Peptides最新文献_第6页

Spexin expression in the human bile duct and perihilar cholangiocarcinoma Spexin在人胆管和肝门周围胆管癌中的表达。

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-04-05 DOI: 10.1016/j.peptides.2025.171405

Sara Huber , Theresia Fitzner , René G. Feichtinger , Theo Kraus , Stefanie Gaisbauer , Sarah Hochmann , Karl Sotlar , Barbara Kofler , Martin Varga

The bile duct transports bile fluid from the liver to the gallbladder and small intestine. It contains bioactive peptides, including galanin (GAL) and its receptors (GAL_1–3-R). Spexin (SPX), a member of the GAL peptide family, activates GAL₂-R and GAL₃-R. Its expression in perihilar bile ducts or in perihilar cholangiocarcinoma (pCCA), the most common biliary cancer, is largely unknown. This study investigated SPX expression in healthy, cholestatic, and malignant bile duct tissues. Immunohistochemistry was used to evaluate SPX in healthy (n = 4), peritumoral (PIT) (n = 23) and pCCA (n = 34) tissues. Score values of SPX expression were calculated and statistically analyzed. In healthy and PIT tissues with or without cholestasis, SPX expression was predominantly observed in cholangiocytes and nerve fibers. In pCCA, tumor cells also expressed SPX. SPX levels were similar across healthy, peritumoral, and cholangiocytes/tumor cells. In a small pCCA patient cohort (n = 19), SPX expression did not correlate with tumor grade or patient survival (p = 0.0838). The substantial expression of SPX in cholangiocytes and nerve fibers in the bile duct indicates that SPX contributes via galaninergic signaling to gall bladder function. The presence of SPX in submucosal nerve fibers suggests a neuromodulatory role, possibly involving bile duct motility. SPX expression did not correlate with survival in pCCA, whereas previous findings on GAL suggest a prognostic value. This highlights the need for joint studies of SPX and GAL in larger cohorts.

胆管将胆汁液从肝脏输送到胆囊和小肠。它含有生物活性肽，包括丙氨酸（GAL）及其受体（GAL1-3-R）。SPX是GAL肽家族的一员，可激活GAL2-R和GAL3-R。它在肝门周围胆管或肝门周围胆管癌（最常见的胆道癌）中的表达在很大程度上是未知的。本研究探讨了SPX在健康、胆汁淤积和恶性胆管组织中的表达。采用免疫组织化学方法评估健康（n = 4）、瘤周（n = 23）和pCCA （n = 34）组织中的SPX。计算SPX表达的评分值并进行统计学分析。在有或没有胆汁淤积的健康和PIT组织中，SPX主要在胆管细胞和神经纤维中表达。在pCCA中，肿瘤细胞也表达SPX。SPX水平在健康细胞、肿瘤周围细胞和胆管细胞/肿瘤细胞中相似。在一个小的pCCA患者队列中（n = 19）， SPX表达与肿瘤分级或患者生存无关（p = 0.0838）。SPX在胆管细胞和神经纤维中的大量表达表明SPX通过半乳糖能信号传导参与胆囊功能。粘膜下神经纤维中SPX的存在提示其具有神经调节作用，可能与胆管运动有关。SPX的表达与pCCA患者的生存无关，而先前关于GAL的研究结果表明其具有预后价值。这突出了在更大的队列中对SPX和GAL进行联合研究的必要性。

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引用次数: 0

Oxyntomodulin - past, present and future oxyntomodulin -过去，现在和未来。

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-04-03 DOI: 10.1016/j.peptides.2025.171393

Jens Juul Holst , Mette M. Rosenkilde

Almost since its discovery, glucagon was suspected to be formed in the gastrointestinal tract, and the L-cells were shown to contain glucagon-like immunoreactivity. This was due to the presence of two peptides that both contained the full glucagon sequence:glicentin of 69 amino acids and oxyntomodulin of 37 amino acids. While glicentin is a part of the glucagon precursor, proglucagon, and probably is inactive, oxyntomodulin, a fragment of glicentin, interacts although weakly with the glucagon as well as the GLP-1 receptor. However, in agreement with these activities, oxyntomodulin inhibited appetite and food intake in humans and inspired development of long acting, potent glucagon-GLP-1 co-agonists. Several such co-agonists are currently in clinical development and show promise because they combine GLP-1 like activities with those of glucagon agonism: additive weight loss and a stimulation of hepatic lipid metabolism with unique effectiveness on hepatic steatosis. They may therefore be effective in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD).

