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ZCCHC8 p.P410A disrupts nucleocytoplasmic localization, promoting idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease ZCCHC8 p.P410A 会破坏核胞质定位,促进特发性肺纤维化和慢性阻塞性肺病的发生
IF 5.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1186/s10020-024-00913-9
Chen-Yu Wang, Si-Hua Chang, Cheng-Feng Hu, Yi-Qiao Hu, Hong Luo, Lv Liu, Liang-Liang Fan
Idiopathic pulmonary fibrosis (IPF) is a special kind of chronic interstitial lung disease with insidious onset. Previous studies have revealed that mutations in ZCCHC8 may lead to IPF. The aim of this study is to explore the ZCCHC8 mutations in Chinese IPF patients. Here, we enrolled 124 patients with interstitial lung disease from 2017 to 2023 in our hospital. Whole exome sequencing and Sanger sequencing were employed to explore the genetic lesions of these patients. Among these 124 patients, a novel mutation (NM_017612: c.1228 C > G/p.P410A) of Zinc Finger CCHC-Type Containing 8 (ZCCHC8)was identified in a family with IPF and chronic obstructive lung disease. As a component of the nuclear exosome-targeting complex that regulates the turnover of human telomerase RNA, ZCCHC8 mutations have been reported may lead to IPF in European population and American population. Functional study confirmed that the novel mutation can disrupt the nucleocytoplasmic localization of ZCCHC8, which further decreased the expression of DKC1 and RTEL1, and finally reduced the length of telomere and led to IPF and related disorders. We may first report the ZCCHC8 mutation in Asian population with IPF. Our study broadens the mutation, phenotype, and population spectrum of ZCCHC8 deficiency.
特发性肺纤维化(IPF)是一种特殊的慢性间质性肺病,起病隐匿。以往的研究显示,ZCCHC8基因突变可能导致IPF。本研究旨在探讨中国 IPF 患者的 ZCCHC8 基因突变情况。在此,我们纳入了2017年至2023年在我院就诊的124例间质性肺疾病患者。采用全外显子组测序和Sanger测序方法探讨这些患者的基因病变。在这124名患者中,在一个患有IPF和慢性阻塞性肺病的家族中发现了锌指CCHC型含8(ZCCHC8)的新型突变(NM_017612:c.1228 C > G/p.P410A)。作为调节人类端粒酶 RNA 更替的核外泌体靶向复合物的一个组成部分,ZCCHC8 基因突变可能导致欧洲和美国人群中的 IPF。功能研究证实,新型突变可破坏ZCCHC8的核胞质定位,进一步降低DKC1和RTEL1的表达,最终导致端粒长度减少,引发IPF及相关疾病。我们可能是首次报道亚洲人群中的IPF患者存在ZCCHC8突变。我们的研究扩大了ZCCHC8缺乏症的突变、表型和人群范围。
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引用次数: 0
Advanced glycation end products and reactive oxygen species: uncovering the potential role of ferroptosis in diabetic complications 高级糖化终产物和活性氧:揭示铁氧化酶在糖尿病并发症中的潜在作用
IF 5.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-09 DOI: 10.1186/s10020-024-00905-9
Yanchi Chen, Zihan Meng, Yong Li, Shibo Liu, Pei Hu, En Luo
Advanced glycation end products (AGEs) are a diverse range of compounds that are formed when free amino groups of proteins, lipids, and nucleic acids are carbonylated by reactive carbonyl species or glycosylated by reducing sugars. Hyperglycemia in patients with diabetes can cause an overabundance of AGEs. Excess AGEs are generally acknowledged as major contributing factors to the development of diabetic complications because of their ability to break down