首页 > 最新文献

Cells最新文献

英文 中文
Chronic Low-Dose-Rate Radiation-Induced Persistent DNA Damage and miRNA/mRNA Expression Changes in Mouse Hippocampus and Blood. 慢性低剂量辐射诱导的小鼠海马和血液持续DNA损伤及miRNA/mRNA表达变化
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-15 DOI: 10.3390/cells13201705
Hong Wang, Salihah Lau, Amanda Tan, Feng Ru Tang

Our previous study demonstrated that the acute high-dose-rate (3.3 Gy/min) γ-ray irradiation (γ-irradiation) of postnatal day-3 (P3) mice with 5 Gy induced depression and drastic neuropathological changes in the dentate gyrus of the hippocampus of adult mice. The present study investigated the effects of chronic low-dose-rate (1.2 mGy/h) γ-irradiation from P3 to P180 with a cumulative dose of 5 Gy on animal behaviour, hippocampal cellular change, and miRNA and mRNA expression in the hippocampus and blood in female mice. The radiation exposure did not significantly affect the animal's body weight, and neuropsychiatric changes such as anxiety and depression were examined by neurobehavioural tests, including open field, light-dark box, elevated plus maze, tail suspension, and forced swim tests. Immunohistochemical staining did not detect any obvious loss of mature and immature neurons (NeuN and DCX) or any inflammatory glial response (IBA1, GFAP, and PDGFRα). Nevertheless, γH2AX foci in the stratum granulosum of the dentate gyrus were significantly increased, suggesting the chronic low-dose-rate irradiation induced persistent DNA damage foci in mice. miRNA sequencing and qRT-PCR indicated an increased expression of miR-448-3p and miR-361-5p but decreased expression of miR-193a-3p in the mouse hippocampus. Meanwhile, mRNA sequencing and qRT-PCR showed the changed expression of some genes, including Fli1, Hs3st5, and Eif4ebp2. Database searching by miRDB and TargetScan predicted that Fli1 and Hs3st5 are the targets of miR-448-3p, and Eif4ebp2 is the target of miR-361-5p. miRNA/mRNA sequencing and qRT-PCR results in blood showed the increased expression of miR-6967-3p and the decreased expression of its target S1pr5. The interactions of these miRNAs and mRNAs may be related to the chronic low-dose-rate radiation-induced persistent DNA damage.

我们以前的研究表明,用 5 Gy 对出生后第 3 天(P3)的小鼠进行急性高剂量率(3.3 Gy/min)γ 射线照射(γ-辐照)会诱发抑郁和成年小鼠海马齿状回的神经病理学剧变。本研究调查了雌性小鼠从出生后第3天到第180天长期接受累积剂量为5 Gy的低剂量γ射线照射(1.2 mGy/h)对动物行为、海马细胞变化以及海马和血液中miRNA和mRNA表达的影响。辐照对动物的体重没有明显影响,通过神经行为测试,包括开阔地、光暗箱、高架加迷宫、尾悬浮和强迫游泳测试,考察了焦虑和抑郁等神经精神变化。免疫组化染色未检测到成熟和不成熟神经元(NeuN和DCX)的明显损失,也未检测到任何炎症性胶质细胞反应(IBA1、GFAP和PDGFRα)。miRNA测序和qRT-PCR表明,小鼠海马中miR-448-3p和miR-361-5p的表达增加,但miR-193a-3p的表达减少。同时,mRNA 测序和 qRT-PCR 显示,一些基因的表达发生了变化,包括 Fli1、Hs3st5 和 Eif4ebp2。通过 miRDB 和 TargetScan 的数据库搜索,预测 Fli1 和 Hs3st5 是 miR-448-3p 的靶标,Eif4ebp2 是 miR-361-5p 的靶标。这些 miRNA 与 mRNA 的相互作用可能与长期低剂量辐射诱导的持续 DNA 损伤有关。
{"title":"Chronic Low-Dose-Rate Radiation-Induced Persistent DNA Damage and miRNA/mRNA Expression Changes in Mouse Hippocampus and Blood.","authors":"Hong Wang, Salihah Lau, Amanda Tan, Feng Ru Tang","doi":"10.3390/cells13201705","DOIUrl":"https://doi.org/10.3390/cells13201705","url":null,"abstract":"<p><p>Our previous study demonstrated that the acute high-dose-rate (3.3 Gy/min) γ-ray irradiation (γ-irradiation) of postnatal day-3 (P3) mice with 5 Gy induced depression and drastic neuropathological changes in the dentate gyrus of the hippocampus of adult mice. The present study investigated the effects of chronic low-dose-rate (1.2 mGy/h) γ-irradiation from P3 to P180 with a cumulative dose of 5 Gy on animal behaviour, hippocampal cellular change, and miRNA and mRNA expression in the hippocampus and blood in female mice. The radiation exposure did not significantly affect the animal's body weight, and neuropsychiatric changes such as anxiety and depression were examined by neurobehavioural tests, including open field, light-dark box, elevated plus maze, tail suspension, and forced swim tests. Immunohistochemical staining did not detect any obvious loss of mature and immature neurons (NeuN and DCX) or any inflammatory glial response (IBA1, GFAP, and PDGFRα). Nevertheless, γH2AX foci in the stratum granulosum of the dentate gyrus were significantly increased, suggesting the chronic low-dose-rate irradiation induced persistent DNA damage foci in mice. miRNA sequencing and qRT-PCR indicated an increased expression of miR-448-3p and miR-361-5p but decreased expression of miR-193a-3p in the mouse hippocampus. Meanwhile, mRNA sequencing and qRT-PCR showed the changed expression of some genes, including <i>Fli1</i>, <i>Hs3st5</i>, and <i>Eif4ebp2</i>. Database searching by miRDB and TargetScan predicted that <i>Fli1</i> and <i>Hs3st5</i> are the targets of miR-448-3p, and <i>Eif4ebp2</i> is the target of miR-361-5p. miRNA/mRNA sequencing and qRT-PCR results in blood showed the increased expression of miR-6967-3p and the decreased expression of its target <i>S1pr5</i>. The interactions of these miRNAs and mRNAs may be related to the chronic low-dose-rate radiation-induced persistent DNA damage.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11505968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495931","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
A Comparative Analysis of Models for AAV-Mediated Gene Therapy for Inherited Retinal Diseases. AAV 基因疗法治疗遗传性视网膜疾病的模型比较分析。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-15 DOI: 10.3390/cells13201706
Almaqdad Alsalloum, Ekaterina Gornostal, Natalia Mingaleva, Roman Pavlov, Ekaterina Kuznetsova, Ekaterina Antonova, Aygun Nadzhafova, Daria Kolotova, Vitaly Kadyshev, Olga Mityaeva, Pavel Volchkov