几乎自胰高血糖素被发现以来，人们就怀疑它是在胃肠道中形成的，并且l细胞显示出含有胰高血糖素样免疫反应性。这是由于两种多肽的存在，它们都含有胰高血糖素的完整序列：由69个氨基酸组成的甘肽肽和由37个氨基酸组成的氧合调节肽。虽然glicentin是胰高血糖素前体，胰高血糖素原的一部分，并且可能是无活性的，但glicentin的一个片段，氧合调节素，虽然与胰高血糖素和GLP-1受体相互作用微弱。然而，与这些活性一致的是，氧调素抑制人类的食欲和食物摄入，并激发了长效、有效的胰高血糖素- glp -1协同激动剂的发展。一些这样的协同激动剂目前正处于临床开发阶段，并显示出前景，因为它们将GLP-1样活性与胰高血糖素激动剂的活性结合起来：增加体重减轻和刺激肝脏脂质代谢，对肝脏脂肪变性具有独特的效果。因此，它们可能对代谢功能障碍相关的脂肪变性肝病（MASLD）的治疗有效。

引用次数: 0

Irisin prevents visceral hypersensitivity and colonic hyperpermeability in a rat model of irritable bowel syndrome 鸢尾素预防肠易激综合征大鼠模型的内脏过敏和结肠高渗透性

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-03-26 DOI: 10.1016/j.peptides.2025.171394

Tsukasa Nozu , Saori Miyagishi , Masatomo Ishioh , Kaoru Takakusaki , Toshikatsu Okumura

Visceral hypersensitivity and impaired gut barrier function, accompanied by minor inflammation, are crucial components of the pathophysiology of irritable bowel syndrome (IBS). Research has demonstrated that corticotropin-releasing factor (CRF) and toll-like receptor 4 (TLR4) signaling mutually activate to produce proinflammatory cytokines, which modulate these gastrointestinal changes. Irisin, a myokine, has been shown to inhibit TLR4-proinflammatory cytokine signaling, thereby improving inflammation driven by obesity and metabolic syndrome. Based on this, we hypothesized that irisin could improve visceral hypersensitivity and impaired gut barrier function induced by lipopolysaccharide (LPS) or CRF (IBS rat models), and tested this hypothesis. The visceral pain threshold, triggered by colonic balloon distention, was assessed by electrophysiologically monitoring abdominal muscle contractions in male Sprague-Dawley rats. Colonic permeability was evaluated by measuring the amount of Evans blue dye absorbed within the colonic tissue. Intraperitoneal irisin prevented LPS-induced visceral hypersensitivity and colonic hyperpermeability in a dose-dependent manner. Irisin also prevented CRF-induced gastrointestinal alterations. The beneficial effects of irisin in the LPS model were reversed by compound C, an AMP-activated protein kinase (AMPK) inhibitor; N^G-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor; sulpiride or domperidone, a dopamine D₂ receptor antagonist; atropine and intracisternal injection of SB-334867, a selective orexin 1 receptor antagonist. Overall, these findings suggest that irisin improves visceral sensation and colonic barrier function through AMPK, NO and dopamine D₂, cholinergic and brain orexin signaling in IBS model. Thus, irisin may be a promising therapeutic agent for treating IBS.