the extracellular matrix directly and initiate intracellular signaling pathways by binding to the receptor for advanced glycation end products (RAGE). Inflammation and oxidative stress are the two most well-defined pathophysiological states induced by the AGE–RAGE interaction. In addition to oxidative stress, AGEs can also inhibit antioxidative systems and disturb iron homeostasis, all of which may induce ferroptosis. Ferroptosis is a newly identified contributor to diabetic complications. This review outlines the formation of AGEs in individuals with diabetes, explores the oxidative damage resulting from downstream reactions of the AGE-RAGE axis, and proposes a novel connection between AGEs and the ferroptosis pathway. This study introduces the concept of a vicious cycle involving AGEs, oxidative stress, and ferroptosis in the development of diabetic complications.
高级糖化终产物(AGEs)是蛋白质、脂类和核酸的游离氨基被活性羰基羰基化或被还原糖糖基化后形成的多种化合物。糖尿病患者的高血糖会导致 AGEs 过量。过量的 AGEs 能够直接分解细胞外基质,并通过与高级糖化终产物受体(RAGE)结合启动细胞内信号通路,因此被普遍认为是导致糖尿病并发症的主要因素。炎症和氧化应激是 AGE-RAGE 相互作用诱发的两种最明确的病理生理状态。除了氧化应激外,AGEs 还能抑制抗氧化系统并扰乱铁的稳态,所有这些都可能诱发铁变态反应。铁蛋白沉积是新发现的糖尿病并发症的诱因之一。本综述概述了糖尿病患者体内 AGEs 的形成,探讨了 AGE-RAGE 轴下游反应导致的氧化损伤,并提出了 AGEs 与铁褐斑病途径之间的新联系。本研究提出了糖尿病并发症的发生过程中涉及 AGEs、氧化应激和铁氧化的恶性循环概念。
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引用次数: 0
Protective effect of ghrelin in oxidative stress-induced age-related macular degeneration in vitro and in vivo 胃泌素在体外和体内氧化应激诱导的老年性黄斑变性中的保护作用
IF 5.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-09 DOI: 10.1186/s10020-024-00920-w
Jie Bai, Yanqing Wang, Yanze Li, Yan Liu, Shan Wang
Oxidative damage to human retinal pigment epithelial (RPE) cells is the main cause of age-related macular degeneration (AMD), in our previous work, we showed that ghrelin has an antioxidative effect on human lens epithelium (HLE) cells, however, the studies of using ghrelin in treating the degenerative diseases of the retina have rarely been reported. In this article, we assessed the effect of ghrelin on preventing oxidative stress induced by hydrogen peroxide (H2O2) in ARPE-19 cells and its mechanism. We observed that pretreatment with ghrelin protected ARPE-19 cells from H2O2-induced cell oxidative injuries and apoptosis responses. Furthermore, an oxidative stress-induced mouse model of AMD was established via injection of sodium iodate (NaIO3) to tail veins, and treatment with ghrelin preserved retinal function, and protected photoreceptors. The first to report ghrelin’ protective effect on H2O2-induced RPE cells. Treatment with ghrelin inhibits NaIO3-induced retinal cell apoptosis in vivo. Combined with in vitro and in vivo experiments, the results are comprehensive and reliable.
人类视网膜色素上皮(RPE)细胞的氧化损伤是老年性黄斑变性(AMD)的主要病因,在我们之前的研究中,我们发现胃泌素对人类晶状体上皮(HLE)细胞具有抗氧化作用,然而,利用胃泌素治疗视网膜退行性疾病的研究却鲜有报道。本文评估了胃泌素对防止过氧化氢(H2O2)诱导的 ARPE-19 细胞氧化应激的作用及其机制。我们观察到,预处理胃泌素能保护ARPE-19细胞免受H2O2诱导的细胞氧化损伤和凋亡反应。此外,通过向小鼠尾静脉注射碘酸钠(NaIO3),建立了氧化应激诱导的小鼠老年性视网膜病变模型。首次报道了胃泌素对 H2O2 诱导的 RPE 细胞的保护作用。使用胃泌素可抑制 NaIO3 诱导的体内视网膜细胞凋亡。结合体外和体内实验,结果全面可靠。