Inherited retinal diseases (IRDs) represent a diverse group of genetic disorders leading to progressive degeneration of the retina due to mutations in over 280 genes. This review focuses on the various methodologies for the preclinical characterization and evaluation of adeno-associated virus (AAV)-mediated gene therapy as a potential treatment option for IRDs, particularly focusing on gene therapies targeting mutations, such as those in the RPE65 and FAM161A genes. AAV vectors, such as AAV2 and AAV5, have been utilized to deliver therapeutic genes, showing promise in preserving vision and enhancing photoreceptor function in animal models. Despite their advantages-including high production efficiency, low pathogenicity, and minimal immunogenicity-AAV-mediated therapies face limitations such as immune responses beyond the retina, vector size constraints, and challenges in large-scale manufacturing. This review systematically compares different experimental models used to investigate AAV-mediated therapies, such as mouse models, human retinal explants (HREs), and induced pluripotent stem cell (iPSC)-derived retinal organoids. Mouse models are advantageous for genetic manipulation and detailed investigations of disease mechanisms; however, anatomical differences between mice and humans may limit the translational applicability of results. HREs offer valuable insights into human retinal pathophysiology but face challenges such as tissue degradation and lack of systemic physiological effects. Retinal organoids, on the other hand, provide a robust platform that closely mimics human retinal development, thereby enabling more comprehensive studies on disease mechanisms and therapeutic strategies, including AAV-based interventions. Specific outcomes targeted in these studies include vision preservation and functional improvements of retinas damaged by genetic mutations. This review highlights the strengths and weaknesses of each experimental model and advocates for their combined use in developing targeted gene therapies for IRDs. As research advances, optimizing AAV vector design and delivery methods will be critical for enhancing therapeutic efficacy and improving clinical outcomes for patients with IRDs.

遗传性视网膜疾病(IRDs)是一组因 280 多种基因突变而导致视网膜进行性变性的遗传性疾病。本综述重点介绍临床前表征和评估腺相关病毒(AAV)介导的基因疗法作为IRDs潜在治疗方案的各种方法,尤其关注针对RPE65和FAM161A基因突变的基因疗法。AAV 载体,如 AAV2 和 AAV5,已被用于传递治疗基因,在动物模型中显示出保护视力和增强感光器功能的前景。尽管AAV介导的疗法具有生产效率高、致病性低和免疫原性小等优点,但也面临着一些限制,如视网膜以外的免疫反应、载体大小限制和大规模生产的挑战。本综述系统地比较了用于研究AAV介导疗法的不同实验模型,如小鼠模型、人类视网膜外植体(HRE)和诱导多能干细胞(iPSC)衍生的视网膜器官组织。小鼠模型有利于遗传操作和疾病机制的详细研究;然而,小鼠与人类在解剖学上的差异可能会限制研究结果的转化应用。HRE 为人类视网膜病理生理学提供了宝贵的见解,但也面临着组织退化和缺乏系统生理效应等挑战。另一方面,视网膜器官组织提供了一个近似人类视网膜发育的强大平台,从而可以对疾病机制和治疗策略(包括基于 AAV 的干预)进行更全面的研究。这些研究的具体目标结果包括视力保护和因基因突变而受损的视网膜的功能改善。本综述强调了每种实验模型的优缺点,并主张将它们结合起来用于开发针对 IRD 的基因疗法。随着研究的深入,优化 AAV 载体设计和递送方法对于提高 IRD 患者的治疗效果和临床预后至关重要。
{"title":"A Comparative Analysis of Models for AAV-Mediated Gene Therapy for Inherited Retinal Diseases.","authors":"Almaqdad Alsalloum, Ekaterina Gornostal, Natalia Mingaleva, Roman Pavlov, Ekaterina Kuznetsova, Ekaterina Antonova, Aygun Nadzhafova, Daria Kolotova, Vitaly Kadyshev, Olga Mityaeva, Pavel Volchkov","doi":"10.3390/cells13201706","DOIUrl":"10.3390/cells13201706","url":null,"abstract":"<p><p>Inherited retinal diseases (IRDs) represent a diverse group of genetic disorders leading to progressive degeneration of the retina due to mutations in over 280 genes. This review focuses on the various methodologies for the preclinical characterization and evaluation of adeno-associated virus (AAV)-mediated gene therapy as a potential treatment option for IRDs, particularly focusing on gene therapies targeting mutations, such as those in the <i>RPE65</i> and <i>FAM161A</i> genes. AAV vectors, such as AAV2 and AAV5, have been utilized to deliver therapeutic genes, showing promise in preserving vision and enhancing photoreceptor function in animal models. Despite their advantages-including high production efficiency, low pathogenicity, and minimal immunogenicity-AAV-mediated therapies face limitations such as immune responses beyond the retina, vector size constraints, and challenges in large-scale manufacturing. This review systematically compares different experimental models used to investigate AAV-mediated therapies, such as mouse models, human retinal explants (HREs), and induced pluripotent stem cell (iPSC)-derived retinal organoids. Mouse models are advantageous for genetic manipulation and detailed investigations of disease mechanisms; however, anatomical differences between mice and humans may limit the translational applicability of results. HREs offer valuable insights into human retinal pathophysiology but face challenges such as tissue degradation and lack of systemic physiological effects. Retinal organoids, on the other hand, provide a robust platform that closely mimics human retinal development, thereby enabling more comprehensive studies on disease mechanisms and therapeutic strategies, including AAV-based interventions. Specific outcomes targeted in these studies include vision preservation and functional improvements of retinas damaged by genetic mutations. This review highlights the strengths and weaknesses of each experimental model and advocates for their combined use in developing targeted gene therapies for IRDs. As research advances, optimizing AAV vector design and delivery methods will be critical for enhancing therapeutic efficacy and improving clinical outcomes for patients with IRDs.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495905","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
Novel TSPO Ligand 2-Cl-MGV-1 Can Counteract Lipopolysaccharide Induced Inflammatory Response in Murine RAW264.7 Macrophage Cell Line and Lung Models. 新型 TSPO 配体 2-Cl-MGV-1 可抵消脂多糖诱导的小鼠 RAW264.7 巨噬细胞系和肺部模型的炎症反应。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-15 DOI: 10.3390/cells13201702
Fadi Obeid, Meygal Kahana, Baraah Dahle, Sheelu Monga, Yaniv Zohar, Abraham Weizman, Moshe Gavish

