Biochemical pharmacology最新文献_第5页

Exploring tryptophan metabolism: The transition from disturbed balance to diagnostic and therapeutic potential in metabolic diseases 探索色氨酸代谢：从代谢疾病的平衡紊乱到诊断和治疗潜力的转变。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-25 DOI: 10.1016/j.bcp.2024.116554

The rapidly rising prevalence of metabolic diseases has turned them into an escalating global health concern. By producing or altering metabolic products, the gut microbiota plays a pivotal role in maintaining human health and influencing disease development. These metabolites originate from the host itself or the external environment. In the system of interactions between microbes and the host, tryptophan (Trp) plays a central role in metabolic processes. As the amino acid in the human body that must be obtained through dietary intake, it is crucial for various physiological functions. Trp can be metabolized in the gut into three main products: The gut microbiota regulates the transformation of 5-hydroxytryptamine (5-HT, serotonin), kynurenine (Kyn), and various indole derivatives. It has been revealed that a substantial correlation exists between alterations in Trp metabolism and the initiation and progression of metabolic disorders, including obesity, diabetes, non-alcoholic fatty liver disease, and atherosclerosis, but Trp metabolites have not been comprehensively reviewed in metabolic diseases. As such, this review summarizes and analyzes the latest research, emphasizing the importance of further studying Trp metabolism within the gut microbiota to understand and treat metabolic diseases. This carries potential significance for improving human health and may introduce new therapeutic strategies.

代谢性疾病的发病率迅速上升，已成为日益严重的全球健康问题。通过产生或改变代谢产物，肠道微生物群在维持人类健康和影响疾病发展方面发挥着举足轻重的作用。这些代谢产物来自宿主本身或外部环境。在微生物与宿主的相互作用系统中，色氨酸（Trp）在代谢过程中发挥着核心作用。色氨酸是人体内必须从膳食中获取的氨基酸，对各种生理功能至关重要。Trp 可在肠道中代谢为三种主要产物：肠道微生物群调节 5-羟色胺（5-HT，血清素）、犬尿氨酸（Kyn）和各种吲哚衍生物的转化。研究发现，Trp 代谢的改变与代谢性疾病（包括肥胖、糖尿病、非酒精性脂肪肝和动脉粥样硬化）的发生和发展之间存在很大的相关性，但尚未对代谢性疾病中的 Trp 代谢物进行全面研究。因此，本综述总结并分析了最新研究，强调进一步研究肠道微生物群中的 Trp 代谢对了解和治疗代谢性疾病的重要性。这对改善人类健康具有潜在意义，并可能引入新的治疗策略。

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引用次数: 0

Role of the RNA binding protein IGF2BP1 in cancer multidrug resistance RNA 结合蛋白 IGF2BP1 在癌症多药耐药性中的作用

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-25 DOI: 10.1016/j.bcp.2024.116555

The insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1), a member of a conserved family of single-stranded RNA-binding proteins (IGF2BP1-3), is expressed in a broad range of fetal tissues, placenta and more than sixteen cancer types but only in a limited number of normal adult tissues. IGF2BP1is required for the transport from nucleus to cytoplasm of certain mRNAs that play essential roles in embryogenesis, carcinogenesis, and multidrug resistance (MDR), by affecting their stability, translation, or localization. The purpose of this review is to gather and present information on MDR mechanisms in cancer and the significance of IGF2BP1 in this context. Within this review, we will provide an overview of IGF2BP1, including its tissue distribution, expression, molecular targets in the context of tumorigenesis and its inhibitors. Our main focus will be on elucidating the interplay between IGF2BP1 and MDR, particularly with regard to chemoresistance mediated by ABC transporters.