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引用次数: 0
NAT10-mediated ac4C acetylation of TFRC promotes sepsis-induced pulmonary injury through regulating ferroptosis NAT10 介导的 TFRC ac4C 乙酰化通过调节铁蛋白沉积促进脓毒症诱发的肺损伤
IF 5.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-09 DOI: 10.1186/s10020-024-00912-w
Pengcheng Xing, Minjie Zhou, Jian Sun, Donglian Wang, Weipeng Huang, Peng An
Sepsis-induced pulmonary injury (SPI) is a common complication of sepsis with a high rate of mortality. N4-acetylcytidine (ac4C) is mediated by the ac4C “writer”, N-acetyltransferase (NAT)10, to regulate the stabilization of mRNA. This study aimed to investigate the role of NAT10 in SPI and the underlying mechanism. Twenty-three acute respiratory distress syndrome (ARDS) patients and 27 non-ARDS volunteers were recruited. A sepsis rat model was established. Reverse transcription-quantitative polymerase chain reaction was used to detect the expression of NAT10 and transferrin receptor (TFRC). Cell viability was detected by cell counting kit-8. The levels of Fe2+, glutathione, and malondialdehyde were assessed by commercial kits. Lipid reactive oxygen species production was measured by flow cytometric analysis. Western blot was used to detect ferroptosis-related protein levels. Haematoxylin & eosin staining was performed to observe the pulmonary pathological symptoms. The results showed that NAT10 was increased in ARDS patients and lipopolysaccharide-treated human lung microvascular endothelial cell line-5a (HULEC-5a) cells. NAT10 inhibition increased cell viability and decreased ferroptosis in HULEC-5a cells. TFRC was a downstream regulatory target of NAT10-mediated ac4C acetylation. Overexpression of TFRC decreased cell viability and promoted ferroptosis. In in vivo study, NAT10 inhibition alleviated SPI. NAT10-mediated ac4C acetylation of TFRC aggravated SPI through promoting ferroptosis.
败血症诱发的肺损伤(SPI)是败血症的一种常见并发症,死亡率很高。N4-乙酰胞苷(ac4C)由ac4C "作家 "N-乙酰转移酶(NAT)10介导,调节mRNA的稳定。本研究旨在探讨 NAT10 在 SPI 中的作用及其内在机制。研究人员招募了 23 名急性呼吸窘迫综合征(ARDS)患者和 27 名非 ARDS 志愿者。建立了败血症大鼠模型。采用逆转录-定量聚合酶链反应检测 NAT10 和转铁蛋白受体(TFRC)的表达。用细胞计数试剂盒-8检测细胞活力。Fe2+、谷胱甘肽和丙二醛的水平由商用试剂盒进行评估。脂质活性氧的产生是通过流式细胞分析测定的。Western 印迹法用于检测铁变态反应相关蛋白质的水平。采用血红素和伊红染色法观察肺部病理症状。结果显示,NAT10在ARDS患者和脂多糖处理的人肺微血管内皮细胞系-5a(HULEC-5a)细胞中增加。抑制NAT10可提高HULEC-5a细胞的存活率并降低其铁蛋白沉积。TFRC是NAT10介导的ac4C乙酰化的下游调控靶标。过表达 TFRC 会降低细胞活力并促进铁凋亡。在体内研究中,抑制 NAT10 可减轻 SPI。NAT10介导的TFRC的ac4C乙酰化通过促进铁变态反应加重了SPI。
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引用次数: 0
Key subdomains of mesencephalic astrocyte-derived neurotrophic factor attenuate myocardial ischemia/reperfusion injury by JAK1/STAT1/NF-κB signaling pathway. 间脑星形胶质细胞源性神经营养因子的关键亚域通过 JAK1/STAT1/NF-κB 信号通路减轻心肌缺血再灌注损伤
IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-06 DOI: 10.1186/s10020-024-00916-6
Haibin Dong, Wenjuan Jia, Chunxiao Wang, Da Teng, Bowen Xu, Xiaoning Ding, Jun Yang, Lin Zhong, Lei Gong

