Experimental and molecular pathology最新文献

英文中文

The role of lactate and lactylation in ischemic cardiomyopathy: Mechanisms and gene expression 乳酸和乳酸化在缺血性心肌病中的作用：机制和基因表达

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-03-01 DOI: 10.1016/j.yexmp.2025.104957

Mei Zhang , Xue Kong , Chenlu Wu , Jiuhong Li , Hui Yang , Lingzhi Huang

Ischemic cardiomyopathy (ICM) is a significant global public health issue, with its pathophysiology encompassing atherosclerotic plaque formation, thrombosis, hypoperfusion, ischemic cell death, and left ventricular remodeling. Lactate is not only regarded as an energy metabolite but also acts as a signaling molecule that influences various physiological processes, regulating metabolism and muscle contraction. Lactylation, an emerging epigenetic modification, affects protein functionality and gene expression through the P300 enzyme. In ICM, lactate accumulation leads to pH imbalance and myocardial cell dysfunction, impacting cellular signaling. This paper will analyze the role of lactylation in ICM, focusing on coronary artery disease (ASCVD) and myocardial infarction (MI). It will also explore the differential expression and immunological characteristics of lactylation-related genes in normal and ICM tissues, providing potential targets for future research.

缺血性心肌病（ICM）是一个重要的全球公共卫生问题，其病理生理学包括动脉粥样硬化斑块形成、血栓形成、灌注不足、缺血性细胞死亡和左心室重构。乳酸不仅被认为是一种能量代谢物，而且作为一种影响各种生理过程的信号分子，调节代谢和肌肉收缩。乳酸化是一种新兴的表观遗传修饰，通过P300酶影响蛋白质功能和基因表达。在ICM中，乳酸积累导致pH失衡和心肌细胞功能障碍，影响细胞信号传导。本文将分析乳酸化在ICM中的作用，重点是冠状动脉疾病（ASCVD）和心肌梗死（MI）。探索正常组织和ICM组织中乳酸化相关基因的差异表达和免疫学特征，为今后的研究提供潜在的靶点。

引用次数: 0

Dynamic full-field optical coherence tomography for extemporaneous high-resolution imaging of adrenal glands 动态全视野光学相干断层成像技术用于肾上腺的即时高分辨率成像

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-02-19 DOI: 10.1016/j.yexmp.2025.104958

Irene A. Spiridon , Michel Vix , Didier Mutter , Barbara Seeliger

Background

There is an interindividual variance in postoperative adrenocortical capacity, and the minimal functional remnant size is unknown. New imaging technologies may allow for improved intraoperative assessment of adrenal tissue morphology, cell activity, and surgery-related changes. The aim of this experimental study was to provide a pilot assessment of adrenal gland architecture with dynamic full-field optical coherence tomography (D-FF-OCT) in comparison to standard hematoxylin-eosin (HE) examination.

Methods

D-FF-OCT was performed on freshly resected porcine adrenal glands to simultaneously assess both morphology and metabolic activity in real time, and for comparison with standard histopathology. Left and right adrenal glands were assessed from 8 pigs (1 M, 7 F, mean weight 43.9 ± 8.3 kg).

Results

The evaluation with D-FF-OCT proved fast in terms of acquisition time, averaging 32 min/specimen. The technique required a relatively short learning curve and provided morphological details similar to standard microscopy. In the comparative analysis of both methods, D-FF-OCT scans allowed easy identification of normal adrenal morphology and facilitated differentiation of the structural components of the cortical and medullary areas based on architectural and vascular patterns. Furthermore, it was possible to distinguish more accurately between cell subpopulations based on their metabolic activity.

Conclusion

While HE examination remains the gold standard for morphological evaluation, time weighs heavy on this ancillary technique. In our study, we prove that D-FF-OCT is effective in achieving a comparable level of morphological details, with added metabolic activity of the cells, a combination which can prove useful in the real-time assessment of various diseases requiring adrenal surgery.