We assessed the anti-inflammatory activity of the TSPO ligand 2-Cl-MGV-1. Lipopolysaccharide (LPS) was used to induce inflammatory response in a murine RAW264.7 macrophage model (LPS: 100 ng/mL) and a mouse model (C57BL/6) of lung inflammation (LPS: 5 mg/kg). In the macrophage model, the presence of 2-Cl-MGV-1 (25 µM) caused the LPS-induced elevation in nitrite levels to decrease by 70% (p < 0.0001) and interleukin (IL)-6 by 50% (p < 0.05). In the mouse model, 2-Cl-MGV-1, administered 30 min before, or co-administered with, an LPS injection, significantly inhibited the elevation in serum IL-5 levels (both by 65%; p < 0.001 and p < 0.01, respectively). 2-Cl-MGV-1 administration to mice 30 min before LPS injection and 1 h thereafter significantly inhibited the elevation in IL-1β serum levels (both by 63%, p < 0.005). IL-6 elevation was inhibited by 73% (p < 0.005) when 2-Cl-MGV-1 was administered 30 min before LPS, by 60% (p < 0.05) when co-administered with LPS, and by 64% (p < 0.05) when administered 1 h after LPS. All cytokine assessments were conducted 6 h post LPS injection. Histological analyses showed decreased leukocyte adherence in the lung tissue of the ligand-treated mice. 2-Cl-MGV-1 administration 30 min prior to exposure to LPS inhibited inflammation-induced open field immobility. The beneficial effect of 2-Cl-MGV-1 suggests its potential as a therapeutic option for inflammatory diseases.

我们评估了TSPO配体2-Cl-MGV-1的抗炎活性。在小鼠 RAW264.7 巨噬细胞模型(LPS:100 ng/mL)和小鼠(C57BL/6)肺部炎症模型(LPS:5 mg/kg)中,我们使用脂多糖(LPS)诱导炎症反应。在巨噬细胞模型中,2-Cl-MGV-1(25 µM)的存在使 LPS 诱导的亚硝酸盐水平升高降低了 70%(p < 0.0001),白细胞介素(IL)-6 降低了 50%(p < 0.05)。在小鼠模型中,在注射 LPS 前 30 分钟注射或同时注射 2-Cl-MGV-1 可显著抑制血清 IL-5 水平的升高(均降低 65%;p < 0.001 和 p < 0.01)。在注射 LPS 前 30 分钟和注射后 1 小时给小鼠服用 2-Cl-MGV-1 可明显抑制 IL-1β 血清水平的升高(两者均升高 63%,p < 0.005)。在注射 LPS 前 30 分钟注射 2-Cl-MGV-1 可抑制 IL-6 水平升高 73%(p < 0.005),与 LPS 同时注射可抑制 60%(p < 0.05),在注射 LPS 后 1 小时注射可抑制 64%(p < 0.05)。所有细胞因子评估均在注射 LPS 6 小时后进行。组织学分析表明,配体处理过的小鼠肺组织中的白细胞粘附性降低。在暴露于 LPS 前 30 分钟注射 2-Cl-MGV-1 可抑制炎症引起的开放性活动障碍。2-Cl-MGV-1 的有益作用表明,它有可能成为治疗炎症性疾病的一种选择。
{"title":"Novel TSPO Ligand 2-Cl-MGV-1 Can Counteract Lipopolysaccharide Induced Inflammatory Response in Murine RAW264.7 Macrophage Cell Line and Lung Models.","authors":"Fadi Obeid, Meygal Kahana, Baraah Dahle, Sheelu Monga, Yaniv Zohar, Abraham Weizman, Moshe Gavish","doi":"10.3390/cells13201702","DOIUrl":"https://doi.org/10.3390/cells13201702","url":null,"abstract":"<p><p>We assessed the anti-inflammatory activity of the TSPO ligand 2-Cl-MGV-1. Lipopolysaccharide (LPS) was used to induce inflammatory response in a murine RAW264.7 macrophage model (LPS: 100 ng/mL) and a mouse model (C57BL/6) of lung inflammation (LPS: 5 mg/kg). In the macrophage model, the presence of 2-Cl-MGV-1 (25 µM) caused the LPS-induced elevation in nitrite levels to decrease by 70% (<i>p</i> < 0.0001) and interleukin (IL)-6 by 50% (<i>p</i> < 0.05). In the mouse model, 2-Cl-MGV-1, administered 30 min before, or co-administered with, an LPS injection, significantly inhibited the elevation in serum IL-5 levels (both by 65%; <i>p</i> < 0.001 and <i>p</i> < 0.01, respectively). 2-Cl-MGV-1 administration to mice 30 min before LPS injection and 1 h thereafter significantly inhibited the elevation in IL-1β serum levels (both by 63%, <i>p</i> < 0.005). IL-6 elevation was inhibited by 73% (<i>p</i> < 0.005) when 2-Cl-MGV-1 was administered 30 min before LPS, by 60% (<i>p</i> < 0.05) when co-administered with LPS, and by 64% (<i>p</i> < 0.05) when administered 1 h after LPS. All cytokine assessments were conducted 6 h post LPS injection. Histological analyses showed decreased leukocyte adherence in the lung tissue of the ligand-treated mice. 2-Cl-MGV-1 administration 30 min prior to exposure to LPS inhibited inflammation-induced open field immobility. The beneficial effect of 2-Cl-MGV-1 suggests its potential as a therapeutic option for inflammatory diseases.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495926","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
Decreased Circulating Gonadotropin-Releasing Hormone Associated with Keratoconus. 与角膜炎有关的促性腺激素释放激素循环减少。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-15 DOI: 10.3390/cells13201704
Paulina Escandon, Alexander J Choi, Steve Mabry, Sarah E Nicholas, Rebecca L Cunningham, Liam Redden, David A Murphy, Kamran M Riaz, Tina B McKay, Dimitrios Karamichos

Keratoconus (KC) is a corneal thinning dystrophy that leads to visual impairment. While the cause of KC remains poorly understood, changes in sex hormone levels have been correlated with KC development. This study investigated circulating gonadotropin-releasing hormone (GnRH) in control and KC subjects to determine if this master hormone regulator is linked to the KC pathology. Plasma and saliva were collected from KC subjects (n = 227 and n = 274, respectively) and non-KC controls (n = 58 and n = 101, respectively), in concert with patient demographics and clinical features. GnRH levels in both plasma and saliva were significantly lower in KC subjects compared to controls. This finding was retained in plasma when subjects were stratified based on age, sex, and KC severity. Control and KC corneal fibroblasts (HKCs) stimulated with recombinant GnRH protein in vitro revealed significantly increased luteinizing hormone receptor by HKCs and reduced expression of α-smooth muscle actin with treatment suggesting that GnRH may modulate hormonal and fibrotic responses in the KC corneal stroma. Further studies are needed to reveal the role of the hypothalamic-pituitary-gonadal axis in the onset and progression of KC and to explore this pathway as a novel therapeutic target.