Background: Myocardial ischemia/reperfusion (I/R) injury is a common pathological process in clinical practice. Developing effective therapeutic strategies to reduce or prevent this injury is crucial. The article aimed to investigate the role and mechanism of mesencephalic astrocyte-derived neurotrophic factor (MANF) and its key subdomains in modulating myocardial I/R-induced cardiomyocyte apoptosis.

Methods: MANF stable knockout cell line and MANF mutant overexpression plasmids were constructed. The effects of MANF and mutants on apoptosis and endoplasmic reticulum (ER) stress related proteins were evaluated in hypoxia/reoxygenation-induced HL-1 cardiomyocytes by western blot, immunofluorescence, Tunel and flow cytometry. Echocardiography, ELISA, TTC and Masson were used to observe the effects of recombinant MANF protein (rMANF) on cardiac function in myocardial I/R mice.

Results: This study observed increased expression of MANF in both myocardial infarction patients and I/R mice. MANF overexpression in cardiomyocytes decreased ER stress-induced apoptosis, while MANF knockout exacerbated it. rMANF improved cardiac function in I/R mice by reducing injury and inflammation. This study specifically demonstrates that mutations in the α-helix of MANF were more effective in reducing ER stress and cardiomyocyte apoptosis. Mechanistically, MANF and the α-helix mutant attenuated I/R injury by inhibiting the JAK1/STAT1/NF-κB signaling pathway in addition to reducing ER stress-induced apoptosis.

Conclusion: These findings highlight MANF and its subdomains as critical regulators of myocardial I/R injury, offering promising therapeutic targets with significant clinical implications for I/R-related diseases.

背景:心肌缺血/再灌注(I/R)损伤是临床实践中常见的病理过程。开发有效的治疗策略以减轻或预防这种损伤至关重要。本文旨在研究间脑星形胶质细胞源性神经营养因子(MANF)及其关键亚域在调节心肌I/R诱导的心肌细胞凋亡中的作用和机制:方法:构建MANF稳定敲除细胞系和MANF突变体过表达质粒。方法:通过Western印迹、免疫荧光、Tunel和流式细胞术评估MANF和突变体对缺氧/复氧诱导的HL-1心肌细胞凋亡和内质网(ER)应激相关蛋白的影响。利用超声心动图、ELISA、TTC 和 Masson 观察重组 MANF 蛋白(rMANF)对心肌 I/R 小鼠心脏功能的影响:结果:本研究观察到心肌梗死患者和心肌缺血/缺氧小鼠体内 MANF 的表达均有所增加。MANF在心肌细胞中的过表达减少了ER应激诱导的细胞凋亡,而MANF基因敲除则加剧了ER应激诱导的细胞凋亡。这项研究特别表明,MANF α-螺旋的突变在减少ER应激和心肌细胞凋亡方面更为有效。从机理上讲,MANF及其α-螺旋突变体除了能减少ER应激诱导的细胞凋亡外,还能通过抑制JAK1/STAT1/NF-κB信号通路减轻I/R损伤:这些发现强调了 MANF 及其亚域是心肌 I/R 损伤的关键调控因子,为 I/R 相关疾病提供了具有重大临床意义的治疗靶点。
{"title":"Key subdomains of mesencephalic astrocyte-derived neurotrophic factor attenuate myocardial ischemia/reperfusion injury by JAK1/STAT1/NF-κB signaling pathway.","authors":"Haibin Dong, Wenjuan Jia, Chunxiao Wang, Da Teng, Bowen Xu, Xiaoning Ding, Jun Yang, Lin Zhong, Lei Gong","doi":"10.1186/s10020-024-00916-6","DOIUrl":"10.1186/s10020-024-00916-6","url":null,"abstract":"<p><strong>Background: </strong>Myocardial ischemia/reperfusion (I/R) injury is a common pathological process in clinical practice. Developing effective therapeutic strategies to reduce or prevent this injury is crucial. The article aimed to investigate the role and mechanism of mesencephalic astrocyte-derived neurotrophic factor (MANF) and its key subdomains in modulating myocardial I/R-induced cardiomyocyte apoptosis.</p><p><strong>Methods: </strong>MANF stable knockout cell line and MANF mutant overexpression plasmids were constructed. The effects of MANF and mutants on apoptosis and endoplasmic reticulum (ER) stress related proteins were evaluated in hypoxia/reoxygenation-induced HL-1 cardiomyocytes by western blot, immunofluorescence, Tunel and flow cytometry. Echocardiography, ELISA, TTC and Masson were used to observe the effects of recombinant MANF protein (rMANF) on cardiac function in myocardial I/R mice.</p><p><strong>Results: </strong>This study observed increased expression of MANF in both myocardial infarction patients and I/R mice. MANF overexpression in cardiomyocytes decreased ER stress-induced apoptosis, while MANF knockout exacerbated it. rMANF improved cardiac function in I/R mice by reducing injury and inflammation. This study specifically demonstrates that mutations in the α-helix of MANF were more effective in reducing ER stress and cardiomyocyte apoptosis. Mechanistically, MANF and the α-helix mutant attenuated I/R injury by inhibiting the JAK1/STAT1/NF-κB signaling pathway in addition to reducing ER stress-induced apoptosis.</p><p><strong>Conclusion: </strong>These findings highlight MANF and its subdomains as critical regulators of myocardial I/R injury, offering promising therapeutic targets with significant clinical implications for I/R-related diseases.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145984","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}
引用次数: 0
Role of the GalNAc-galectin pathway in the healing of premature rupture of membranes. GalNAc-Galectin 通路在胎膜早破愈合中的作用。
IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-04 DOI: 10.1186/s10020-024-00908-6
Jia-Le Chen, Lou Liu, Xin-Rui Peng, Yan Wang, Xiang Xiang, Yu Chen, De-Xiang Xu, Dao-Zhen Chen