背景术后肾上腺皮质容量存在个体间差异，最小功能残余大小尚不清楚。新的成像技术可以改善术中对肾上腺组织形态、细胞活性和手术相关变化的评估。本实验研究的目的是提供动态全场光学相干断层扫描（D-FF-OCT）对肾上腺结构的初步评估，并与标准苏木精-伊红（HE）检查进行比较。方法采用sd - ff - oct对新鲜切除的猪肾上腺进行实时形态学和代谢活性评估，并与标准组织病理学进行比较。对8头猪（1 M, 7 F，平均体重43.9±8.3 kg）的左右肾上腺进行了评估。结果D-FF-OCT评估的采集时间较短，平均为32 min/个标本。该技术需要相对较短的学习曲线，并提供类似于标准显微镜的形态学细节。在两种方法的对比分析中，D-FF-OCT扫描可以很容易地识别正常肾上腺形态，并根据建筑和血管模式促进皮质和髓质区域结构成分的区分。此外，根据细胞的代谢活性更准确地区分细胞亚群是可能的。结论虽然HE检查仍然是形态学评价的金标准，但时间对这种辅助技术的影响很大。在我们的研究中，我们证明了D-FF-OCT在获得相当水平的形态学细节方面是有效的，并且增加了细胞的代谢活性，这一组合可以被证明在实时评估需要肾上腺手术的各种疾病中是有用的。

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引用次数: 0

Diagnostic next-generation sequencing to detect MYD88 L265P in Lymphoplasmacytic lymphoma compared to ddPCR 诊断新一代测序检测淋巴浆细胞性淋巴瘤MYD88 L265P与ddPCR的比较

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-02-15 DOI: 10.1016/j.yexmp.2025.104956

Lauren M. Wainman, Guohong Huang, Donald C. Green, Gregory J. Tsongalis, Laura J. Tafe, Wahab A. Khan, Prabhjot Kaur, Parth S. Shah , Jeremiah X. Karrs

Lymphoplasmacytic lymphoma (LPL) is a B-cell lymphoproliferative disorder typically involving the bone marrow with infiltration by small lymphocytes and plasma cells. Studies have identified MYD88 L265P mutation as a diagnostic marker to distinguish LPL from other small B-cell lymphomas. Detection rates for this mutation have varied depending on the analytic methodology, with previous data suggesting that routine next-generation sequencing (NGS) does not demonstrate the required sensitivity to reliably detect MYD88 L265P. NGS has become part of routine clinical testing because it allows detection of variants across multiple genes. To study the utility of NGS in the detection of MYD88 L265P, we performed droplet digital PCR (ddPCR) and routine NGS on a cohort of 34 cases of lymphoid neoplasms (22 LPL, 4 CLL, 1 MCL, 1 MGUS, 2 plasma cell myeloma, and 4 negative bone marrow cases). We utilized manual review and BAMtools to assess MYD88 L265P in NGS cases. Limit of detection for ddPCR was determined to be 0.4 % variant allele frequency (VAF) with 10 ng DNA input. MYD88 L265P VAF detection by NGS and ddPCR was comparable down to 0.5 % VAF (R² = 0.968). Setting an appropriate threshold for detection based on ddPCR results resulted in zero NGS false positives. We found that low tumor content did not impact the detection of MYD88 L265P by NGS. This study demonstrates that NGS can be a sensitive and reliable method for detection of MYD88 L265P with adequate coverage and specific assessment parameters.

淋巴浆细胞性淋巴瘤（LPL）是一种b淋巴细胞增生性疾病，通常累及骨髓，并有小淋巴细胞和浆细胞浸润。研究发现MYD88 L265P突变是区分LPL与其他小b细胞淋巴瘤的诊断标记。该突变的检出率因分析方法的不同而不同，先前的数据表明常规的下一代测序（NGS）不能证明可靠检测MYD88 L265P所需的灵敏度。NGS已经成为常规临床检测的一部分，因为它可以检测到多个基因的变异。为了研究NGS在MYD88 L265P检测中的应用，我们对34例淋巴样肿瘤（LPL 22例，CLL 4例，MCL 1例，MGUS 1例，浆细胞骨髓瘤2例，骨髓阴性4例）进行了液滴数字PCR和常规NGS检测。我们使用人工检查和BAMtools评估NGS病例的MYD88 L265P。ddPCR检测限为0.4%变异等位基因频率（VAF），输入10 ng DNA。NGS和ddPCR检测MYD88 L265P VAF可达0.5% （R2 = 0.968）。根据ddPCR结果设置合适的检测阈值，NGS假阳性为零。我们发现低肿瘤含量并不影响NGS对MYD88 L265P的检测。本研究表明，NGS检测MYD88 L265P具有足够的覆盖率和特定的评估参数，是一种敏感可靠的检测方法。

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引用次数: 0

Matrix metalloproteinase-3 is a potent prognostic factor associated with cell proliferation and migration in prostate cancer 基质金属蛋白酶-3是前列腺癌细胞增殖和迁移的重要预后因子