内脏过敏和肠道屏障功能受损，伴随着轻微的炎症，是肠易激综合征（IBS）病理生理学的重要组成部分。研究表明，促肾上腺皮质激素释放因子（CRF）和toll样受体4 （TLR4）信号相互激活，产生促炎细胞因子，调节这些胃肠道变化。鸢尾素是一种肌因子，已被证明可以抑制tlr4促炎细胞因子信号，从而改善肥胖和代谢综合征引起的炎症。基于此，我们假设鸢尾素可以改善脂多糖（LPS）或CRF （IBS大鼠模型）引起的内脏超敏反应和肠道屏障功能受损，并对这一假设进行了验证。通过电生理学监测雄性Sprague-Dawley大鼠腹部肌肉收缩，评估由结肠球囊膨胀引发的内脏痛阈。通过测定结肠组织内埃文斯蓝染料的吸收量来评估结肠通透性。鸢尾素以剂量依赖性的方式阻止lps诱导的内脏超敏反应和结肠高渗透性。鸢尾素还能防止crf诱导的胃肠道改变。鸢尾素在LPS模型中的有益作用被化合物C逆转，化合物C是一种amp激活的蛋白激酶（AMPK）抑制剂；NO合成抑制剂ng -硝基- l -精氨酸甲酯；舒必利或多潘立酮，多巴胺D2受体拮抗剂；阿托品和腹腔注射SB-334867，一种选择性食欲素1受体拮抗剂。综上所述，这些发现表明鸢尾素在IBS模型中通过AMPK、NO和多巴胺D2、胆碱能和脑促食欲素信号通路改善内脏感觉和结肠屏障功能。因此，鸢尾素可能是一种很有前途的治疗肠易激综合征的药物。

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引用次数: 0

Evaluation of plasma arginine vasopressin during hypertonic saline loading: A comparison of radioimmunoassay and liquid chromatography–tandem mass spectrometry 高渗生理盐水负荷期间血浆精氨酸加压素的评价：放射免疫法和液相色谱-串联质谱法的比较。

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-03-18 DOI: 10.1016/j.peptides.2025.171392

Narantsatsral Daramjav , Junko Takagi , Fumio Nomura , Kazuo Otake , Akiyoshi Takami

Plasma arginine vasopressin (AVP) measurement is critical for diagnosing central diabetes insipidus (CDI). Conventional radioimmunoassay (RIA) is widely used for AVP quantification, but its limited sensitivity, specificity, and dynamic range have prompted exploration of alternative methods. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as a promising technique for AVP measurement, offering potential advantages over RIA. This study aimed to evaluate LC-MS/MS performance for AVP quantification during hypertonic saline loading and compare its diagnostic accuracy with that of RIA in differentiating CDI patients from controls. A total of 335 plasma samples were collected from 77 individuals—23 diagnosed with CDI and 54 controls—during hypertonic saline loading. AVP concentrations were measured using both LC-MS/MS and RIA. Statistical analyses included Wilcoxon tests to compare AVP levels, correlation analysis between LC-MS/MS and RIA, and receiver operating characteristic (ROC) curve analysis to assess diagnostic performance. LC-MS/MS demonstrated a lower detection limit (0.3 pg/mL) and a broader quantification range than RIA. Regression analysis showed a strong correlation between LC-MS/MS and RIA in the control group, but no correlation in the CDI group. ROC analysis indicated that LC-MS/MS provided diagnostic accuracy comparable to RIA for distinguishing CDI patients from controls. Bland-Altman analysis showed the agreement between two methods at the low range of AVP. LC-MS/MS offers equivalent specificity and sensitivity to RIA for AVP measurement, while providing added benefits in time efficiency, cost-effectiveness, and differential diagnosis of CDI. These findings suggest that LC-MS/MS is a viable alternative to RIA for clinical AVP quantification.

血浆精氨酸加压素（AVP）测定是诊断中枢性尿崩症（CDI）的关键。传统放射免疫分析法（RIA）被广泛用于AVP定量，但其有限的灵敏度、特异性和动态范围促使人们探索替代方法。液相色谱-串联质谱（LC-MS/MS）已成为一种很有前途的AVP测量技术，与RIA相比具有潜在的优势。本研究旨在评估LC-MS/MS在高渗生理盐水负荷时AVP定量的性能，并比较其与RIA在区分CDI患者和对照组中的诊断准确性。在高渗生理盐水负荷期间，共收集了77名患者的335份血浆样本，其中23名诊断为CDI， 54名对照组。采用LC-MS/MS和RIA检测AVP浓度。统计分析包括比较AVP水平的Wilcoxon检验，LC-MS/MS与RIA的相关性分析，以及评估诊断效果的受试者工作特征（ROC）曲线分析。LC-MS/MS的检出限较低（0.3pg/mL），定量范围较RIA宽。回归分析显示，对照组LC-MS/MS与RIA有较强的相关性，CDI组无相关性。ROC分析表明LC-MS/MS在区分CDI患者和对照组方面具有与RIA相当的诊断准确性。Bland-Altman分析显示两种方法在AVP低范围内一致。LC-MS/MS在AVP测量方面与RIA具有相同的特异性和敏感性，同时在时间效率、成本效益和CDI鉴别诊断方面提供了额外的好处。这些结果表明LC-MS/MS是一种可行的替代RIA的临床AVP定量方法。