Background: Premature rupture of the membranes (PROM) is a key cause of preterm birth and represents a major cause of neonatal mortality and morbidity. Natural products N-acetyl-d-galactosamine (GalNAc), which are basic building blocks of important polysaccharides in biological cells or tissues, such as chitin, glycoproteins, and glycolipids, may improve possible effects of wound healing.

Methods: An in vitro inflammation and oxidative stress model was constructed using tumor necrosis-α (TNF-α) and lipopolysaccharide (LPS) action on WISH cells. Human amniotic epithelial cells (hAECs) were primarily cultured by digestion to construct a wound model. The effects of GalNAc on anti-inflammatory and anti-oxidative stress, migration and proliferation, epithelial-mesenchymal transition (EMT), glycosaminoglycan (GAG)/hyaluronic acid (HA) production, and protein kinase B (Akt) pathway in hAECs and WISH cells were analyzed using the DCFH-DA fluorescent probe, ELISA, CCK-8, scratch, transwell migration, and western blot to determine the mechanism by which GalNAc promotes amniotic wound healing.

Results: GalNAc decreased IL-6 expression in TNF-α-stimulated WISH cells and ROS expression in LPS-stimulated WISH cells (P < 0.05). GalNAc promoted the expression of Gal-1 and Gal-3 with anti-inflammatory and anti-oxidative stress effects. GalNAc promoted the migration of hAECs (50% vs. 80%) and WISH cells through the Akt signaling pathway, EMT reached the point of promoting fetal membrane healing, and GalNAc did not affect the activity of hAECs and WISH cells (P > 0.05). GalNAc upregulated the expression of sGAG in WISH cells (P < 0.05) but did not affect HA levels (P > 0.05).

Conclusions: GalNAc might be a potential target for the prevention and treatment of PROM through the galectin pathway, including (i) inflammation; (ii) epithelial-mesenchymal transition; (iii) proliferation and migration; and (iv) regression, remodeling, and healing.