胰岛素样生长因子-2 mRNA 结合蛋白 1（IGF2BP1）是单链 RNA 结合蛋白（IGF2BP1-3）保守家族的成员，在胎儿组织、胎盘和超过 16 种癌症类型中广泛表达，但只在数量有限的正常成人组织中表达。IGF2BP1 需要通过影响某些 mRNA 的稳定性、翻译或定位，将其从细胞核转运到细胞质，这些 mRNA 在胚胎发生、癌变和多药耐药性（MDR）中发挥着重要作用。本综述旨在收集和介绍癌症中 MDR 机制的相关信息，以及 IGF2BP1 在其中的重要作用。在这篇综述中，我们将概述 IGF2BP1，包括其组织分布、表达、肿瘤发生过程中的分子靶点及其抑制剂。我们的主要重点是阐明 IGF2BP1 与 MDR 之间的相互作用，尤其是 ABC 转运体介导的化疗耐药性。

引用次数: 0

The stimulatory effect of HI 129, a novel indole derivative, on glucose-induced insulin secretion 新型吲哚衍生物 HI 129 对葡萄糖诱导的胰岛素分泌的刺激作用。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-25 DOI: 10.1016/j.bcp.2024.116558

Indole derivatives exhibit a broad spectrum of beneficial effects, encompassing anti-inflammatory, antiviral, antimalarial, anti-diabetic, antioxidant, anti-hepatitis, and antidepressant properties. Here, we describe the potentiation of insulin secretion in pancreatic islets and INS-1 cells through methyl 2-(2-ethoxy-1-hydroxy-2-oxoethyl)-1-(pyrimidine-2-yl)-1H-indole-3-carboxylate (HI 129), a novel indole derivative. Treatment with HI 129 led to notably decreased ADP/ATP ratios in pancreatic islets and INS-1 cells compared to those in the vehicle-treated controls, indicating a shift in cellular ATP production. Moreover, the augmentation of insulin secretion by HI 129 was closely correlated with its ability to enhance the mitochondrial membrane potential and respiration, partly by reducing the phosphorylation levels of AMP-activated protein kinase (AMPK). Mechanistically, HI 129 enhanced the association between AMPK and β-arrestin-1, critical molecules for glucose-induced insulin secretion. Furthermore, β-arrestin-1 depletion attenuated the effect of HI 129 on glucose-induced insulin secretion, suggesting that HI 129 potentiates insulin secretion via β-arrestin-1/AMPK signaling. These results collectively underscore the potential of HI 129 in enhancing insulin secretion as a novel candidate for improving glucose homeostasis in type 2 diabetes.

吲哚衍生物具有广泛的有益作用，包括抗炎、抗病毒、抗疟、抗糖尿病、抗氧化、抗肝炎和抗抑郁等特性。在这里，我们描述了新型吲哚衍生物 2-（2-乙氧基-1-羟基-2-氧代乙基）-1-（嘧啶-2-基）-1H-吲哚-3-羧酸甲酯（HI 129）对胰岛和 INS-1 细胞胰岛素分泌的增效作用。用 HI 129 治疗后，胰岛和 INS-1 细胞中的 ADP/ATP 比率与用药物治疗的对照组相比明显下降，这表明细胞 ATP 的产生发生了变化。此外，HI 129 对胰岛素分泌的促进作用与它增强线粒体膜电位和呼吸的能力密切相关，部分原因是它降低了 AMP 激活蛋白激酶（AMPK）的磷酸化水平。从机制上讲，HI 129 增强了 AMPK 与β-arrestin-1（葡萄糖诱导胰岛素分泌的关键分子）之间的关联。此外，β-arrestin-1 的耗竭减弱了 HI 129 对葡萄糖诱导的胰岛素分泌的影响，这表明 HI 129 可通过 β-arrestin-1/AMPK 信号转导增强胰岛素分泌。这些结果共同强调了 HI 129 在增强胰岛素分泌方面的潜力，是改善 2 型糖尿病患者血糖稳态的新型候选药物。

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引用次数: 0

Design, synthesis and biological evaluation of novel curcumin-fluorouracil hybrids as potential anti-cancer agents 作为潜在抗癌剂的新型姜黄素-氟尿嘧啶混合物的设计、合成和生物学评价。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-24 DOI: 10.1016/j.bcp.2024.116559