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引用次数: 0

Adropin: A cardio-metabolic hormone in the periphery, a neurohormone in the brain? 促肾上腺素：外周的心脏代谢激素，大脑中的神经激素？

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-03-15 DOI: 10.1016/j.peptides.2025.171391

Andrew A. Butler , Peter J. Havel

Whole-body metabolic homeostasis is regulated by physiological responses across organs and tissues to proteins and peptides (<50 amino acids) released into the interstitial and circulatory spaces. These secreted factors integrate signals of metabolic status at both the cellular and systemic level, regulate the intake and distribution of ingested and stored energy substrates across tissues, and minimize toxicity from excessive excursions in circulating concentrations of energy substrates (for example, glucotoxicity and lipotoxicity). The proteins and peptides that are known to be secreted into circulation that are involved in regulating metabolic processes represent a fraction of the secretome predicted by the Human Proteome Atlas. Many undiscovered leads for targeting new therapies for metabolic diseases may therefore exist. In this review, we discuss the biology of adropin, the peptide encoded by the Energy Homeostasis Associated (ENHO) gene. First described as a feeding-responsive, liver-secreted peptide (“hepatokine”) involved in metabolic homeostasis, > 2 decades of research indicate adropin is a stress-responsive peptide acting across multiple tissues, vascular, and organ systems. Adropin modulates the responses of liver and muscle to insulin and glucagon in regulating glucose homeostasis. Adropin inhibits hepatic glucose production and stimulates glycolysis but also inhibits tissue fibrosis and maintains vascular health in aging and metabolic disease states. Adropin is also highly expressed in the central nervous system where recent data suggest neuroprotective actions. Collectively, these results suggest the potential for targeting adropin in reducing risk of both metabolic (metabolic syndrome/type-2 diabetes) and neurodegenerative diseases in the context of aging and obesity.

全身代谢稳态是通过器官和组织对蛋白质和肽的生理反应来调节的（20年的研究表明，adropin是一种应激反应肽，作用于多个组织、血管和器官系统）。Adropin调节肝脏和肌肉对胰岛素和胰高血糖素的反应，调节葡萄糖稳态。Adropin抑制肝脏葡萄糖生成并刺激糖酵解，但也抑制组织纤维化并在衰老和代谢性疾病状态下维持血管健康。Adropin在中枢神经系统中也高度表达，最近的数据表明它具有神经保护作用。总的来说，这些结果表明，在衰老和肥胖的背景下，靶向adropin在降低代谢（代谢综合征/ 2型糖尿病）和神经退行性疾病的风险方面具有潜力。

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引用次数: 0

Multifunctional incretin peptides in therapies for type 2 diabetes, obesity and associated co-morbidities 多功能肠促胰岛素肽在治疗2型糖尿病、肥胖及相关合并症中的应用

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-03-11 DOI: 10.1016/j.peptides.2025.171380