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-02-11 DOI: 10.1016/j.yexmp.2025.104954

Ai Sato , Kiyoshi Takagi , Mio Yamaguchi-Tanaka , Jotaro Okushima , Yuto Yamazaki , Akihiro Ito , Takashi Suzuki

Prostate cancer is a common malignancy in men around the world, and it is crucial to explore novel biomarkers to improve its treatment. Prostate cancer cells typically invade the surrounding stroma, and remodeling of the extracellular matrix (ECM) is a crucial step in the progress of prostate cancer. Matrix metalloproteinase-3 (MMP3) is an enzyme that degrades several ECM components and is implicated in human malignancies. However, the clinical and biological significance of MMP3 has not been well elucidated.

We therefore immunolocalized MMP3 in prostate cancer tissues (n = 117) and demonstrated that MMP3 immunoreactivity was correlated with aggressive phenotype of prostate cancer, including higher proliferation/invasion ability, and shorter disease-free survival. In addition, subsequent in vitro analysis revealed that overexpression of MMP3 significantly increased the proliferative and migratory abilities of PC-3 and DU-145 prostate cancer cell lines, depending on conditioned media from WMPY-1 prostate stromal cells.

It was concluded that MMP3 might contribute to prostate cancer progression by modifying the ECM surrounding prostate cancer cells and could serve as a potent prognostic factor in prostate cancer.

前列腺癌是全球男性常见的恶性肿瘤，探索新的生物标志物来改善其治疗是至关重要的。前列腺癌细胞通常侵入周围基质，细胞外基质（ECM）的重塑是前列腺癌发展的关键步骤。基质金属蛋白酶-3 （MMP3）是一种降解几种ECM成分的酶，与人类恶性肿瘤有关。然而，MMP3的临床和生物学意义尚未得到很好的阐明。因此，我们在前列腺癌组织中免疫定位了MMP3 (n = 117)，并证明MMP3的免疫反应性与前列腺癌的侵袭性表型相关，包括更高的增殖/侵袭能力和更短的无病生存期。此外，随后的体外分析显示，MMP3的过表达显著增加PC-3和DU-145前列腺癌细胞系的增殖和迁移能力，依赖于WMPY-1前列腺基质细胞的条件培养基。由此得出结论，MMP3可能通过改变前列腺癌细胞周围的ECM而促进前列腺癌的进展，并可能作为前列腺癌的一个强有力的预后因素。

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引用次数: 0

Hyperinsulinemic male LEW.1WR1 rats show early signs of impaired liver metabolism 高胰岛素血症的雄性LEW.1WR1大鼠表现出肝脏代谢受损的早期迹象

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-02-11 DOI: 10.1016/j.yexmp.2025.104955

Madushika Wimalarathne , Bailey L. Bowser , Albert B. Arul , Quiana C. Wilkerson-Vidal , Moses A. David , Emily C. Hunt , Helen Gibson , Renã A.S. Robinson , Sharifa T. Love-Rutledge

Weanling LEW.1WR1 (1WR1) rats are susceptible to type 1 diabetes (T1D) and hyperinsulinemic. Similar to human patients with T1D, these animals are susceptible to developing fatty liver infiltrates. Insulin resistance-related steatosis can lead to the development of severe forms of nonalcoholic fatty liver disease (NAFLD). Previous work in 1WR1 rats suggests that in the absence of T1D, they have increased body mass that is not reconciled by measuring their abdominal fat pads; this suggests 1WR1 rats have an underlying predisposition to store fat in the liver unrelated to diabetes status. We hypothesized that 1WR1 rats show early signs of NAFLD development. We assessed proteomics changes in the livers of glucose intolerant and hyperinsulinemic young adult 1WR1 rats to identify early detectable characteristics of NAFLD development.

Our results show young adult 1WR1 rats have UBD/FAT10 gene over expression in the liver. Additionally, they have decreased mitochondrial protein levels, which may lead to lipid accumulation in the liver. A quantitative proteomic analysis showed protein expression related to branch chain fatty acid metabolism, fatty acid beta-oxidation, and oxidative phosphorylation in the liver is significantly different in 1WR1 rats compared to control LEW/SsNHsd (SsNHsd) rats. In summary, our study shows that 1WR1 rats developed early characteristics of mitochondrial dysfunction and insulin resistance in the liver independent of T1D, which are commonly observed with NAFLD development.