角膜塑形镜(KC)是一种角膜变薄营养不良症,会导致视力受损。虽然人们对 KC 的病因仍然知之甚少,但性激素水平的变化与 KC 的发病有一定的相关性。本研究调查了对照组和 KC 受试者体内的促性腺激素释放激素(GnRH)循环情况,以确定这种激素调节剂是否与 KC 病理学有关。研究人员收集了 KC 受试者(分别为 227 人和 274 人)和非 KC 对照组(分别为 58 人和 101 人)的血浆和唾液,并结合患者的人口统计学特征和临床特征进行了分析。与对照组相比,KC 受试者血浆和唾液中的 GnRH 水平明显较低。根据年龄、性别和 KC 严重程度对受试者进行分层后,血浆中的这一结果依然存在。体外用重组 GnRH 蛋白刺激对照组和 KC 角膜成纤维细胞(HKCs)后发现,HKCs 的黄体生成素受体明显增加,α-平滑肌肌动蛋白的表达在治疗过程中减少,这表明 GnRH 可能会调节 KC 角膜基质中的激素和纤维化反应。要揭示下丘脑-垂体-性腺轴在 KC 发病和发展过程中的作用,并将这一途径作为新的治疗靶点,还需要进一步的研究。
{"title":"Decreased Circulating Gonadotropin-Releasing Hormone Associated with Keratoconus.","authors":"Paulina Escandon, Alexander J Choi, Steve Mabry, Sarah E Nicholas, Rebecca L Cunningham, Liam Redden, David A Murphy, Kamran M Riaz, Tina B McKay, Dimitrios Karamichos","doi":"10.3390/cells13201704","DOIUrl":"https://doi.org/10.3390/cells13201704","url":null,"abstract":"<p><p>Keratoconus (KC) is a corneal thinning dystrophy that leads to visual impairment. While the cause of KC remains poorly understood, changes in sex hormone levels have been correlated with KC development. This study investigated circulating gonadotropin-releasing hormone (GnRH) in control and KC subjects to determine if this master hormone regulator is linked to the KC pathology. Plasma and saliva were collected from KC subjects (n = 227 and n = 274, respectively) and non-KC controls (n = 58 and n = 101, respectively), in concert with patient demographics and clinical features. GnRH levels in both plasma and saliva were significantly lower in KC subjects compared to controls. This finding was retained in plasma when subjects were stratified based on age, sex, and KC severity. Control and KC corneal fibroblasts (HKCs) stimulated with recombinant GnRH protein in vitro revealed significantly increased luteinizing hormone receptor by HKCs and reduced expression of α-smooth muscle actin with treatment suggesting that GnRH may modulate hormonal and fibrotic responses in the KC corneal stroma. Further studies are needed to reveal the role of the hypothalamic-pituitary-gonadal axis in the onset and progression of KC and to explore this pathway as a novel therapeutic target.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495952","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
Polo-like Kinase 1 Predicts Lymph Node Metastasis in Middle Eastern Colorectal Cancer Patients; Its Inhibition Reverses 5-Fu Resistance in Colorectal Cancer Cells. Polo-like Kinase 1 预测中东结直肠癌患者的淋巴结转移;抑制该酶可逆转结直肠癌细胞对 5-Fu 的耐药性
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-14 DOI: 10.3390/cells13201700
Pratheesh Kumar Poyil, Abdul K Siraj, Divya Padmaja, Sandeep Kumar Parvathareddy, Khadija Alobaisi, Saravanan Thangavel, Rafia Begum, Roxanne Diaz, Fouad Al-Dayel, Khawla S Al-Kuraya

Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase essential for regulating multiple stages of cell cycle progression in mammals. Aberrant regulation of PLK1 has been observed in numerous human cancers and is linked to poor prognoses. However, its role in the pathogenesis of colorectal cancer (CRC) in the Middle East remains unexplored. PLK1 overexpression was noted in 60.3% (693/1149) of CRC cases and was significantly associated with aggressive clinico-pathological parameters and p-ERK1/2 overexpression. Intriguingly, multivariate logistic regression analysis identified PLK1 as an independent predictor of lymph node metastasis. Our in vitro experiments demonstrated that CRC cells with high PLK1 levels were resistant to 5-Fu treatment, while those with low PLK1 expression were sensitive. To investigate PLK1's role in chemoresistance, we used the specific inhibitor volasertib, which effectively reversed 5-Fu resistance. Interestingly, forced PLK1 expression activated the CRAF-MEK-ERK signaling cascade, while its inhibition suppressed this cascade. PLK1 knockdown reduced epithelial-to-mesenchymal transition (EMT) progression and stem cell-like traits in 5-Fu-resistant cells, implicating PLK1 in EMT induction and stemness in CRC. Moreover, silencing ERK1/2 significantly mitigated chemoresistance, EMT, and stemness properties in CRC cell lines that express PLK1. Furthermore, the knockdown of Zeb1 attenuated EMT and stemness, suggesting a possible link between EMT activation and the maintenance of stemness in CRC. Our findings underscore the pivotal role of PLK1 in mediating chemoresistance and suggest that PLK1 inhibition may represent a potential therapeutic strategy for the management of aggressive colorectal cancer subtypes.