Clifford J. Bailey , Peter R. Flatt , J. Michael Conlon

Recent studies with peptide-based incretin therapies have focussed mainly on the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide and the dual agonist tirzepatide that engages receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Randomised clinical trials and ‘real-world’ studies have confirmed the marked glucose-lowering and weight-lowering efficacy of these agents across diverse populations. These include different ethnic groups, young and elderly individuals with and without diabetes and/or overweight or obesity. Recent studies have also confirmed protections against the development and progression of cardiovascular and renal diseases that are additive to the benefits conferred by improved control of blood glucose and body weight. Emerging evidence suggests that incretin therapies could additionally ameliorate fatty liver disease, chronic inflammation, sleep apnea and possibly degenerative bone disorders and cognitive decline. New incretin-based peptide therapies in development include a long-acting glucagon receptor agonist (LY3324954), dual GLP-1/glucagon receptor agonists (survodutide, pemvidutide, mazdutide, G49), triple GLP-1/GIP/glucagon receptor agonists (retatrutide, efocipegtrutide), a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), a unimolecular GLP-1/amylin receptor dual agonist (amycretin), and a GIP receptor antibody with GLP-1 receptor agonism (MariTide). The creation of multi-targeting incretin-based synthetic peptides provides opportunities for improved management of type 2 diabetes and obesity as well as new therapeutic approaches to an expanding list of associated co-morbidities. The aim of the review is to acquaint the reader with developments in the field from 2023 to the present (February 2025).

最近关于以肽为基础的肠促胰岛素治疗的研究主要集中在胰高血糖素样肽-1 （GLP-1）受体激动剂semaglutide和双重激动剂tizepatide，它们结合GLP-1和葡萄糖依赖性胰岛素性多肽（GIP）受体。随机临床试验和“现实世界”研究已经证实，这些药物在不同人群中具有显著的降糖和减肥功效。这些人包括不同的种族群体、有或没有糖尿病和/或超重或肥胖的年轻人和老年人。最近的研究还证实，除了改善血糖和体重控制所带来的好处外，还可以预防心血管和肾脏疾病的发生和发展。新出现的证据表明，肠促胰岛素疗法可以额外改善脂肪肝疾病、慢性炎症、睡眠呼吸暂停以及可能的退行性骨疾病和认知能力下降。正在开发的新的基于肠促胰岛素的肽疗法包括长效胰高血糖素受体激动剂（LY3324954），双GLP-1/胰高血糖素受体激动剂（survodutide, pemvidutide, mazdutide, G49），三重GLP-1/GIP/胰高血糖素受体激动剂（利特鲁肽，依福西肽类），半马鲁肽与胰高血糖素类似物cagrilintide的组合（CagriSema），单分子GLP-1/胰高血糖素受体双激动剂（amycretin），以及具有GLP-1受体激动剂的GIP受体抗体（MariTide）。基于多靶点肠促胰岛素的合成肽的创造为改善2型糖尿病和肥胖的管理提供了机会，并为扩大相关合并症提供了新的治疗方法。回顾的目的是让读者熟悉2023年到现在（2025年2月）该领域的发展。

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引用次数: 0

A novel regulator of NLRP3 inflammasome: Peptides NLRP3炎性小体的一种新调节剂：多肽

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-03-08 DOI: 10.1016/j.peptides.2025.171381

Zhuo Zuo, Yaxing Wang, Yanwei Fang, Mengya Zhao, Zhe Wang, Zhouqi Yang, Bin Jia, Yulong Sun

The NLRP3 inflammasome plays a crucial role as a critical regulator of the immune response and has been implicated in the pathogenesis of numerous diseases. Peptides, known for their remarkable potency, selectivity, and low toxicity, have been extensively employed in disease treatment. Recent research has unveiled the potential of peptides in modulating the activity of the NLRP3 inflammasome. This review begins by examining the structure of the NLRP3 inflammasome, encompassing NLRP3, ASC, and Caspase-1, along with the three activation pathways: canonical, non-canonical, and alternative. Subsequently, we provide a comprehensive summary of peptide modulators targeting the NLRP3 inflammasome and elucidate their underlying mechanisms. The efficacy of these modulators has been validated through in vitro and in vivo experiments on NLRP3 inflammasome regulation. Furthermore, we conduct sequence alignment of the identified peptides and investigate their binding sites on the NLRP3 protein. This work is a foundational exploration for advancing peptides as potential therapeutic agents for NLRP3-related diseases.

