Experimental and molecular pathology最新文献

英文中文

Modulation of IL-6 receptor/STAT3 downstream signaling in rheumatoid arthritis patients 类风湿关节炎患者IL-6受体/STAT3下游信号的调节

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2024-12-25 DOI: 10.1016/j.yexmp.2024.104951

Fabio Cacciapaglia , Simone Perniola , Stefano Stano , Vincenzo Venerito , Dorotea Natuzzi , Rita Bizzoca , Florenzo Iannone

Interleukin-6 (IL-6) is a relevant cytokine in rheumatoid arthritis (RA) pathogenesis, potentially activating Janus kinases (JAK)-1, −2, and tyrosine kinase 2 (TYK2), and thus, three signal transducer and activator of transcription (STAT)-1, −3 or − 5 pathways. This pilot study aims to explore differences in phosphorylated (p)STAT3 levels among patients with RA, those not classified as RA (nRA), and healthy donors (HD), providing some clues on the relative contribution of each JAK protein to the downstream of the IL-6-induced STAT3 pathway. Clinical data and blood samples from 80 subjects (41 RA, 14 nRA, and 25 HD) were collected. The activity of the JAK-STAT3 pathway was assessed by Western Blot and Real Time-PCR analysis for the quantification of STAT3 in peripheral blood mononuclear cells (PBMC). Furthermore, the impact of JAK-1, −2, and TYK2 inhibitors on pSTAT3 was assessed in vitro by FACS, with and without IL-6 stimulation in RA patients naïve to treatment with DMARD and steroids. The pSTAT3 (%) was significantly higher in PBMC from RA compared to nRA patients and HD. Furthermore, pSTAT3 (%) was significantly associated with inflammation and disease activity (ESR, CRP, and DAS28). The JAK-1 inhibitor was more effective in reducing pSTAT3 expression in CD14^pos cells of RA patients, while the JAK-2 selective compound was more effective in CD4^pos cells of RA patients. On the contrary, the TYK2 selective agent showed no significant effects. This study highlights the importance of the JAK/STAT3 pathway in RA. Some differences among various JAK proteins have been pointed out, with JAK1 and JAK2 standing as the most relevant mediators of the STAT3 pathway in this in-vitro model after IL-6R activation.

白细胞介素-6 （IL-6）是类风湿关节炎（RA）发病过程中的一种相关细胞因子，可能激活Janus激酶(JAK)-1、-2和酪氨酸激酶2 (TYK2)，因此是三种信号转导和转录激活因子(STAT)-1、-3或- 5途径。本初步研究旨在探讨RA患者、非RA患者（nRA）和健康供者（HD）之间磷酸化(p)STAT3水平的差异，为每种JAK蛋白在il -6诱导的STAT3通路下游的相对贡献提供一些线索。收集了80例受试者（41例RA， 14例nRA， 25例HD）的临床资料和血液样本。Western Blot和Real - Time-PCR检测JAK-STAT3通路的活性，定量外周血单核细胞（PBMC）中STAT3的表达。此外，通过体外FACS评估JAK-1， -2和TYK2抑制剂对pSTAT3的影响，在RA患者中，有和没有IL-6刺激naïve对DMARD和类固醇治疗。与非RA患者和HD患者相比，RA患者PBMC中的pSTAT3（%）显著升高。此外，pSTAT3（%）与炎症和疾病活动性（ESR、CRP和DAS28）显著相关。JAK-1抑制剂在RA患者CD14pos细胞中降低pSTAT3表达更有效，而JAK-2选择性化合物在RA患者CD4pos细胞中更有效。与之相反，TYK2选择剂没有表现出明显的作用。本研究强调了JAK/STAT3通路在RA中的重要性。各种JAK蛋白之间存在一些差异，在IL-6R激活后的体外模型中，JAK1和JAK2是STAT3通路最相关的介质。