Polo-like kinase 1(PLK1)是一种丝氨酸/苏氨酸蛋白激酶,对调节哺乳动物细胞周期进展的多个阶段至关重要。在许多人类癌症中都发现了 PLK1 的异常调控,并且与预后不良有关。然而,在中东地区,PLK1 在结直肠癌(CRC)发病机制中的作用仍有待探索。在 60.3% 的 CRC 病例(693/1149)中发现 PLK1 过表达,并且与侵袭性临床病理参数和 p-ERK1/2 过表达密切相关。有趣的是,多变量逻辑回归分析发现 PLK1 是淋巴结转移的独立预测因子。我们的体外实验表明,PLK1水平高的CRC细胞对5-Fu治疗有抵抗力,而PLK1表达低的细胞对5-Fu治疗敏感。为了研究PLK1在化疗耐药性中的作用,我们使用了特异性抑制剂volasertib,它能有效逆转5-Fu耐药性。有趣的是,强迫PLK1表达会激活CRAF-MEK-ERK信号级联,而抑制PLK1表达则会抑制该级联。PLK1的敲除减少了5-Fu耐药细胞的上皮细胞向间质转化(EMT)进程和干细胞样特征,这表明PLK1与CRC的EMT诱导和干性有关。此外,沉默ERK1/2能显著减轻表达PLK1的CRC细胞系的化疗耐药性、EMT和干细胞特性。此外,敲除Zeb1可减轻EMT和干性,这表明EMT激活与CRC干性维持之间可能存在联系。我们的发现强调了PLK1在介导化疗耐药性中的关键作用,并表明抑制PLK1可能是治疗侵袭性结直肠癌亚型的一种潜在治疗策略。
{"title":"Polo-like Kinase 1 Predicts Lymph Node Metastasis in Middle Eastern Colorectal Cancer Patients; Its Inhibition Reverses 5-Fu Resistance in Colorectal Cancer Cells.","authors":"Pratheesh Kumar Poyil, Abdul K Siraj, Divya Padmaja, Sandeep Kumar Parvathareddy, Khadija Alobaisi, Saravanan Thangavel, Rafia Begum, Roxanne Diaz, Fouad Al-Dayel, Khawla S Al-Kuraya","doi":"10.3390/cells13201700","DOIUrl":"https://doi.org/10.3390/cells13201700","url":null,"abstract":"<p><p>Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase essential for regulating multiple stages of cell cycle progression in mammals. Aberrant regulation of PLK1 has been observed in numerous human cancers and is linked to poor prognoses. However, its role in the pathogenesis of colorectal cancer (CRC) in the Middle East remains unexplored. PLK1 overexpression was noted in 60.3% (693/1149) of CRC cases and was significantly associated with aggressive clinico-pathological parameters and p-ERK1/2 overexpression. Intriguingly, multivariate logistic regression analysis identified PLK1 as an independent predictor of lymph node metastasis. Our in vitro experiments demonstrated that CRC cells with high PLK1 levels were resistant to 5-Fu treatment, while those with low PLK1 expression were sensitive. To investigate PLK1's role in chemoresistance, we used the specific inhibitor volasertib, which effectively reversed 5-Fu resistance. Interestingly, forced PLK1 expression activated the CRAF-MEK-ERK signaling cascade, while its inhibition suppressed this cascade. PLK1 knockdown reduced epithelial-to-mesenchymal transition (EMT) progression and stem cell-like traits in 5-Fu-resistant cells, implicating PLK1 in EMT induction and stemness in CRC. Moreover, silencing ERK1/2 significantly mitigated chemoresistance, EMT, and stemness properties in CRC cell lines that express PLK1. Furthermore, the knockdown of Zeb1 attenuated EMT and stemness, suggesting a possible link between EMT activation and the maintenance of stemness in CRC. Our findings underscore the pivotal role of PLK1 in mediating chemoresistance and suggest that PLK1 inhibition may represent a potential therapeutic strategy for the management of aggressive colorectal cancer subtypes.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495944","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
β-Mangostin Alleviates Renal Tubulointerstitial Fibrosis via the TGF-β1/JNK Signaling Pathway. β-曼戈斯汀通过 TGF-β1/JNK 信号通路缓解肾小管间质纤维化
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-14 DOI: 10.3390/cells13201701
Po-Yu Huang, Ying-Hsu Juan, Tung-Wei Hung, Yuan-Pei Tsai, Yi-Hsuan Ting, Chu-Che Lee, Jen-Pi Tsai, Yi-Hsien Hsieh

The epithelial-to-mesenchymal transition (EMT) plays a key role in the pathogenesis of kidney fibrosis, and kidney fibrosis is associated with an adverse renal prognosis. Beta-mangostin (β-Mag) is a xanthone derivative obtained from mangosteens that is involved in the generation of antifibrotic and anti-oxidation effects. The purpose of this study was to examine the effects of β-Mag on renal tubulointerstitial fibrosis both in vivo and in vitro and the corresponding mechanisms involved. As shown through an in vivo study conducted on a unilateral ureteral obstruction mouse model, oral β-Mag administration, in a dose-dependent manner, caused a lesser degree of tubulointerstitial damage, diminished collagen I fiber deposition, and the depressed expression of fibrotic markers (collagen I, α-SMA) and EMT markers (N-cadherin, Vimentin, Snail, and Slug) in the UUO kidney tissues. The in vitro part of this research revealed that β-Mag, when co-treated with transforming growth factor-β1 (TGF-β1), decreased cell motility and downregulated the EMT (in relation to Vimentin, Snail, and N-cadherin) and phosphoryl-JNK1/2/Smad2/Smad3 expression. Furthermore, β-Mag co-treated with SB (Smad2/3 kinase inhibitor) or SP600125 (JNK kinase inhibitor) significantly inhibited the TGF-β1-associated downstream phosphorylation and activation of JNK1/2-mediated Smad2 targeting the Snail/Vimentin axis. To conclude, β-Mag protects against EMT and kidney fibrotic processes by mediating the TGF-β1/JNK/Smad2 targeting Snail-mediated Vimentin expression and may have therapeutic implications for renal tubulointerstitial fibrosis.