NLRP3炎症小体作为免疫反应的关键调节因子起着至关重要的作用，并与许多疾病的发病机制有关。多肽以其显著的效力、选择性和低毒性而闻名，已广泛应用于疾病治疗。最近的研究揭示了多肽在调节NLRP3炎性体活性方面的潜力。本综述首先检查NLRP3炎性小体的结构，包括NLRP3、ASC和Caspase-1，以及三种激活途径：典型、非典型和替代。随后，我们全面总结了针对NLRP3炎性体的肽调节剂，并阐明了它们的潜在机制。这些调节剂对NLRP3炎性小体调控的有效性已通过体内和体外实验得到验证。此外，我们对鉴定的肽进行了序列比对，并研究了它们在NLRP3蛋白上的结合位点。这项工作是推进肽作为nlrp3相关疾病潜在治疗剂的基础探索。

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引用次数: 0

Corrigendum to “Oxytocin attenuates cardiac hypertrophy by improving cardiac glucose metabolism and regulating OXTR/JAK2/STAT3 axis” [Peptides 182 (2024) 171323] “催产素通过改善心脏糖代谢和调节OXTR/JAK2/STAT3轴来减轻心脏肥厚”的更正[Peptides 182(2024) 171323]。

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-03-08 DOI: 10.1016/j.peptides.2025.171365

Yuqiao Yang , Jin Liu , Lingyan Wang , Wen Wu, Quan Wang, Yu Zhao, Xi Qian, Zhuoran Wang, Na Fu, Yanqiong Wang, Jinqiao Qian

引用次数: 0

KLF4 regulates FAM3A to promotes angiotensin II-induced proliferation and migration of vascular smooth muscle cells through the PI3K/AKT signaling pathway KLF4通过PI3K/AKT信号通路调控FAM3A，促进血管紧张素ii诱导的血管平滑肌细胞增殖和迁移。

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-02-25 DOI: 10.1016/j.peptides.2025.171379

Min Zhang, Rong Lei, Liqiong Wang, Yimin Jiang, Xiaoyan Zhou, Yuquan Wang

Background

Hypertension, a major cause of cardiovascular disease, is linked to vascular remodeling, which is influenced by phenotypic changes in vascular smooth muscle cells (VSMCs). Studies have shown that KLF4 influences vascular remodeling by promoting VSMC dedifferentiation, increasing proliferation, and enhancing inflammatory responses, while FAM3 may play a key role in VSMC migration and proliferation. Angiotensin II (Ang II) contributes to remodeling, but the mechanisms are unclear.

Methods

Ang II was used to stimulate VSMCs in order to evaluate the expression levels of KLF4 and FAM3A. EdU assays, transwell and scratch wound healing assays measured proliferation and migration. KLF4 knockdown and overexpression experiments were performed to examine the effects on FAM3A expression and VSMC behavior. Western blotting was conducted to analyze protein expression levels of KLF4, FAM3A, and PI3K/AKT signaling components. Bioinformatics analysis was used to predict KLF4 binding sites on the FAM3A promoter. Luciferase and CHIP assays confirmed regulation.

Results

Ang II stimulation increased VSMC proliferation, migration, and the expression of KLF4 and FAM3A. Knockdown of KLF4 reduced Ang II-induced proliferation and migration of VSMCs, accompanied by decreased FAM3A expression. Conversely, overexpression of KLF4 enhanced FAM3A levels, promoting VSMC proliferation and migration. Bioinformatics, luciferase reporter assays and CHIP assay confirmed that KLF4 directly binds to the FAM3A promoter. FAM3A knockdown inhibited Ang II-induced VSMC proliferation and migration by reducing PI3K/AKT pathway activation, whereas FAM3A overexpression reversed the inhibitory effects of KLF4 knockdown.

Conclusion

KLF4 transcriptionally regulates FAM3A, modulating Ang II-induced VSMC proliferation and migration through the PI3K/AKT signaling pathway.