背景:胎膜早破(PROM)是早产的一个主要原因,也是新生儿死亡和发病的一个主要原因。天然产物 N-乙酰-d-半乳糖胺(GalNAc)是生物细胞或组织中重要多糖(如甲壳素、糖蛋白和糖脂)的基本组成成分,可改善伤口愈合的可能效果:方法:利用肿瘤坏死-α(TNF-α)和脂多糖(LPS)对 WISH 细胞的作用,构建了一个体外炎症和氧化应激模型。人羊膜上皮细胞(hAECs)主要通过消化培养来构建伤口模型。采用DCFH-DA荧光探针、ELISA、CCK-8、划痕、透孔迁移和Western blot等方法分析了GalNAc对hAECs和WISH细胞抗炎和抗氧化应激、迁移和增殖、上皮-间质转化(EMT)、糖胺聚糖(GAG)/透明质酸(HA)生成和蛋白激酶B(Akt)通路的影响,以确定GalNAc促进羊膜伤口愈合的机制。结果GalNAc 降低了 TNF-α 刺激的 WISH 细胞中 IL-6 的表达和 LPS 刺激的 WISH 细胞中 ROS 的表达(P 0.05)。GalNAc 上调了 WISH 细胞中 sGAG 的表达(P 0.05):GalNAc可能是通过galectin通路预防和治疗PROM的潜在靶点,包括(i)炎症;(ii)上皮-间质转化;(iii)增殖和迁移;以及(iv)回归、重塑和愈合。
{"title":"Role of the GalNAc-galectin pathway in the healing of premature rupture of membranes.","authors":"Jia-Le Chen, Lou Liu, Xin-Rui Peng, Yan Wang, Xiang Xiang, Yu Chen, De-Xiang Xu, Dao-Zhen Chen","doi":"10.1186/s10020-024-00908-6","DOIUrl":"10.1186/s10020-024-00908-6","url":null,"abstract":"<p><strong>Background: </strong>Premature rupture of the membranes (PROM) is a key cause of preterm birth and represents a major cause of neonatal mortality and morbidity. Natural products N-acetyl-d-galactosamine (GalNAc), which are basic building blocks of important polysaccharides in biological cells or tissues, such as chitin, glycoproteins, and glycolipids, may improve possible effects of wound healing.</p><p><strong>Methods: </strong>An in vitro inflammation and oxidative stress model was constructed using tumor necrosis-α (TNF-α) and lipopolysaccharide (LPS) action on WISH cells. Human amniotic epithelial cells (hAECs) were primarily cultured by digestion to construct a wound model. The effects of GalNAc on anti-inflammatory and anti-oxidative stress, migration and proliferation, epithelial-mesenchymal transition (EMT), glycosaminoglycan (GAG)/hyaluronic acid (HA) production, and protein kinase B (Akt) pathway in hAECs and WISH cells were analyzed using the DCFH-DA fluorescent probe, ELISA, CCK-8, scratch, transwell migration, and western blot to determine the mechanism by which GalNAc promotes amniotic wound healing.</p><p><strong>Results: </strong>GalNAc decreased IL-6 expression in TNF-α-stimulated WISH cells and ROS expression in LPS-stimulated WISH cells (P < 0.05). GalNAc promoted the expression of Gal-1 and Gal-3 with anti-inflammatory and anti-oxidative stress effects. GalNAc promoted the migration of hAECs (50% vs. 80%) and WISH cells through the Akt signaling pathway, EMT reached the point of promoting fetal membrane healing, and GalNAc did not affect the activity of hAECs and WISH cells (P > 0.05). GalNAc upregulated the expression of sGAG in WISH cells (P < 0.05) but did not affect HA levels (P > 0.05).</p><p><strong>Conclusions: </strong>GalNAc might be a potential target for the prevention and treatment of PROM through the galectin pathway, including (i) inflammation; (ii) epithelial-mesenchymal transition; (iii) proliferation and migration; and (iv) regression, remodeling, and healing.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11375961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133248","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}
引用次数: 0
Fetal origin of bronchopulmonary dysplasia: contribution of intrauterine inflammation. 支气管肺发育不良的胎儿起源:宫内炎症的作用。
IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-03 DOI: 10.1186/s10020-024-00909-5
Haoting Yu, Danni Li, Xinyi Zhao, Jianhua Fu

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in infants and the most frequent adverse outcome of premature birth, despite major efforts to minimize injury. It is thought to result from aberrant repair response triggered by either prenatal or recurrent postnatal injury to the lungs during development. Intrauterine inflammation is an important risk factor for prenatal lung injury, which is also increasingly linked to BPD. However, the specific mechanisms remain unclear. This review summarizes clinical and animal research linking intrauterine inflammation to BPD. We assess how intrauterine inflammation affects lung alveolarization and vascular development. In addition, we discuss prenatal therapeutic strategies targeting intrauterine inflammation to prevent or treat BPD.