上皮细胞向间质转化(EMT)在肾脏纤维化的发病机制中起着关键作用,肾脏纤维化与不良的肾脏预后有关。β-山竹素(β-Mag)是从山竹中提取的一种氧杂蒽酮衍生物,具有抗纤维化和抗氧化作用。本研究的目的是探讨β-Mag在体内和体外对肾小管间质纤维化的影响以及相应的作用机制。在单侧输尿管梗阻小鼠模型上进行的体内研究表明,口服β-Mag能减轻UUO肾组织中肾小管间质的损伤程度、减少胶原蛋白I纤维沉积、抑制纤维化标记物(胶原蛋白I、α-SMA)和EMT标记物(N-粘连蛋白、波形蛋白、蜗牛和蛞蝓)的表达,其作用呈剂量依赖性。这项研究的体外部分显示,β-Mag 与转化生长因子-β1(TGF-β1)共同处理时,可降低细胞的运动性,并下调 EMT(与波形蛋白、蜗牛和 N-钙粘连蛋白有关)和磷酸化-JNK1/2/Smad2/Smad3 的表达。此外,β-Mag 与 SB(Smad2/3 激酶抑制剂)或 SP600125(JNK 激酶抑制剂)联合处理可显著抑制 TGF-β1 相关的下游磷酸化和 JNK1/2 介导的 Smad2 靶向蜗牛/波形蛋白轴的激活。总之,β-Mag 通过介导 TGF-β1/JNK/Smad2 靶向 Snail 介导的 Vimentin 表达,保护 EMT 和肾脏纤维化过程,可能对肾小管间质纤维化有治疗意义。
{"title":"β-Mangostin Alleviates Renal Tubulointerstitial Fibrosis via the TGF-β1/JNK Signaling Pathway.","authors":"Po-Yu Huang, Ying-Hsu Juan, Tung-Wei Hung, Yuan-Pei Tsai, Yi-Hsuan Ting, Chu-Che Lee, Jen-Pi Tsai, Yi-Hsien Hsieh","doi":"10.3390/cells13201701","DOIUrl":"https://doi.org/10.3390/cells13201701","url":null,"abstract":"<p><p>The epithelial-to-mesenchymal transition (EMT) plays a key role in the pathogenesis of kidney fibrosis, and kidney fibrosis is associated with an adverse renal prognosis. Beta-mangostin (β-Mag) is a xanthone derivative obtained from mangosteens that is involved in the generation of antifibrotic and anti-oxidation effects. The purpose of this study was to examine the effects of β-Mag on renal tubulointerstitial fibrosis both in vivo and in vitro and the corresponding mechanisms involved. As shown through an in vivo study conducted on a unilateral ureteral obstruction mouse model, oral β-Mag administration, in a dose-dependent manner, caused a lesser degree of tubulointerstitial damage, diminished collagen I fiber deposition, and the depressed expression of fibrotic markers (collagen I, α-SMA) and EMT markers (N-cadherin, Vimentin, Snail, and Slug) in the UUO kidney tissues. The in vitro part of this research revealed that β-Mag, when co-treated with transforming growth factor-β1 (TGF-β1), decreased cell motility and downregulated the EMT (in relation to Vimentin, Snail, and N-cadherin) and phosphoryl-JNK1/2/Smad2/Smad3 expression. Furthermore, β-Mag co-treated with SB (Smad2/3 kinase inhibitor) or SP600125 (JNK kinase inhibitor) significantly inhibited the TGF-β1-associated downstream phosphorylation and activation of JNK1/2-mediated Smad2 targeting the Snail/Vimentin axis. To conclude, β-Mag protects against EMT and kidney fibrotic processes by mediating the TGF-β1/JNK/Smad2 targeting Snail-mediated Vimentin expression and may have therapeutic implications for renal tubulointerstitial fibrosis.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11505648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495974","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
Bromodomain-Containing 4 Is a Positive Regulator of Interleukin-34 Production in the Gut. 含溴结构域的 4 是肠道内白细胞介素-34 生成的积极调节因子
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-14 DOI: 10.3390/cells13201698
Eleonora Franzè, Federica Laudisi, Rachele Frascatani, Lorenzo Tomassini, Elena De Cristofaro, Carmine Stolfi, Giovanni Monteleone

Experimental evidence suggests that, in the inflamed gut of inflammatory bowel disease (IBD) patients, interleukin-34 (IL-34) triggers detrimental signaling pathways. Factors/mechanisms regulating IL-34 production in IBD remain poorly characterized. Bromodomain-containing 4 (BRD4), a transcriptional and epigenetic regulator, is over-expressed in IBD, and studies in cancer cells suggest that BRD4 might positively control IL-34 expression. This study aimed to assess whether, in IBD, BRD4 regulates IL-34 expression. In IBD, there was an up-regulation of both IL-34 and BRD4 compared to the controls, and the two proteins co-localized in both lamina propria mononuclear cells (LPMCs) and epithelial cells. Flow cytometry analysis of CD45+ LPMCs confirmed that the percentages of IL-34- and BRD4-co-expressing cells were significantly higher in IBD than in the controls and showed that more than 80% of the IL-34-positive CD45-LPMCs expressed BRD4. IL-34 and BRD4 were mainly expressed by T cells and macrophages. IL-34 expression was reduced in IBD LPMCs transfected with BRD4 antisense oligonucleotide and in the colons of mice with dextran sulfate sodium-induced colitis treated with JQ1, a pharmacological inhibitor of BRD4. These data indicate that BRD4 is a positive regulator of IL-34 in IBD, further supporting the pathogenic role of BRD4 in IBD-associated mucosal inflammation.

实验证据表明,在炎症性肠病(IBD)患者发炎的肠道中,白细胞介素-34(IL-34)会触发有害的信号通路。IBD中调节IL-34产生的因素/机制仍然特征不清。含溴结构域 4(BRD4)是一种转录和表观遗传调节因子,在 IBD 中过度表达,而对癌细胞的研究表明,BRD4 可能会积极控制 IL-34 的表达。本研究旨在评估IBD中BRD4是否调控IL-34的表达。与对照组相比,IL-34和BRD4在IBD中均有上调,这两种蛋白在固有层单核细胞(LPMCs)和上皮细胞中均有共定位。对 CD45+ LPMCs 的流式细胞术分析证实,IBD 患者 IL-34 和 BRD4 协同表达细胞的百分比明显高于对照组,并显示超过 80% 的 IL-34 阳性 CD45-LPMCs 表达 BRD4。IL-34和BRD4主要由T细胞和巨噬细胞表达。IL-34在转染了BRD4反义寡核苷酸的IBD LPMCs中以及在使用BRD4药理抑制剂JQ1治疗的右旋糖酐硫酸钠诱导的结肠炎小鼠的结肠中表达减少。这些数据表明,BRD4是IBD中IL-34的正向调节因子,进一步支持了BRD4在IBD相关粘膜炎症中的致病作用。
{"title":"Bromodomain-Containing 4 Is a Positive Regulator of Interleukin-34 Production in the Gut.","authors":"Eleonora Franzè, Federica Laudisi, Rachele Frascatani, Lorenzo Tomassini, Elena De Cristofaro, Carmine Stolfi, Giovanni Monteleone","doi":"10.3390/cells13201698","DOIUrl":"https://doi.org/10.3390/cells13201698","url":null,"abstract":"<p><p>Experimental evidence suggests that, in the inflamed gut of inflammatory bowel disease (IBD) patients, interleukin-34 (IL-34) triggers detrimental signaling pathways. Factors/mechanisms regulating IL-34 production in IBD remain poorly characterized. Bromodomain-containing 4 (BRD4), a transcriptional and epigenetic regulator, is over-expressed in IBD, and studies in cancer cells suggest that BRD4 might positively control IL-34 expression. This study aimed to assess whether, in IBD, BRD4 regulates IL-34 expression. In IBD, there was an up-regulation of both IL-34 and BRD4 compared to the controls, and the two proteins co-localized in both lamina propria mononuclear cells (LPMCs) and epithelial cells. Flow cytometry analysis of CD45+ LPMCs confirmed that the percentages of IL-34- and BRD4-co-expressing cells were significantly higher in IBD than in the controls and showed that more than 80% of the IL-34-positive CD45-LPMCs expressed BRD4. IL-34 and BRD4 were mainly expressed by T cells and macrophages. IL-34 expression was reduced in IBD LPMCs transfected with BRD4 antisense oligonucleotide and in the colons of mice with dextran sulfate sodium-induced colitis treated with JQ1, a pharmacological inhibitor of BRD4. These data indicate that BRD4 is a positive regulator of IL-34 in IBD, further supporting the pathogenic role of BRD4 in IBD-associated mucosal inflammation.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11505644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495927","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
Modulatory Effects of Regulated Cell Death: An Innovative Preventive Approach for the Control of Mastitis. 调控细胞死亡的调节作用:控制乳腺炎的创新预防方法。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-14 DOI: 10.3390/cells13201699
Xiaojing Xia, Pengfei Ren, Yilin Bai, Jingjing Li, Huihui Zhang, Lei Wang, Jianhe Hu, Xinwei Li, Ke Ding