背景：高血压是心血管疾病的主要原因之一，与血管重构有关，血管重构受血管平滑肌细胞（VSMCs）表型变化的影响。研究表明KLF4通过促进VSMC去分化、增加增殖、增强炎症反应等方式影响血管重构，而FAM3可能在VSMC迁移和增殖中发挥关键作用。血管紧张素II （Ang II）有助于重塑，但机制尚不清楚。方法：采用Angⅱ刺激VSMCs，评价KLF4和FAM3A的表达水平。EdU试验、transwell和划伤愈合试验测量了增殖和迁移。通过KLF4敲低和过表达实验，观察对FAM3A表达和VSMC行为的影响。Western blotting分析KLF4、FAM3A、PI3K/AKT信号组分的蛋白表达水平。利用生物信息学分析预测FAM3A启动子上KLF4的结合位点。荧光素酶和CHIP检测证实有调节作用。结果：Ang II刺激增加VSMC的增殖、迁移和KLF4、FAM3A的表达。敲低KLF4可降低Angⅱ诱导的VSMCs的增殖和迁移，同时降低FAM3A的表达。相反，过表达KLF4可增强FAM3A水平，促进VSMC的增殖和迁移。生物信息学、荧光素酶报告基因检测和CHIP检测证实KLF4直接结合FAM3A启动子。FAM3A敲低通过降低PI3K/AKT通路激活抑制Ang ii诱导的VSMC增殖和迁移，而FAM3A过表达逆转了KLF4敲低的抑制作用。结论：KLF4转录调控FAM3A，通过PI3K/AKT信号通路调节Ang ii诱导的VSMC增殖和迁移。

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引用次数: 0

A murine model of obesity with hyperinsulinemia and hepatic steatosis involving neurosecretory protein GL gene and a low-fat/medium-sucrose diet 高胰岛素血症和肝脂肪变性的小鼠模型，涉及神经分泌蛋白GL基因和低脂/中糖饮食。

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-02-23 DOI: 10.1016/j.peptides.2025.171376

Yuki Narimatsu , Masaki Kato , Eiko Iwakoshi-Ukena, Megumi Furumitsu, Kazuyoshi Ukena

Metabolic dysfunction-associated steatotic liver disease (MASLD) featuring hepatic steatosis and insulin dysregulation is becoming a common cause of chronic hepatic diseases. Although the involvement of endocrine disruption in the onset and progression of MASLD is thought to be critical, there are limited effective animal models reflecting hyperinsulinemia and hepatic steatosis. Here, we propose a MASLD mouse model that combines neuropeptide effects and dietary nutrition. We employed chronic overexpression of the gene encoding neurosecretory protein GL (NPGL) in the hypothalamus of ICR mice under a low-fat/medium-sucrose diet (LFMSD). Npgl overexpression promoted fat accumulation in the white adipose tissues in 2 weeks. Basal insulin levels were increased and pancreatic islets expanded following Npgl overexpression. Histological and molecular biological approaches revealed that Npgl overexpression enhanced de novo lipogenesis, leading to hepatic steatosis. Nine-week overexpression of Npgl exacerbated obesity and hyperinsulinemia, resulting in hyperglycemia. Moreover, prolonged Npgl overexpression aggravated fat accumulation in the liver with a change in the lipid metabolic pathway. These findings suggest that Npgl overexpression readily leads to obesity with hyperinsulinemia and hepatic steatosis in ICR mice under an LFMSD.

以肝脏脂肪变性和胰岛素失调为特征的代谢功能障碍相关脂肪变性肝病（MASLD）正在成为慢性肝脏疾病的常见原因。虽然内分泌干扰在MASLD的发生和发展中被认为是至关重要的，但反映高胰岛素血症和肝脂肪变性的有效动物模型有限。在这里，我们提出了一个结合神经肽效应和膳食营养的MASLD小鼠模型。我们采用低脂/中糖饮食（LFMSD）下ICR小鼠下丘脑中编码神经分泌蛋白GL （NPGL）的基因的慢性过表达。Npgl过表达促进白色脂肪组织在2周内的脂肪积累。Npgl过表达后，基础胰岛素水平升高，胰岛扩大。组织学和分子生物学方法显示，Npgl过表达增强了肝脏脂肪生成，导致肝脏脂肪变性。9周后，Npgl的过度表达加重了肥胖和高胰岛素血症，导致高血糖。此外，Npgl过表达的延长通过改变脂质代谢途径加剧了肝脏中的脂肪积累。这些发现表明，Npgl过表达容易导致LFMSD下的ICR小鼠肥胖并伴有高胰岛素血症和肝脏脂肪变性。

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引用次数: 0