The latest global cancer data statistics report shows that cancer poses a serious threat to human life and health; The number of new cancer and death cases worldwide is severe. Molecular hybridization is considered an effective strategy for developing new anti-cancer drugs. Curcumin (Cur) is a natural active compound containing Michael receptors that target thioredoxin reductase (TrxR). Fluorouracil (5-FU) is the first anti-metabolic drug synthesized based on certain assumptions for tumor treatment, acting on thymidylate synthase (TS). This study synthesized a series of novel hybrid derivatives of Cur and 5-FU, and evaluated their anti-tumor cell proliferation effects. Several compounds with good cytotoxic activity against tumor cells were discovered; and they exhibited high selectivity towards A549 cells, compared to normal THLE cells. Among them, the hybrid derivative F-4 has the best anti-proliferative activity in tumor cells. F-4 can target TrxR, increase reactive oxygen species levels in tumor cells, and lead to tumor cell apoptosis, which may be related to the Michael receptor structure in the chemical structure of F-4; F-4 can also target TS, leading to cell cycle arrest in G0/G1 phase, which may be related to the 5-FU structure in the chemical structure of F-4. Moreover, F-4 can effectively exert anti-tumor activity in mice, significantly reduce tumor volume and weight, and has low toxic side effects. These results indicate that Cur-5-FU hybrid derivative F-4 is a novel lead compound with in vivo anti-tumor activity and minimal side effects, which deserves further investigation.

最新的全球癌症数据统计报告显示，癌症严重威胁着人类的生命和健康；全球新增癌症病例和死亡病例数量严重。分子杂交被认为是开发新型抗癌药物的有效策略。姜黄素（Cur）是一种天然活性化合物，含有针对硫代氧化还原酶（TrxR）的迈克尔受体。氟尿嘧啶（5-FU）是第一种基于特定假设合成的抗代谢药物，用于治疗肿瘤，作用于胸苷酸合成酶（TS）。本研究合成了一系列 Cur 和 5-FU 的新型混合衍生物，并评估了它们的抗肿瘤细胞增殖效果。研究发现了几种对肿瘤细胞具有良好细胞毒活性的化合物；与正常的THLE细胞相比，它们对A549细胞具有较高的选择性。其中，混合衍生物 F-4 对肿瘤细胞的抗增殖活性最佳。F-4能靶向TrxR，增加肿瘤细胞内活性氧水平，导致肿瘤细胞凋亡，这可能与F-4化学结构中的迈克尔受体结构有关；F-4还能靶向TS，导致细胞周期停滞在G0/G1期，这可能与F-4化学结构中的5-FU结构有关。此外，F-4 还能有效发挥小鼠的抗肿瘤活性，显著减少肿瘤体积和重量，且毒副作用小。这些结果表明，Cur-5-FU 杂交衍生物 F-4 是一种新型先导化合物，具有体内抗肿瘤活性，且副作用小，值得进一步研究。

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引用次数: 0

Microglia in retinal diseases: From pathogenesis towards therapeutic strategies 视网膜疾病中的小胶质细胞：从发病机制到治疗策略。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-20 DOI: 10.1016/j.bcp.2024.116550

Microglia, a widely dispersed cohort of immune cells in the retina, are intricately involved in a diverse range of pivotal biological processes, including inflammation, vascular development, complement activation, antigen presentation, and phagocytosis. Within the retinal milieu, microglia are crucial for the clearance of dead cells and cellular debris, release of anti-inflammatory agents, and orchestration of vascular network remodeling to maintain homeostasis. In addition, microglia are key mediators of neuroinflammation. Triggered by oxidative stress, elevated intraocular pressure, genetic anomalies, and immune dysregulation, microglia release numerous inflammatory cytokines, contributing to the pathogenesis of various retinal disorders. Recent studies on the ontogeny and broad functions of microglia in the retina have elucidated their characteristics during retinal development, homeostasis, and disease. Furthermore, therapeutic strategies that target microglia and their effector cytokines have been developed and shown positive results for some retinal diseases. Therefore, we systematically review the microglial ontogeny in the retina, elucidate their dual roles in retinal homeostasis and disease pathogenesis, and demonstrate microglia-based targeted therapeutic strategies for retinal diseases.