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引用次数: 0

Transcriptomic analysis of the HPT axis in a model of oligoasthenozoospermia induced by Adenine in rats 腺嘌呤诱导大鼠少弱精子症模型HPT轴转录组学分析。

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2024-12-18 DOI: 10.1016/j.yexmp.2024.104948

Nan Yang , Xiao-ge Wei , Kaiying Li , Fei Wang , Fei Song , Wenjing Sun , Yan Wang , Zhenning Zhao , Jing Mu , Huisheng Ma

Male infertility is most commonly caused by oligozoospermia, and its pathogenesis is still poorly understood at the molecular level. This study used RNA sequencing (RNA-Seq) technology to identify candidate genes and regulatory pathways that regulate semen quality in the hypothalamic, pituitary, and testicular tissues of healthy rats and Adenine-induced oligozoospermia model rats. Semen quality testing and histological analysis of testicular tissues were performed on both groups of rats. We identified 627, 692, and 437 differentially expressed genes in the hypothalamus, pituitary gland, and testes, respectively. Functional analysis indicates that “neuronal projections,” “positive regulation of hormone biosynthetic process,” and “neuroactive ligand-receptor interaction pathways” are closely related to the hypothalamic-pituitary-testicular (HPT) axis hormone regulation and sperm production. Seven genes (Pomc, Rxfp1, Tac1, Npy, Insl3, Hsd3b3, Lhcgr) have been identified as key candidate genes responsible for regulating sperm quality within the HPT axis, potentially affecting rat reproductive function by influencing testicular development and testosterone secretion. These data provide a theoretical basis for further understanding the molecular mechanisms of reproductive performance in a rat model of oligoasthenozoospermia.

男性不育症最常见的原因是少精子症，而人们对其发病机制的分子水平还知之甚少。本研究利用 RNA 测序（RNA-Seq）技术，在健康大鼠和腺嘌呤诱导的少精子症模型大鼠的下丘脑、垂体和睾丸组织中鉴定调控精液质量的候选基因和调控通路。我们对两组大鼠的精液质量进行了检测，并对睾丸组织进行了组织学分析。我们在下丘脑、垂体和睾丸中分别发现了 627、692 和 437 个差异表达基因。功能分析表明，"神经元投射"、"激素生物合成过程的正向调节 "和 "神经活性配体-受体相互作用途径 "与下丘脑-垂体-睾丸（HPT）轴激素调节和精子生成密切相关。七个基因（Pomc、Rxfp1、Tac1、Npy、Insl3、Hsd3b3、Lhcgr）被确定为负责调节 HPT 轴内精子质量的关键候选基因，可能通过影响睾丸发育和睾酮分泌来影响大鼠的生殖功能。这些数据为进一步了解少精症大鼠模型中生殖功能的分子机制提供了理论基础。

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引用次数: 0

In Silico analysis unveils rs2109069 of DPP9 as a potential catalyst for COVID-19 severity and risk of inflammatory symptoms In Silico分析揭示了DPP9的rs2109069是COVID-19严重程度和炎症症状风险的潜在催化剂

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2024-12-01 DOI: 10.1016/j.yexmp.2024.104946

Chi-Ying Lee , Zih-Yin Lai , Yung-Jen Chuang

Background

During the COVID-19 pandemic, the viral illness caused by SARS-CoV-2 spread through respiratory droplets, resulting in a global pandemic with a range of symptoms from mild to severe. Pathological inflammation posed a critical issue, yet the genetic mechanisms behind the excessive activation of inflammatory responses remained unclear. To uncover the genetic and regulatory basis of the pathogenesis, we first explored possible genetic mechanisms from phenome-wide association studies (PWAS) with different severity levels of COVID-19. PWAS is a genetic research approach that identifies pleiotropic risk variants that contribute to elucidating potential physiological mechanisms from different traits.

Methods

We used the PWAS approach to link the multiple clinical symptoms to the variants. We discovered a common variant, rs2109069, in dipeptidyl peptidase 9 (DPP9), which relates to the elevated odds ratio of developing severe illness from COVID-19. Interestingly, the proxy of rs2109069 has been identified as the susceptible locus of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). We thus examined the DPP9 expression patterns in selected organs, including the lungs, blood vessels, and skin.