支气管肺发育不良(BPD)是一种常见的婴儿慢性肺部疾病,也是早产最常见的不良后果,尽管早产的主要原因是尽量减少损伤。它被认为是由于肺部在发育过程中受到产前或产后反复损伤所引发的异常修复反应所致。宫内炎症是产前肺损伤的一个重要风险因素,而产前肺损伤与早产儿肺发育不良的关系也日益密切。然而,其具体机制仍不清楚。本综述总结了将宫内炎症与 BPD 联系起来的临床和动物研究。我们评估了宫内炎症如何影响肺泡化和血管发育。此外,我们还讨论了针对宫内炎症的产前治疗策略,以预防或治疗 BPD。
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引用次数: 0
Insights into RNA N6-methyladenosine and programmed cell death in atherosclerosis. 透视动脉粥样硬化中的 RNA N6-甲基腺苷和程序性细胞死亡
IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-03 DOI: 10.1186/s10020-024-00901-z
Haijiao Long, Yulu Yu, Jie Ouyang, Hongwei Lu, Guojun Zhao

N6-methyladenosine (m6A) modification stands out among various RNA modifications as the predominant form within eukaryotic cells, influencing numerous cellular processes implicated in disease development. m6A modification has gained increasing attention in the development of atherosclerosis and has become a research hotspot in recent years. Programmed cell death (PCD), encompassing apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis, plays a pivotal role in atherosclerosis pathogenesis. In this review, we delve into the intricate interplay between m6A modification and diverse PCD pathways, shedding light on their complex association during the onset and progression of atherosclerosis. Clarifying the relationship between m6A and PCD in atherosclerosis is of great significance to provide novel strategies for cardiovascular disease treatment.

N6-甲基腺苷(m6A)修饰是真核细胞内各种 RNA 修饰的主要形式,影响着许多与疾病发展有关的细胞过程。m6A 修饰在动脉粥样硬化的发展过程中日益受到关注,近年来已成为研究热点。程序性细胞死亡(PCD)包括细胞凋亡、自噬、热凋亡、铁凋亡和坏死,在动脉粥样硬化发病机制中起着关键作用。在这篇综述中,我们将深入探讨 m6A 修饰与多种 PCD 途径之间错综复杂的相互作用,揭示它们在动脉粥样硬化发生和发展过程中的复杂关联。厘清动脉粥样硬化中 m6A 与 PCD 的关系对于提供治疗心血管疾病的新策略具有重要意义。
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引用次数: 0
Molecular mechanism and potential role of mitophagy in acute pancreatitis. 有丝分裂在急性胰腺炎中的分子机制和潜在作用
IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-03 DOI: 10.1186/s10020-024-00903-x
Lili Zhu, Yunfei Xu, Jian Lei

Acute pancreatitis (AP) is a multifaceted inflammatory disorder stemming from the aberrant activation of trypsin within the pancreas. Despite the contribution of various factors to the pathogenesis of AP, such as trypsin activation, dysregulated increases in cytosolic Ca2+ levels, inflammatory cascade activation, and mitochondrial dysfunction, the precise molecular mechanisms underlying the disease are still not fully understood. Mitophagy, a cellular process that preserves mitochondrial homeostasis under stress, has emerged as a pivotal player in the context of AP. Research suggests that augmenting mitophagy can mitigate pancreatic injury by clearing away malfunctioning mitochondria. Elucidating the role of mitophagy in AP may pave the way for novel therapeutic strategies. This review article aims to synthesize the current research findings on mitophagy in AP and underscore its significance in the clinical management of the disorder.

急性胰腺炎(AP)是一种多方面的炎症性疾病,源于胰腺内胰蛋白酶的异常激活。尽管胰蛋白酶活化、细胞膜Ca2+水平失调升高、炎症级联激活和线粒体功能障碍等多种因素对急性胰腺炎的发病机制起着重要作用,但该疾病的确切分子机制仍未完全明了。有丝分裂是一种在应激状态下维持线粒体平衡的细胞过程,已成为导致 AP 的关键因素。研究表明,增强有丝分裂可通过清除功能失常的线粒体减轻胰腺损伤。阐明有丝分裂在胰腺癌中的作用可为新型治疗策略铺平道路。这篇综述文章旨在综述目前关于有丝分裂在胰腺癌中的作用的研究成果,并强调有丝分裂在胰腺癌临床治疗中的重要意义。
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引用次数: 0
Phosphodiesterase 4 is overexpressed in keloid epidermal scars and its inhibition reduces keratinocyte fibrotic alterations. 磷酸二酯酶 4 在瘢痕表皮疤痕中过度表达,抑制磷酸二酯酶 4 可减少角质细胞纤维化改变。
IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-02 DOI: 10.1186/s10020-024-00906-8
Javier Milara, Pilar Ribera, Severiano Marín, Paula Montero, Inés Roger, Julio Cortijo

Background: Epidermal remodeling and hypertrophy are hallmarks of skin fibrotic disorders, and keratinocyte to mesenchymal (EMT)-like transformations drive epidermis alteration in skin fibrosis such as keloids and hypertrophic scars (HTS). While phosphodiesterase 4 (PDE4) inhibitors have shown effectiveness in various fibrotic disorders, their role in skin fibrosis is not fully understood. This study aimed to explore the specific role of PDE4B in epidermal remodeling and hypertrophy seen in skin fibrosis.