小胶质细胞是视网膜中广泛分布的一组免疫细胞，它们错综复杂地参与了各种关键的生物过程，包括炎症、血管发育、补体激活、抗原呈递和吞噬。在视网膜环境中，小胶质细胞对清除死亡细胞和细胞碎片、释放抗炎药物以及协调血管网络重塑以保持平衡至关重要。此外，小胶质细胞还是神经炎症的关键介质。在氧化应激、眼压升高、遗传异常和免疫失调的触发下，小胶质细胞会释放多种炎症细胞因子，导致各种视网膜疾病的发病机制。最近关于视网膜中小胶质细胞的本体和广泛功能的研究阐明了它们在视网膜发育、平衡和疾病过程中的特征。此外，针对小胶质细胞及其效应细胞因子的治疗策略已经开发出来，并在一些视网膜疾病的治疗中取得了积极的效果。因此，我们系统地回顾了视网膜中小胶质细胞的本体，阐明了它们在视网膜稳态和疾病发病机制中的双重作用，并展示了针对视网膜疾病的基于小胶质细胞的靶向治疗策略。

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引用次数: 0

Exendin-4 exhibits cardioprotective effects against high glucose-induced mitochondrial abnormalities: Potential role of GLP-1 receptor and mTOR signaling Exendin-4 对高血糖诱导的线粒体异常具有心脏保护作用：GLP-1 受体和 mTOR 信号转导的潜在作用

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-20 DOI: 10.1016/j.bcp.2024.116552

Mitochondrial dysfunction is associated with hyperglycemic conditions and insulin resistance leading to cellular damage and apoptosis of cardiomyocytes in diabetic cardiomyopathy. The dysregulation of glucagon-like peptide-1 (GLP-1) receptor and mammalian target of rapamycin (mTOR) is linked to cardiomyopathies and myocardial dysfunctions mediated by hyperglycemia. However, the involvements of mTOR for GLP-1 receptor-mediated cardioprotection against high glucose (HG)-induced mitochondrial disturbances are not clearly identified. The present study demonstrated that HG-induced cellular stress and mitochondrial damage resulted in impaired ATP production and oxidative defense markers such as catalase and SOD2, along with a reduction in survival markers such as Bcl-2 and p-Akt, while an increased expression of pro-apoptotic marker Bax was observed in H9c2 cardiomyoblasts. In addition, the autophagic marker LC3-II was considerably reduced, together with the disruption of autophagy regulators (p-mTOR and p-AMPKα) under the hyperglycemic state. Furthermore, there was a dysregulated expression of several indicators related to mitochondrial homeostasis, including MFN2, p-DRP1, FIS1, MCU, UCP3, and Parkin. Remarkably, treatment with either exendin-4 (GLP-1 receptor agonist) or rapamycin (mTOR inhibitor) significantly inhibited HG-induced mitochondrial damage while co-treatment of exendin-4 and rapamycin completely reversed all mitochondrial abnormalities. Antagonism of GLP-1 receptors using exendin-(9–39) abolished these cardioprotective effects of exendin-4 and rapamycin under HG conditions. In addition, exendin-4 attenuated HG-induced phosphorylation of mTOR, and this inhibitory effect was antagonized by exendin-(9–39), indicating the regulation of mTOR by GLP-1 receptor. Therefore, improvement of mitochondrial dysfunction by stimulating the GLP-1 receptor/AMPK/Akt pathway and inhibiting mTOR signaling could ameliorate cardiac abnormalities caused by hyperglycemic conditions.