Results

In silico analysis revealed conserved driver activation between COVID-19-induced inflammation and the association with ILD and IPF. Multi-omics analysis further verified the association of DPP9 with abnormal inflammatory responses in COVID-19. Lastly, gene homology analysis inferred a potential regulatory role of DPP9 in inhibiting inflammasome activation, which suggests that DPP9 deficiency may exacerbate inflammation observed in some COVID-19 patients.

Conclusions

Our in silico findings reveal that severe COVID-19 inflammatory responses and inflammatory lung diseases share the same genetic risk loci, helping to elucidate the underlying physiological mechanisms of severe COVID-19 inflammation. Additionally, the individual differences in immune sensitivity may contribute to the varying multi-organ inflammatory effects among patients. The rs2109069 of DPP9 could be a genetic marker to predict the risk of specific COVID-19 symptoms and severity.

在2019冠状病毒病大流行期间，由SARS-CoV-2引起的病毒性疾病通过呼吸道飞沫传播，导致全球大流行，症状从轻微到严重不等。病理性炎症是一个关键问题，但过度激活炎症反应背后的遗传机制尚不清楚。为了揭示发病机制的遗传和调控基础，我们首先通过不同严重程度的COVID-19全现象关联研究（PWAS）探索了可能的遗传机制。PWAS是一种识别多效性风险变异的遗传研究方法，有助于阐明不同性状的潜在生理机制。方法采用PWAS方法将多种临床症状与变异联系起来。我们在二肽基肽酶9 （DPP9）中发现了一种常见的变异rs2109069，它与COVID-19引发严重疾病的风险比升高有关。有趣的是，rs2109069的代理基因已被确定为间质性肺疾病（ILD）和特发性肺纤维化（IPF）的易感位点。因此，我们检查了DPP9在选定器官中的表达模式，包括肺、血管和皮肤。结果计算机分析显示，covid -19诱导的炎症与ILD和IPF之间存在保守的驱动因子激活。多组学分析进一步证实了DPP9与COVID-19异常炎症反应的相关性。最后，基因同源性分析推断DPP9在抑制炎症小体激活方面具有潜在的调节作用，这表明DPP9缺乏可能会加剧部分COVID-19患者的炎症。结论我们的研究结果表明，严重的COVID-19炎症反应与炎症性肺部疾病具有相同的遗传风险位点，有助于阐明严重的COVID-19炎症的潜在生理机制。此外，免疫敏感性的个体差异可能导致患者多器官炎症反应的不同。DPP9的rs2109069可能是预测特定COVID-19症状和严重程度风险的遗传标记。

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引用次数: 0

Corrigendum to “Irisin and neuroinflammation: Challenges and opportunities” [Experimental and Molecular Pathology 140 (2024) 104941] 鸢尾素与神经炎症：挑战与机遇》[《实验与分子病理学》140 (2024) 104941]。

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2024-12-01 DOI: 10.1016/j.yexmp.2024.104943

Erika Yolanda Hernández Sandoval, Zulma Dueñas

引用次数: 0

Influence of diet and exercise on leukocyte telomere length, markers of oxidative stress and inflammation in rats 饮食和运动对大鼠白细胞端粒长度、氧化应激和炎症标志物的影响

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2024-12-01 DOI: 10.1016/j.yexmp.2024.104947

Mehmet Mustafa Tilekli , Ali Kerim Yılmaz , Yavuz Yasul , Nurhan Çon , Sevcan Mercan , Nilüfer Tek

