIP assays verified NCAPD3 could be anchored at the promoter of SIRT1 by TFII I and then supported the transcription of SIRT1 via recognizing H3K9 monomethylation (H3K9me1) on SIRT1 promoter. Function reversion assay verified the oncogenic role of NCAPD3 in DLBCL was partially mediated by SIRT1.

Conclusion

This study demonstrated that dysregulation of NCAPD3 could disturb chromosome compaction and segregation and regulate the transcription activity of SIRT1 in an H3K9me1-dependent manner, which provided novel insights into targeted strategy for DLBCL.

导言凝集素是染色体复合物结构维护的一个家族，在有丝分裂过程中调节染色体的压实和分离。NCAPD3是冷凝蛋白II的一个HEAT重复亚基，在冷凝蛋白介导的染色体动力学中起着主导作用，但在淋巴瘤中仍未得到研究：本研究旨在揭示 NCAPD3 在弥漫大 B 细胞淋巴瘤（DLBCL）中的分子功能和机制：方法：在公共数据库和临床标本中评估NCAPD3的表达和临床意义。结果：NCAPD3在弥漫性大B细胞淋巴瘤（DLBCL）中高表达：结果：NCAPD3在DLBCL中高表达，与预后不良相关。结果：NCAPD3在DLBCL中高表达，与预后不良相关，NCAPD3缺乏会阻碍细胞增殖，诱导细胞凋亡，增加化疗敏感性。相反，NCAPD3过表达则会促进细胞增殖。体内实验进一步表明，靶向 NCAPD3 可抑制肿瘤生长。值得注意的是，NCAPD3 缺乏会扰乱有丝分裂，引发非整倍体的形成。为了揭示NCAPD3在DLBCL中的功能，研究人员进行了染色体扩增，结果显示，NCAPD3过表达时，染色体变得紧凑，而NCAPD3缺乏时，染色体变得松散、扭曲，缺乏轴向刚性。同时，经典的转录激活标记--H3K4三甲基化在NCAPD3敲除后出现全局性上调，表明NCAPD3可能参与了染色质重塑和转录调控。质谱显示，NCAPD3可与转录因子TFII I相互作用。进一步的co-IP和ChIP检测验证了NCAPD3可被TFII I锚定在SIRT1的启动子上，然后通过识别SIRT1启动子上的H3K9单甲基化（H3K9me1）支持SIRT1的转录。功能逆转实验验证了NCAPD3在DLBCL中的致癌作用部分是由SIRT1介导的：该研究表明，NCAPD3的失调会扰乱染色体的压实和分离，并以H3K9me1依赖的方式调控SIRT1的转录活性，这为DLBCL的靶向策略提供了新的见解。

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引用次数: 0

Therapeutic application and potential mechanism of plant-derived extracellular vesicles in inflammatory bowel disease 植物源性细胞外囊泡在炎症性肠病中的治疗应用和潜在机制。

IF 11.4 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2025-02-01 DOI: 10.1016/j.jare.2024.01.035

Jinling Li , Ting Luo , Dou Wang , Yao Zhao , Yuanxiang Jin , Guiling Yang , Xin Zhang

Background

Plant-derived extracellular vesicles (PDEVs) are membrane vesicles characterized by a phospholipid bilayer as the basic skeleton that is wrapped by various functional components of proteins and nucleic acids. An increasing number of studies have confirmed that PDEVs can be a potential treatment of inflammatory bowel disease (IBD) and can, to some extent, compensate for the limitations of existing therapies.

Aim of review

This review summarizes the recent advances and potential mechanisms underlying PDEVs obtained from different sources to alleviate IBD. In addition, the review discusses the possible applications and challenges of PDEVs, providing a theoretical basis for exploring novel and practical therapeutic strategies for IBD.

Key scientific concepts of review

In IBD, the crosstalk mechanism of PDEVs may regulate the intestinal microenvironment homeostasis, especially immune responses, the intestinal barrier, and the gut microbiota. In addition, drug loading enhances the therapeutic potential of PDEVs, particularly regarding improved tissue targeting and stability. In the future, not only immunotherapy based on PDEVs may be an effective treatment for IBD, but also the intestinal barrier and intestinal microbiota will be a new direction for the treatment of IBD.

背景：植物源性细胞外囊泡(PDEVs)是一种以磷脂双分子层为基本骨架，由蛋白质和核酸等多种功能成分包裹的膜泡。越来越多的研究证实，PDEVs 是治疗炎症性肠病（IBD）的潜在药物，并能在一定程度上弥补现有疗法的局限性：本综述总结了从不同来源获得的 PDEVs 在缓解 IBD 方面的最新进展和潜在机制。此外，该综述还讨论了 PDEVs 的可能应用和挑战，为探索新型、实用的 IBD 治疗策略提供理论依据：在 IBD 中，PDEVs 的串联机制可能会调节肠道微环境的平衡，尤其是免疫反应、肠道屏障和肠道微生物群。此外，药物负载可增强 PDEVs 的治疗潜力，尤其是在改善组织靶向性和稳定性方面。未来，不仅基于 PDEVs 的免疫疗法可能成为 IBD 的有效治疗方法，肠道屏障和肠道微生物群也将成为治疗 IBD 的新方向。

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引用次数: 0