线粒体功能障碍与高血糖和胰岛素抵抗有关，导致糖尿病心肌病中心肌细胞的细胞损伤和凋亡。胰高血糖素样肽-1（GLP-1）受体和哺乳动物雷帕霉素靶标（mTOR）的失调与高血糖介导的心肌病和心肌功能障碍有关。然而，mTOR 在 GLP-1 受体介导的心脏保护中对高糖（HG）诱导的线粒体紊乱的参与尚未明确。本研究表明，HG 诱导的细胞应激和线粒体损伤导致 ATP 生成和氧化防御标志物（如过氧化氢酶和 SOD2）受损，生存标志物（如 Bcl-2 和 p-Akt）减少，同时在 H9c2 心肌细胞中观察到促凋亡标志物 Bax 的表达增加。此外，在高血糖状态下，自噬标记物 LC3-II 显著减少，自噬调节因子（p-mTOR 和 p-AMPKα）也受到破坏。此外，与线粒体平衡相关的一些指标（如 MFN2、p-DRP1、FIS1、MCU、UCP3 和 Parkin）的表达也出现失调。值得注意的是，用外显子-4（GLP-1 受体激动剂）或雷帕霉素（mTOR 抑制剂）治疗可显著抑制 HG 诱导的线粒体损伤，而外显子-4 和雷帕霉素联合治疗可完全逆转所有线粒体异常。在 HG 条件下，使用 exendin-（9-39）拮抗 GLP-1 受体可消除 exendin-4 和雷帕霉素的这些心脏保护作用。此外，exendin-4 可减轻 HG 诱导的 mTOR 磷酸化，exendin-（9-39）可拮抗这种抑制作用，表明 GLP-1 受体可调节 mTOR。因此，通过刺激 GLP-1 受体/AMPK/Akt 通路和抑制 mTOR 信号转导来改善线粒体功能障碍，可以改善高血糖条件下引起的心脏异常。

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引用次数: 0

Recent advances in studies on FtsZ inhibitors FtsZ 抑制剂研究的最新进展。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-20 DOI: 10.1016/j.bcp.2024.116551

With the abuse of antibiotics, multidrug resistant strains continue to emerge and spread rapidly. Therefore, there is an urgent need to develop new antimicrobial drugs. As a highly conserved cell division protein in bacteria, filamenting temperature-sensitive mutant Z (FtsZ) has been identified as a potential antimicrobial target. This paper reviews the structure, function, and action mechanism of FtsZ and a variety of natural and synthetic compounds targeting FtsZ, including 3-MBA derivatives, taxane derivatives, cinnamaldehyde, curcumin, quinoline and quinazoline derivatives, aromatic compounds, purpurin, and totarol. From these studies, FtsZ has a clear supporting role in the field of antimicrobial drug discovery. The urgent need and interest of antibacterial drugs will contribute to the discovery of new clinical drugs targeting FtsZ.

随着抗生素的滥用，耐多药菌株不断出现并迅速扩散。因此，开发新的抗菌药物迫在眉睫。作为细菌中高度保守的细胞分裂蛋白，丝状温度敏感突变体 Z（FtsZ）已被确定为潜在的抗菌靶标。本文综述了 FtsZ 的结构、功能和作用机制，以及多种以 FtsZ 为靶标的天然和合成化合物，包括 3-MBA 衍生物、紫杉烷衍生物、肉桂醛、姜黄素、喹啉和喹唑啉衍生物、芳香族化合物、紫檀香苷和土他洛尔。从这些研究来看，FtsZ 在抗菌药物发现领域具有明显的辅助作用。抗菌药物的迫切需要和人们的兴趣将促进以 FtsZ 为靶点的临床新药的发现。

引用次数: 0

LSD1 is a promising target to treat cancers by modulating cell stemness LSD1 是通过调节细胞干性来治疗癌症的一个很有前景的靶点。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-19 DOI: 10.1016/j.bcp.2024.116549