Telomere length is an important biomarker of biological aging and is affected by nutrition and physical activity. This study investigated the effects of diets with different fat contents and increased physical activity on certain pro/anti-inflammatory and oxidative stress markers and aging. The study is performed in a randomized, experimental, and controlled design with 48 rats, 8 weeks old, divided into 6 different groups (Control (C), exercise (E), unsaturated fat diet (USF), saturated fat diet (SF), unsaturated fat diet + exercise (USF + E), and saturated fat diet + exercise (SF + E)). The rats performed aerobic swimming exercise for 50 days and were fed a diet with different fat content. TAS, TOS, and MDA levels were determined by colorimetric analysis while 8-OHdG, IL-10, and TNF-α were determined by ELISA. Additionally, leukocyte telomere length is determined by the PCR method. Weight changes were also recorded. Plasma TOS, OSI, and TNF-α were lowest in the USF group and highest in the SF and SF + E groups. MDA, 8-OHdG and TG levels were highest in the SF group. The lowest IL-10 level was detected in group C. TL level was the highest in the USF group. There was also a moderate, negative, and significant correlation between telomeres and TOS, OSI, and TNF-α. The groups with the highest body weight gain were C, SF, and SF + E. Diets low in saturated fat or high in unsaturated fat, and physical activity were associated with leukocyte telomere length and alteration of oxidative and pro/anti-inflammatory markers.

端粒长度是生物衰老的重要生物指标，受营养和体力活动的影响。本研究探讨了不同脂肪含量的饮食和增加体力活动对某些促/抗炎和氧化应激标志物以及衰老的影响。研究采用随机、实验和对照设计，将48只8周龄大鼠分为6个不同组(对照组(C)、运动组（E)、不饱和脂肪饮食（USF）、饱和脂肪饮食（SF）、不饱和脂肪饮食+运动组（USF + E）和饱和脂肪饮食+运动组（SF + E））。大鼠进行有氧游泳运动50天，并喂食不同脂肪含量的饮食。比色法测定TAS、TOS、MDA水平，ELISA法测定8-OHdG、IL-10、TNF-α水平。此外，白细胞端粒长度由PCR方法确定。体重变化也被记录下来。血浆TOS、OSI、TNF-α在USF组最低，SF和SF + E组最高。SF组MDA、8-OHdG和TG水平最高。c组IL-10水平最低，USF组IL-10水平最高。端粒与TOS、OSI和TNF-α之间也存在中度、负和显著相关。体重增加最多的组是C组、SF组和SF + e组。低饱和脂肪或高不饱和脂肪的饮食，体力活动与白细胞端粒长度以及氧化和促/抗炎标志物的改变有关。

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引用次数: 0

Corrigendum to “Anti-tumor effect of antibody-drug conjugate targeting cell adhesion molecule 1 on GIST cells representing small intestinal GIST” [Experimental and Molecular Pathology 139 (2024) 104922] 以细胞粘附分子 1 为靶点的抗体-药物共轭物对小肠 GIST 细胞的抗肿瘤作用》[实验与分子病理学 139 (2024) 104922] 勘误。

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2024-12-01 DOI: 10.1016/j.yexmp.2024.104934

Makoto Yoshida , Jiayin Yuan , Takako Kihara , Neinei Kimura , Takashi Yamasaki , Mizuka Ohkouchi , Yuka Hashikura , Koji Isozaki , Man Hagiyama , Akihiko Ito , Seiichi Hirota

引用次数: 0

Corrigendum to “Suppression of miR-143-3p contributes to the anti-fibrosis effect of atorvastatin on myocardial tissues via the modulation of Smad2 activity” [Experimental and Molecular Pathology 112 (2020) 104346] “抑制miR-143-3p通过调节Smad2活性有助于阿托伐他汀对心肌组织的抗纤维化作用”[实验与分子病理学112(2020)104346]的勘误。

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2024-12-01 DOI: 10.1016/j.yexmp.2024.104945

Bo Yu , Ming Yu , Hongli Zhang, Di Xie, Wei Nie, Kaiyao Shi

引用次数: 0

Pathobiology of myocardial and cardiomyocyte injury in ischemic heart disease: Perspective from seventy years of cell injury research 缺血性心脏病心肌和心肌细胞损伤的病理生物学：七十年细胞损伤研究的视角。