Methods: In vitro experiments examined the effects of inhibiting PDE4A-D (with Roflumilast) or PDE4B (with siRNA) on TGFβ1-induced EMT differentiation and dedifferentiation in human 3D epidermis. In vivo studies investigated the impact of PDE4 inhibition on HOCl-induced skin fibrosis and epidermal hypertrophy in mice, employing both preventive and therapeutic approaches.

Results: The study found increased levels of PDE4B (mRNA, protein) in keloids > HTS compared to healthy epidermis, as well as in TGFβ-stimulated 3D epidermis. Keloids and HTS epidermis exhibited elevated levels of collagen Iα1, fibronectin, αSMA, N-cadherin, and NOX4 mRNA, along with decreased levels of E-cadherin and ZO-1, confirming an EMT process. Inhibition of both PDE4A-D and PDE4B prevented TGFβ1-induced Smad3 and ERK1/2 phosphorylation and mesenchymal differentiation in vitro. PDE4A-D inhibition also promoted mesenchymal dedifferentiation and reduced TGFβ1-induced ROS and keratinocyte senescence by rescuing PPM1A, a Smad3 phosphatase. In vivo, PDE4 inhibition mitigated HOCl-induced epidermal hypertrophy in mice in both preventive and therapeutic settings.

Conclusions: Overall, the study supports the potential of PDE4 inhibitors, particularly PDE4B, in treating skin fibrosis, including keloids and HTS, shedding light on their functional role in this condition.

背景:表皮重塑和肥厚是皮肤纤维化疾病的特征,角质细胞向间充质(EMT)的类似转化推动了瘢痕疙瘩和增生性疤痕(HTS)等皮肤纤维化中表皮的改变。虽然磷酸二酯酶4(PDE4)抑制剂在各种纤维化疾病中显示出了有效性,但它们在皮肤纤维化中的作用还不完全清楚。本研究旨在探索 PDE4B 在皮肤纤维化过程中表皮重塑和肥厚中的特殊作用:体外实验研究了抑制 PDE4A-D(使用罗氟司特)或 PDE4B(使用 siRNA)对 TGFβ1 诱导的人三维表皮 EMT 分化和去分化的影响。体内研究采用预防和治疗方法调查了 PDE4 抑制对 HOCl 诱导的小鼠皮肤纤维化和表皮肥厚的影响:研究发现,与健康表皮相比,瘢痕疙瘩 > HTS 表皮中的 PDE4B(mRNA、蛋白质)水平以及 TGFβ 刺激的三维表皮中的 PDE4B(mRNA、蛋白质)水平均有所提高。瘢痕疙瘩和HTS表皮的胶原蛋白Iα1、纤连蛋白、αSMA、N-钙粘连蛋白和NOX4 mRNA水平升高,而E-钙粘连蛋白和ZO-1水平下降,证实了EMT过程。抑制 PDE4A-D 和 PDE4B 可阻止 TGFβ1 诱导的 Smad3 和 ERK1/2 磷酸化以及体外间质分化。抑制 PDE4A-D 还能促进间质的去分化,并通过挽救 Smad3 磷酸酶 PPM1A 减少 TGFβ1 诱导的 ROS 和角质形成细胞的衰老。在体内,PDE4抑制剂可在预防和治疗两种情况下减轻HOCl诱导的小鼠表皮肥厚:总之,该研究支持 PDE4 抑制剂(尤其是 PDE4B)在治疗皮肤纤维化(包括瘢痕疙瘩和 HTS)方面的潜力,并揭示了它们在这种情况下的功能性作用。
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Molecular Medicine
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