As the first discovered histone demethylase, LSD1 plays a vital role in maintaining pathological processes such as cancer, infection, and immune diseases. Based on previous researches, LSD1 is highly expressed in sorts of tumor cells such as acute myeloid leukemia, non-small cell lung cancer, prostate cancer, breast cancer and gastric cancer, etc. Therefore, targeting LSD1 is a prospective strategy for tumor treatment. Cancer stem cells could preserve self-renewal, cell proliferation, cell migration and malignant phenotype. So, the reduction of tumor cell stemness can effectively inhibit the growth of tumor cells, which may be a new strategy for the treatment of cancers. Up to now, there exist many researches confirming the significant role of LSD1 in regulating the stemness characteristics such as embryonic stem cells differentiation. Many reports show that inhibition of LSD1 effectively decreases the property of cancer cell stemness. However, there lacks a detailed review about the relationship between LSD1 and cancer cell stemness. Herein, in this review, we summarized the mechanisms how LSD1 regulates cell stemness comprehensively. In addition, some related inhibitors targeting LSD1 to reduce the proliferation characteristics of cancer stem cells are also described.

作为第一个被发现的组蛋白去甲基化酶，LSD1 在维持癌症、感染和免疫疾病等病理过程中发挥着重要作用。根据以往的研究，LSD1 在各种肿瘤细胞中高表达，如急性髓性白血病、非小细胞肺癌、前列腺癌、乳腺癌和胃癌等。因此，靶向 LSD1 是一种治疗肿瘤的前瞻性策略。癌症干细胞可保持自我更新、细胞增殖、细胞迁移和恶性表型。因此，降低肿瘤细胞的干性可以有效抑制肿瘤细胞的生长，这可能是治疗癌症的一种新策略。迄今为止，已有许多研究证实，LSD1 在调控胚胎干细胞分化等干性特征方面发挥着重要作用。许多报告显示，抑制LSD1可有效降低癌细胞的干性特征。然而，目前还缺乏关于LSD1与癌细胞干性之间关系的详细综述。在这篇综述中，我们全面总结了LSD1调控细胞干性的机制。此外，还介绍了一些针对LSD1的相关抑制剂，以降低癌症干细胞的增殖特性。

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引用次数: 0

Exploring P2X receptor activity: A journey from cellular impact to electrophysiological profiling 探索 P2X 受体的活性：从细胞影响到电生理学剖析的旅程。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-19 DOI: 10.1016/j.bcp.2024.116543

The development of in vitro pharmacological assays relies on creating genetically modified cell lines that overexpress the target protein of interest. However, the choice of the host cell line can significantly impact the experimental outcomes. This study explores the functional characterization of P2X7 and P2X4 receptor modulators through cellular assays and advanced electrophysiological techniques. The influence of different host cell lines (HEK-293, HEK-293FT, and 1321N1) on the activity of reference agonists and antagonists targeting human and murine P2X4 and P2X7 receptors was systematically investigated, highlighting the significant impact of the host cell on experimental results. The 1321N1 cell line was identified as the preferred host cell line when investigating the human P2X4 receptor due to more consistent agonist activities, antagonist potencies, and a more stable assay signal window. Furthermore, a patch-clamp protocol that allows for the repetitive recording of ATP-mediated inward currents from isolated human CD4+ T-cells was established, revealing that both P2X7 and P2X4 receptors are crucial for immune cell regulation, positioning them as promising therapeutic targets for managing inflammatory disorders.