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2024-11-21 DOI: 10.1016/j.yexmp.2024.104944

L. Maximilian Buja

This review presents a perspective on the pathobiology of acute myocardial infarction, a major manifestation of ischemic heart disease, and related mechanisms of ischemic and toxic cardiomyocyte injury, based on advances and insights that have accrued over the last seventy years, including my sixty years of involvement in the field as a physician-scientist-pathologist. This analysis is based on integration of my research within the broader context of research in the field. A particular focus has been on direct measurements in cardiomyocytes of electrolyte content by electron probe X-ray microanalysis (EPXMA) and Ca²⁺ fluxes by fura-2 microspectrofluorometry. These studies established that increased intracellular Ca²⁺ develops at a transitional stage in the progression of cardiomyocyte injury in association with ATP depletion, other electrolyte alterations, altered cell volume regulation, and altered membrane phospholipid composition. Subsequent increase in total calcium with mitochondrial calcium accumulation can occur. These alterations are characteristic of oncosis, which is an initial pre-lethal state of cell injury with cell swelling due to cell membrane dysfunction in ATP depleted cells; oncosis rapidly progresses to necrosis/necroptosis with physical disruption of the cell membrane, unless the adverse stimulus is rapidly reversed. The observed sequential changes fit a three-stage model of membrane injury leading to irreversible cell injury. The data establish oncosis as the primary mode of cardiomyocyte injury in evolving myocardial infarcts. Oncosis also has been documented to be the typical form of non-ischemic cell injury due to toxins. Cardiomyocytes with less energy impairment have the capability of undergoing apoptosis and autophagic death as well as oncosis, as is seen in pathological remodeling in chronic heart failure. Work is ongoing to apply the insights from experimental studies to better understand and ameliorate myocardial ischemia and reperfusion injury in patients. The perspective and insights in this review are derived from basic principles of pathology, an integrative discipline focused on mechanisms of disease affecting the cell, the organizing unit of living organisms.

急性心肌梗死是缺血性心脏病的一种主要表现形式，本综述基于过去七十年（包括我作为一名医生、科学家和病理学家参与该领域研究的六十年）积累的进展和见解，从病理生物学的角度阐述了急性心肌梗死的病理生理以及缺血性和毒性心肌细胞损伤的相关机制。这一分析的基础是将我的研究与该领域更广泛的研究相结合。我的研究重点之一是通过电子探针 X 射线显微分析法（EPXMA）直接测量心肌细胞中的电解质含量，以及通过呋喃-2 微谱荧光测定法测量 Ca2+ 通量。这些研究证实，细胞内 Ca2+ 的增加发生在心肌细胞损伤进展的过渡阶段，与 ATP 消耗、其他电解质改变、细胞体积调节改变和膜磷脂成分改变有关。随后会出现总钙增加和线粒体钙积聚。这些变化是细胞坏死的特征。细胞坏死是一种细胞损伤的初始致死前状态，由于 ATP 贫竭细胞的细胞膜功能失调而导致细胞肿胀；除非迅速逆转不良刺激，否则细胞坏死会迅速发展为细胞膜物理破坏的坏死/坏死。观察到的连续变化符合膜损伤导致不可逆细胞损伤的三阶段模型。这些数据确立了瘤变是演变性心肌梗死中心肌细胞损伤的主要模式。据文献记载，瘤变也是毒素导致的非缺血性细胞损伤的典型形式。能量损伤较小的心肌细胞有能力发生凋亡和自噬死亡以及肿瘤病变，这在慢性心力衰竭的病理重塑中可以看到。目前正在努力应用实验研究的见解，以更好地理解和改善患者的心肌缺血和再灌注损伤。本综述的观点和见解来自病理学的基本原理，病理学是一门综合性学科，重点研究影响细胞（生物体的组织单位）的疾病机制。