Mastitis is a common disease worldwide that affects the development of the dairy industry due to its high incidence and complex etiology. Precise regulation of cell death and survival plays a critical role in maintaining internal homeostasis, organ development, and immune function in organisms, and regulatory abnormalities are a common mechanism of various pathological changes. Recent research has shown that regulated cell death (RCD) plays a crucial role in mastitis. The development of drugs to treat cell death and survival abnormalities that can be widely used in mastitis treatment has important clinical significance. This paper will review the molecular mechanisms of apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis and their regulatory roles in mastitis to provide a new perspective for the targeted treatment of mastitis.

乳腺炎是一种世界性常见病,发病率高,病因复杂,影响着奶业的发展。细胞死亡和存活的精确调控在维持生物体内部平衡、器官发育和免疫功能方面起着至关重要的作用,而调控异常是各种病理变化的常见机制。最新研究表明,调节性细胞死亡(RCD)在乳腺炎中起着至关重要的作用。开发治疗细胞死亡和存活异常的药物并广泛应用于乳腺炎的治疗具有重要的临床意义。本文将综述细胞凋亡、自噬、热凋亡、铁凋亡和坏死的分子机制及其在乳腺炎中的调控作用,为乳腺炎的靶向治疗提供新的视角。
{"title":"Modulatory Effects of Regulated Cell Death: An Innovative Preventive Approach for the Control of Mastitis.","authors":"Xiaojing Xia, Pengfei Ren, Yilin Bai, Jingjing Li, Huihui Zhang, Lei Wang, Jianhe Hu, Xinwei Li, Ke Ding","doi":"10.3390/cells13201699","DOIUrl":"https://doi.org/10.3390/cells13201699","url":null,"abstract":"<p><p>Mastitis is a common disease worldwide that affects the development of the dairy industry due to its high incidence and complex etiology. Precise regulation of cell death and survival plays a critical role in maintaining internal homeostasis, organ development, and immune function in organisms, and regulatory abnormalities are a common mechanism of various pathological changes. Recent research has shown that regulated cell death (RCD) plays a crucial role in mastitis. The development of drugs to treat cell death and survival abnormalities that can be widely used in mastitis treatment has important clinical significance. This paper will review the molecular mechanisms of apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis and their regulatory roles in mastitis to provide a new perspective for the targeted treatment of mastitis.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495922","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
Genetic and Molecular Heterogeneity of Synovial Sarcoma and Associated Challenges in Therapy. 滑膜肉瘤的遗传和分子异质性及相关治疗难题。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-14 DOI: 10.3390/cells13201695
Ekaterina A Lesovaya, Timur I Fetisov, Beniamin Yu Bokhyan, Varvara P Maksimova, Evgeny P Kulikov, Gennady A Belitsky, Kirill I Kirsanov, Marianna G Yakubovskaya

Synovial sarcoma (SS) is one of the most common types of pediatric soft tissue sarcoma (STS) being far less frequent in adults. This STS type is characterized by one specific chromosomal translocation SS18-SSX and the associated changes in signaling. However, other genetic and epigenetic abnormalities in SS do not necessarily include SS18-SSX-related events, but abnormalities are more sporadic and do not correlate well with the prognosis and response to therapy. Currently, targeted therapy for synovial sarcoma includes a limited range of drugs, and surgical resection is the mainstay treatment for localized cancer with adjuvant or neoadjuvant chemotherapy and radiotherapy. Understanding the molecular characteristics of synovial sarcoma subtypes is becoming increasingly important for detecting new potential targets and developing innovative therapies. Novel approaches to treating synovial sarcoma include immune-based therapies (such as TCR-T cell therapy to NY-ESO-1, MAGE4, PRAME or using immune checkpoint inhibitors), epigenetic modifiers (HDAC inhibitors, EZH2 inhibitors, BRD disruptors), as well as novel or repurposed receptor tyrosine kinase inhibitors. In the presented review, we aimed to summarize the genetic and epigenetic landscape of SS as well as to find out the potential niches for the development of novel diagnostics and therapies.