断奶期LEW.1WR1 （1WR1）大鼠易患1型糖尿病（T1D）和高胰岛素血症。与人类T1D患者相似，这些动物容易发生脂肪肝浸润。胰岛素抵抗相关的脂肪变性可导致严重形式的非酒精性脂肪性肝病（NAFLD）的发展。先前对1WR1大鼠的研究表明，在缺乏T1D的情况下，它们的体重增加了，这与测量腹部脂肪垫的结果不一致；这表明1WR1大鼠在肝脏中储存脂肪的潜在倾向与糖尿病状态无关。我们假设1WR1大鼠表现出NAFLD发展的早期迹象。我们评估了葡萄糖不耐受和高胰岛素血症的年轻成年1WR1大鼠肝脏中的蛋白质组学变化，以确定NAFLD发展的早期可检测特征。我们的研究结果显示，年轻成年1WR1大鼠肝脏中存在UBD/FAT10基因过表达。此外，它们降低了线粒体蛋白水平，这可能导致肝脏中的脂质积累。定量蛋白质组学分析显示，与对照组LEW/SsNHsd （SsNHsd）大鼠相比，1WR1大鼠肝脏中分支链脂肪酸代谢、脂肪酸β -氧化和氧化磷酸化相关的蛋白质表达显著不同。综上所述，我们的研究表明，1WR1大鼠出现了独立于T1D的肝脏线粒体功能障碍和胰岛素抵抗的早期特征，这些特征在NAFLD的发展中很常见。

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引用次数: 0

Mediterranean diet improves liver health but does not protect against azoxymethane-induced colon tumorigenesis compared to Western diet in A/J mice 与西方饮食相比，地中海饮食可改善A/J小鼠的肝脏健康，但不能防止偶氮甲烷诱导的结肠肿瘤发生

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-02-06 DOI: 10.1016/j.yexmp.2025.104953

Weimin Guo , Nicholas Crossland , Jimmy W. Crott

Introduction

Abundant evidence indicates that the Mediterranean (MED) diet pattern is beneficial for health, especially cardiovascular health. Epidemiological evidence indicates that the MED diet also affords protection against colorectal cancer (CRC). To date, preclinical models have only evaluated specific MED diet components and therefore, although supportive, fall short of confirming the chemoprotective capacity of this complex dietary pattern. We sought to address this gap.

Method

A/J mice were randomized to receive Western (WRN) or MED diets differing in their fat, protein, and carbohydrate sources. Azoxymethane (AOM) was used to initiate colon tumorigenesis and mice were maintained for 19 weeks after the final dose.

Result

Unexpectedly high mortality was observed amongst male mice following the second AOM dose. At the end of the study hepatic Cyp2E1, an enzyme that metabolize AOM, was lower in males than females. Livers from MED diet mice were significantly lighter, had lower histologic Non-Alcoholic Fatty Liver Disease (NAFLD) scores, and contained less triglycerides than WRN mice. Amongst females, serum alanine transaminase (ALT) was also lower in MED than WRN mice. Amongst male mice, those fed MED diet presented with significantly more colonic tumors than those on the WRN diet.

Conclusion

In this study male mice displayed elevated sensitivity to AOM-induced hepatotoxicity and mortality than females. In agreement with human and preclinical data, livers of MED-diet-fed mice were healthier than those fed WRN diets. We could not confirm the chemoprotective capacity of the MED diet. Additional studies are required to evaluate the purported anticancer effect of the MED diet.

大量证据表明，地中海（MED）饮食模式有益于健康，尤其是心血管健康。流行病学证据表明，MED饮食还可以预防结直肠癌（CRC）。迄今为止，临床前模型仅评估了特定的MED饮食成分，因此，尽管具有支持作用，但无法证实这种复杂饮食模式的化学保护能力。我们试图解决这一差距。方法将da /J小鼠随机分为脂肪、蛋白质和碳水化合物来源不同的Western （WRN）或MED饮食。偶氮氧甲烷（AOM）用于启动结肠肿瘤发生，并在末次剂量后维持小鼠19周。结果第二剂量AOM后，雄鼠死亡率高。在研究结束时，肝脏Cyp2E1（一种代谢AOM的酶）在男性中的含量低于女性。与WRN小鼠相比，MED饮食小鼠的肝脏明显更轻，组织学非酒精性脂肪性肝病（NAFLD）评分更低，甘油三酯含量更低。在雌性小鼠中，MED小鼠的血清丙氨酸转氨酶（ALT）也低于WRN小鼠。在雄性小鼠中，饲喂MED饮食的小鼠结肠肿瘤明显多于饲喂WRN饮食的小鼠。结论雄性小鼠对aom肝毒性的敏感性和死亡率均高于雌性小鼠。与人类和临床前数据一致，以med饮食喂养的小鼠的肝脏比以WRN饮食喂养的小鼠更健康。我们无法证实MED饮食的化学保护能力。需要更多的研究来评估所谓的MED饮食的抗癌效果。