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引用次数: 0

Diagnostic criteria and therapeutic implications of rapid-onset demyelinating polyneuropathies 速发型脱髓鞘性多发性神经病的诊断标准和治疗意义

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2024-11-04 DOI: 10.1016/j.yexmp.2024.104942

Wiktoria Rałowska-Gmoch , Magdalena Koszewicz , Beata Łabuz-Roszak , Sławomir Budrewicz , Edyta Dziadkowiak

Guillain-Barré syndrome (GBS) and acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) are the most common autoimmune polyneuropathies. Their aetiology is unclear. The pathomechanism includes damage mainly to the myelin sheath and, in the long-term process, secondary axonal loss. Both inflammatory polyneuropathies involve different combinations of motor, sensory and autonomic fibres in the peripheral nerves. The differential diagnosis should be based on clinical and neurophysiological features, and laboratory tests. Numerous studies aim to demonstrate the most common errors in the diagnosis of Guillain-Barré syndrome and acute-onset CIDP. Misdiagnosis can result in the wrong treatment. We still do not have reliable markers to help diagnose the disease or to monitor the effectiveness of the therapy.

吉兰-巴雷综合征（GBS）和急性发作性慢性炎症性脱髓鞘多发性神经病（A-CIDP）是最常见的自身免疫性多发性神经病。它们的病因尚不清楚。其病理机制主要包括髓鞘受损，以及在长期过程中继发的轴突丢失。这两种炎症性多发性神经病都涉及周围神经中运动、感觉和自主神经纤维的不同组合。鉴别诊断应基于临床和神经生理学特征以及实验室检查。大量研究旨在证明吉兰-巴雷综合征和急发性 CIDP 诊断中最常见的错误。误诊会导致错误的治疗。我们仍然没有可靠的标记物来帮助诊断疾病或监测治疗效果。

引用次数: 0

Irisin and neuroinflammation: Challenges and opportunities 鸢尾素与神经炎症：挑战与机遇

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2024-10-28 DOI: 10.1016/j.yexmp.2024.104941

Erika Yolanda Hernández Sandoval, Zulma Janeth Dueñas Gómez

Irisin is a myokine that is cleaved from 5-domain type III fibronectin (FNDC5), and is known for its metabolic functions as it stimulates browning of white adipose tissue; similarly, effects on the central nervous system have been described, specifically in neurodevelopmental and neuroprotection processes. The purpose of this review is to describe recent information on the effects of irisin on neuroinflammation to contribute to the knowledge about the mechanisms by which irisin and exercise could generate benefits for some neurological diseases. The review conducted found several studies describing the effect of irisin on pathways such as STAT3, p38, cAMP/PKA/CREB, as well as effects on GFAP protein expression or apoptosis processes in both in vitro and in vivo models; likewise, these pathways are associated with better BDNF expression. Despite increasing information on this topic, it is still necessary to clarify the mechanisms by which irisin has effects on neuroinflammation and this could represent an opportunity to generate more treatments for diseases such as Alzheimer's, Parkinson's or Diabetes Mellitus.

鸢尾素是一种肌动素，由 5-结构域 III 型纤维粘连蛋白（FNDC5）裂解而成，因其刺激白色脂肪组织褐变的代谢功能而闻名；同样，它对中枢神经系统的影响也有描述，特别是在神经发育和神经保护过程中。本综述旨在描述鸢尾素对神经炎症影响的最新信息，以帮助人们了解鸢尾素和运动对某些神经系统疾病产生益处的机制。综述发现，有几项研究描述了鸢尾素对 STAT3、p38、cAMP/PKA/CREB 等通路的影响，以及在体外和体内模型中对 GFAP 蛋白表达或细胞凋亡过程的影响；同样，这些通路与更好的 BDNF 表达相关。尽管有关这一主题的信息越来越多，但仍有必要阐明鸢尾素对神经炎症产生影响的机制，这可能是为阿尔茨海默氏症、帕金森氏症或糖尿病等疾病提供更多治疗方法的机会。

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