体外药理学检测的开发依赖于创建过表达相关目标蛋白的转基因细胞系。然而，宿主细胞系的选择会对实验结果产生重大影响。本研究通过细胞实验和先进的电生理技术，探索 P2X7 和 P2X4 受体调节剂的功能特性。研究系统地探讨了不同宿主细胞系（HEK-293、HEK-293FT 和 1321N1）对以人类和鼠类 P2X4 和 P2X7 受体为靶标的参考激动剂和拮抗剂活性的影响，强调了宿主细胞对实验结果的重要影响。在研究人 P2X4 受体时，1321N1 细胞系被确定为首选宿主细胞系，因为它具有更一致的激动剂活性、拮抗剂效力和更稳定的检测信号窗。此外，该研究还建立了一种贴片钳协议，可重复记录离体人类 CD4+ T 细胞的 ATP 介导的内向电流，揭示了 P2X7 和 P2X4 受体对免疫细胞调控的关键作用，使它们成为治疗炎症性疾病的有前途的治疗靶点。

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引用次数: 0

Human placental mesenchymal stem cells transplantation repairs the alveolar epithelial barrier to alleviate lipopolysaccharides-induced acute lung injury 移植人胎盘间充质干细胞可修复肺泡上皮屏障，缓解脂多糖诱发的急性肺损伤。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2024-09-19 DOI: 10.1016/j.bcp.2024.116547

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are accompanied by high mortality rates and few effective treatments. Transplantation of human placental mesenchymal stem cells (hPMSCs) may attenuate ALI and the mechanism is still unclear. Our study aimed to elucidate the potential protective effect and therapeutic mechanism of hPMSCs against lipopolysaccharide (LPS)-induced ALI, An ALI model was induced by tracheal instillation of LPS into wild-type (WT) and angiotensin-converting enzyme 2 (ACE2) knockout (KO) male mice, followed by injection of hPMSCs by tail vein. Treatment with hPMSCs improved pulmonary histopathological injury, reduced pulmonary injury scores, decreased leukocyte count and protein levels in bronchoalveolar lavage fluid(BALF), protected the damaged alveolar epithelial barrier, and reversed LPS-induced upregulation of pro-inflammatory factors Interleukin-6 (IL-6) and Tumor necrosis factor-α(TNF-α) and downregulation of anti-inflammatory factor Interleukin-6(IL-10) in BALF. Moreover, administration of hPMSCs inhibited Angiotensin (Ang)II activation and promoted the expression levels of ACE2 and Ang (1–7) in ALI mice. Pathological damage, inflammation levels, and disruption of alveolar epithelial barrier in ALI mice were elevated after the deletion of ACE2 gene, and the Renin angiotensin system (RAS) imbalance was exacerbated. The therapeutic effect of hPMSCs was significantly reduced in ACE2 KO mice. Our findings suggest that ACE2 plays a key role in hPMSCs repairing the alveolar epithelial barrier to protect against ALI, laying a new foundation for the clinical treatment of ALI.

急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的死亡率很高，而有效的治疗方法却很少。移植人胎盘间充质干细胞（hPMSCs）可减轻急性肺损伤，但其机制尚不清楚。我们的研究旨在阐明人胎盘间充质干细胞（hPMSCs）对脂多糖（LPS）诱导的ALI的潜在保护作用和治疗机制。使用 hPMSCs 治疗可改善肺组织病理学损伤，降低肺损伤评分，减少支气管肺泡灌洗液（BALF）中的白细胞数量和蛋白质水平，保护受损的肺泡上皮屏障、并逆转了 LPS 诱导的白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）在 BALF 中的上调，以及抗炎因子白细胞介素-6（IL-10）的下调。此外，给 ALI 小鼠注射 hPMSCs 可抑制血管紧张素（Ang）II 的激活，促进 ACE2 和 Ang (1-7) 的表达水平。ACE2基因缺失后，ALI小鼠的病理损伤、炎症水平和肺泡上皮屏障破坏程度升高，肾素血管紧张素系统（RAS）失衡加剧。在 ACE2 KO 小鼠中，hPMSCs 的治疗效果明显降低。我们的研究结果表明，ACE2 在 hPMSCs 修复肺泡上皮屏障以防止 ALI 中发挥了关键作用，为 ALI 的临床治疗奠定了新的基础。

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引用次数: 0