滑膜肉瘤(SS)是小儿软组织肉瘤(STS)中最常见的类型之一,在成人中的发病率要低得多。这种 STS 类型的特征是一种特定的染色体易位 SS18-SSX 和相关的信号变化。然而,STS 中的其他遗传和表观遗传异常并不一定包括 SS18-SSX 相关事件,但异常多为散发性,且与预后和治疗反应关系不大。目前,滑膜肉瘤的靶向治疗药物种类有限,手术切除是局部癌症的主要治疗方法,并辅以辅助或新辅助化疗和放疗。了解滑膜肉瘤亚型的分子特征对于发现新的潜在靶点和开发创新疗法越来越重要。治疗滑膜肉瘤的新方法包括基于免疫的疗法(如针对 NY-ESO-1、MAGE4、PRAME 的 TCR-T 细胞疗法或使用免疫检查点抑制剂)、表观遗传修饰剂(HDAC 抑制剂、EZH2 抑制剂、BRD 破坏剂)以及新型或再利用受体酪氨酸激酶抑制剂。在本综述中,我们旨在总结 SS 的遗传和表观遗传学情况,并找出开发新型诊断和疗法的潜在利基。
{"title":"Genetic and Molecular Heterogeneity of Synovial Sarcoma and Associated Challenges in Therapy.","authors":"Ekaterina A Lesovaya, Timur I Fetisov, Beniamin Yu Bokhyan, Varvara P Maksimova, Evgeny P Kulikov, Gennady A Belitsky, Kirill I Kirsanov, Marianna G Yakubovskaya","doi":"10.3390/cells13201695","DOIUrl":"https://doi.org/10.3390/cells13201695","url":null,"abstract":"<p><p>Synovial sarcoma (SS) is one of the most common types of pediatric soft tissue sarcoma (STS) being far less frequent in adults. This STS type is characterized by one specific chromosomal translocation SS18-SSX and the associated changes in signaling. However, other genetic and epigenetic abnormalities in SS do not necessarily include SS18-SSX-related events, but abnormalities are more sporadic and do not correlate well with the prognosis and response to therapy. Currently, targeted therapy for synovial sarcoma includes a limited range of drugs, and surgical resection is the mainstay treatment for localized cancer with adjuvant or neoadjuvant chemotherapy and radiotherapy. Understanding the molecular characteristics of synovial sarcoma subtypes is becoming increasingly important for detecting new potential targets and developing innovative therapies. Novel approaches to treating synovial sarcoma include immune-based therapies (such as TCR-T cell therapy to NY-ESO-1, MAGE4, PRAME or using immune checkpoint inhibitors), epigenetic modifiers (HDAC inhibitors, EZH2 inhibitors, BRD disruptors), as well as novel or repurposed receptor tyrosine kinase inhibitors. In the presented review, we aimed to summarize the genetic and epigenetic landscape of SS as well as to find out the potential niches for the development of novel diagnostics and therapies.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11506332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495959","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
Single-Cell Hypertrophy Promotes Contractile Function of Cultured Human Airway Smooth Muscle Cells via Piezo1 and YAP Auto-Regulation. 单细胞肥大通过 Piezo1 和 YAP 自调控促进培养人气道平滑肌细胞的收缩功能
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-14 DOI: 10.3390/cells13201697
Kai Ni, Bo Che, Rong Gu, Chunhong Wang, Yan Pan, Jingjing Li, Lei Liu, Mingzhi Luo, Linhong Deng

Severe asthma is characterized by increased cell volume (hypertrophy) and enhanced contractile function (hyperresponsiveness) of the airway smooth muscle cells (ASMCs). The causative relationship and underlying regulatory mechanisms between them, however, have remained unclear. Here, we manipulated the single-cell volume of in vitro cultured human ASMCs to increase from 2.7 to 5.2 and 8.2 × 103 μm3 as a simulated ASMC hypertrophy by culturing the cells on micropatterned rectangular substrates with a width of 25 μm and length from 50 to 100 and 200 μm, respectively. We found that as the cell volume increased, ASMCs exhibited a pro-contractile function with increased mRNA expression of contractile proteins, increased cell stiffness and traction force, and enhanced response to contractile stimulation. We also uncovered a concomitant increase in membrane tension and Piezo1 mRNA expression with increasing cell volume. Perhaps more importantly, we found that the enhanced contractile function due to cell volume increase was largely attenuated when membrane tension and Piezo1 mRNA expression were downregulated, and an auto-regulatory loop between Piezo1 and YAP mRNA expression was also involved in perpetuating the contractile function. These findings, thus, provide convincing evidence of a direct link between hypertrophy and enhanced contractile function of ASMCs that was mediated via Piezo1 mRNA expression, which may be specifically targeted as a novel therapeutic strategy to treat pulmonary diseases associated with ASMC hypertrophy such as severe asthma.

严重哮喘的特征是气道平滑肌细胞(ASMCs)的细胞体积增大(肥大)和收缩功能增强(高反应性)。然而,它们之间的因果关系和潜在调控机制仍不清楚。在这里,我们将体外培养的人 ASMC 单细胞体积分别从 2.7 μm3 增加到 5.2 μm3 和 8.2 × 103 μm3,通过在宽度为 25 μm、长度为 50 μm、长度为 100 μm 和 200 μm 的微图案矩形基底上培养细胞来模拟 ASMC 肥大。我们发现,随着细胞体积的增加,ASMC 表现出促进收缩的功能,收缩蛋白的 mRNA 表达增加,细胞硬度和牵引力增加,对收缩刺激的反应增强。我们还发现,随着细胞体积的增加,膜张力和 Piezo1 mRNA 的表达也同时增加。也许更重要的是,我们发现当膜张力和 Piezo1 mRNA 表达被下调时,细胞体积增大导致的收缩功能增强在很大程度上被削弱,而且 Piezo1 和 YAP mRNA 表达之间的自动调节环路也参与了收缩功能的延续。因此,这些发现提供了令人信服的证据,证明肥大与 ASMC 收缩功能增强之间存在直接联系,而这种联系是通过 Piezo1 mRNA 表达介导的。
{"title":"Single-Cell Hypertrophy Promotes Contractile Function of Cultured Human Airway Smooth Muscle Cells via Piezo1 and YAP Auto-Regulation.","authors":"Kai Ni, Bo Che, Rong Gu, Chunhong Wang, Yan Pan, Jingjing Li, Lei Liu, Mingzhi Luo, Linhong Deng","doi":"10.3390/cells13201697","DOIUrl":"https://doi.org/10.3390/cells13201697","url":null,"abstract":"<p><p>Severe asthma is characterized by increased cell volume (hypertrophy) and enhanced contractile function (hyperresponsiveness) of the airway smooth muscle cells (ASMCs). The causative relationship and underlying regulatory mechanisms between them, however, have remained unclear. Here, we manipulated the single-cell volume of in vitro cultured human ASMCs to increase from 2.7 to 5.2 and 8.2 × 10<sup>3</sup> μm<sup>3</sup> as a simulated ASMC hypertrophy by culturing the cells on micropatterned rectangular substrates with a width of 25 μm and length from 50 to 100 and 200 μm, respectively. We found that as the cell volume increased, ASMCs exhibited a pro-contractile function with increased mRNA expression of contractile proteins, increased cell stiffness and traction force, and enhanced response to contractile stimulation. We also uncovered a concomitant increase in membrane tension and Piezo1 mRNA expression with increasing cell volume. Perhaps more importantly, we found that the enhanced contractile function due to cell volume increase was largely attenuated when membrane tension and Piezo1 mRNA expression were downregulated, and an auto-regulatory loop between Piezo1 and YAP mRNA expression was also involved in perpetuating the contractile function. These findings, thus, provide convincing evidence of a direct link between hypertrophy and enhanced contractile function of ASMCs that was mediated via Piezo1 mRNA expression, which may be specifically targeted as a novel therapeutic strategy to treat pulmonary diseases associated with ASMC hypertrophy such as severe asthma.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11505810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495948","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
期刊
Cells
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