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引用次数: 0

Role of A1 adenosine receptor in cardiovascular diseases: Bridging molecular mechanisms with therapeutic opportunities A1腺苷受体在心血管疾病中的作用：连接分子机制与治疗机会

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-01-28 DOI: 10.1016/j.yexmp.2025.104952

Warisara Parichatikanond , Ratchanee Duangrat , Narawat Nuamnaichati , Supachoke Mangmool

Adenosine serves as a critical homeostatic regulator, exerting influence over physiological and pathological conditions in the cardiovascular system. During cellular stress, increased extracellular adenosine levels have been implicated in conferring cardioprotective effects through the activation of adenosine receptors with the A₁ adenosine receptor subtype showing the highest expression in the heart. A₁ adenosine receptor stimulation inhibits adenylyl cyclase activity via heterotrimeric G_i proteins, leading to the activation of distinct downstream effectors involved in cardiovascular homeostasis. While the comprehensive characterization of the pharmacological functions and intracellular signaling pathways associated with the A₁ adenosine receptor subtype is still ongoing, this receptor is widely recognized as a crucial pharmacological target for the treatment of various states of cardiovascular diseases (CVDs). In this review, we focus on elucidating signal transduction of A₁ adenosine receptor, particularly G_i protein-dependent and -independent pathways, and their relevance to cardiovascular protective effects as well as pathological consequences during cellular and tissue stresses in the cardiovascular system. Additionally, we provide comprehensive updates and detailed insights into a range of A₁ adenosine receptor agonists and antagonists, detailing their development and evaluation through preclinical and clinical studies with a specific focus on their potential for the management of CVDs, especially heart diseases.

腺苷是一种重要的体内平衡调节剂，对心血管系统的生理和病理状况产生影响。在细胞应激过程中，增加的细胞外腺苷水平与通过激活腺苷受体而赋予心脏保护作用有关，其中A1腺苷受体亚型在心脏中表达最高。A1腺苷受体刺激通过异三聚体Gi蛋白抑制腺苷酸环化酶活性，导致参与心血管稳态的不同下游效应物的激活。虽然与A1腺苷受体亚型相关的药理学功能和细胞内信号通路的全面表征仍在进行中，但该受体被广泛认为是治疗各种心血管疾病（cvd）状态的关键药理学靶点。在这篇综述中，我们重点阐述了A1腺苷受体的信号转导，特别是Gi蛋白依赖和独立的信号转导途径，以及它们在心血管系统细胞和组织应激过程中与心血管保护作用和病理后果的相关性。此外，我们还提供一系列A1腺苷受体激动剂和拮抗剂的全面更新和详细见解，详细介绍了它们通过临床前和临床研究的开发和评估，特别关注它们在心血管疾病（特别是心脏病）管理方面的潜力。

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引用次数: 0

Expression of concern: “Upregulation of immunomodulatory molecules by matrine treatment in experimental autoimmune encephalomyelitis” [Experimental and Molecular Pathology 97 (2014) 470–476] 关注表达：“实验性自身免疫性脑脊髓炎中苦参碱治疗免疫调节分子的上调”[实验与分子病理学97 (2014)470-476]

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-01-01

引用次数: 0

Expression of concern: “1,25-Dihydroxyvitamin D3 enhances neural stem cell proliferation and oligodendrocyte differentiation” [Experimental and Molecular Pathology 98 (2015) 240–245] 关注表达：“1,25-二羟基维生素D3增强神经干细胞增殖和少突胶质细胞分化”[实验与分子病理学98 (2015)240-245]

IF 3.7 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-01-01

引用次数: 0

Expression of concern: “Matrine ameliorates experimental autoimmune encephalomyelitis by modulating chemokines and their receptors” [Experimental and Molecular Pathology 99 (2015) 212–219] 关注表达：“苦参碱通过调节趋化因子及其受体改善实验性自身免疫性脑脊髓炎”[experimental and Molecular Pathology 99 (2015) 212-219]

IF 2.8 4区医学 Q2 PATHOLOGY

Experimental and molecular pathology

Pub Date : 2025-01-01

引用次数: 0

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