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Adipose tissue in health and disease 健康与疾病中的脂肪组织
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-14 DOI: 10.1016/j.bcp.2024.116475

This Virtual Special Issue on Adipose tissue in health and disease features 26 original articles from different international contexts. It expands our understanding of the adipose tissue as an essential organ involved in relevant physiological functions such as reproduction, metabolism, energy balance, endocrinology, circadian rhythm, and inflammation. The focus is on the adipose tissue as a common key mediator of different severe metabolic pathologies including insulin resistance, liver diseases, cardiometabolic diseases, diabetes, lipodystrophy, Cushing’s syndrome, obesity, and polycystic ovary syndrome. This adipose tissue-associated diseases are linked with a high mortality and increased health care costs worldwide. Thus, the 26 contributions of this Special Issue aim at identifying molecular mechanisms by which the adipose tissue is involved in the progression of its associated pathologies. Deeper understanding of these mechanisms in health and disease and the context-dependent parameters shaping them, is likely key to decipher the full potential of the adipose tissue for novel therapeutic approaches and strategies for managing complications associated with obesity and the metabolic syndrome.

本期虚拟特刊的主题是 "健康与疾病中的脂肪组织",共收录了 26 篇来自不同国际背景的原创文章。它拓展了我们对脂肪组织的认识,脂肪组织是参与生殖、新陈代谢、能量平衡、内分泌、昼夜节律和炎症等相关生理功能的重要器官。重点是脂肪组织作为不同严重代谢病症的共同关键介质,包括胰岛素抵抗、肝脏疾病、心脏代谢疾病、糖尿病、脂肪营养不良、库欣综合征、肥胖症和多囊卵巢综合征。这种与脂肪组织相关的疾病在全球范围内都与高死亡率和医疗成本增加有关。因此,本特刊的 26 篇文章旨在确定脂肪组织参与相关病症发展的分子机制。深入了解这些机制在健康和疾病中的作用以及影响这些机制的相关参数,很可能是充分挖掘脂肪组织潜力的关键所在,从而找到新的治疗方法和策略来控制与肥胖和代谢综合征相关的并发症。
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引用次数: 0
Monocarbonyl analogs of curcumin C66 and B2BrBC modulate oxidative stress, JNK activity, and pancreatic gene expression in rats with streptozotocin-induced diabetes 姜黄素 C66 和 B2BrBC 的单羰基类似物可调节链脲佐菌素诱导糖尿病大鼠的氧化应激、JNK 活性和胰腺基因表达。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-13 DOI: 10.1016/j.bcp.2024.116491

The pathogenesis of type 1 diabetes mellitus (T1DM) involves oxidative stress and inflammation. Curcumin, a natural polyphenolic compound found in turmeric, known to exhibit antioxidative and anti-inflammatory properties, is characterized by poor chemical stability, low bioavailability, and rapid metabolism. Monocarbonyl analogs of curcumin (MACs) with a structural absence of β-diketone and enhanced stability and bioavailability present a potential solution to the challenges associated with the use of curcumin. This study aimed to evaluate the effect of two MACs, C66 and B2BrBC, on oxidative stress markers, antioxidant enzyme activity, expression of diabetes-associated genes, and signaling pathway proteins in the context of T1DM. Streptozotocin (STZ)-induced male Wistar rats or rat pancreatic RIN-m cells were used for in vivo and in vitro experiments, respectively. C66 or B2BrBC were given either before or after STZ treatment. Oxidative stress markers and antioxidant enzyme activities were determined in various tissues. Expression of diabetes-associated genes was assessed using RT-qPCR, and the activity of signaling pathway proteins in the pancreas was determined through Western blot analysis. Treatment with C66 and B2BrBC significantly reduced oxidative stress markers and positively influenced antioxidant enzyme activities. Moreover, both compounds inhibited JNK activity in the pancreas while enhancing the expression of genes crucial for β-cell survival and glucose and redox homeostasis. The findings highlight the multifaceted potential of C66 and B2BrBC in ameliorating oxidative stress, influencing gene expression patterns linked to diabetes, and modulating key signaling pathways in the pancreas. The findings suggest that these compounds can potentially address diabetes-related pathological processes.

1 型糖尿病(T1DM)的发病机制涉及氧化应激和炎症。姜黄素是姜黄中的一种天然多酚化合物,具有抗氧化和抗炎特性,但其化学稳定性差、生物利用率低、代谢快。姜黄素的单羰基类似物(MACs)在结构上不含β-二酮,具有更高的稳定性和生物利用度,是解决姜黄素使用难题的潜在方案。本研究旨在评估两种澳门美高梅国际娱乐平台(C66和B2BrBC)对T1DM患者氧化应激指标、抗氧化酶活性、糖尿病相关基因表达和信号通路蛋白的影响。体内和体外实验分别使用链脲佐菌素(STZ)诱导的雄性 Wistar 大鼠或大鼠胰腺 RIN-m 细胞。在 STZ 处理之前或之后给予 C66 或 B2BrBC。测定了各种组织中的氧化应激标记物和抗氧化酶活性。使用 RT-qPCR 评估了糖尿病相关基因的表达,并通过 Western 印迹分析确定了胰腺中信号通路蛋白的活性。使用 C66 和 B2BrBC 治疗后,氧化应激标记物明显减少,抗氧化酶活性也受到积极影响。此外,这两种化合物还能抑制胰腺中的 JNK 活性,同时提高对 β 细胞存活以及葡萄糖和氧化还原平衡至关重要的基因的表达。研究结果凸显了 C66 和 B2BrBC 在改善氧化应激、影响与糖尿病相关的基因表达模式以及调节胰腺关键信号通路方面的多方面潜力。研究结果表明,这些化合物有可能解决与糖尿病相关的病理过程。
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引用次数: 0
Isoquinoline small molecule ligands are agonists and probe-dependent allosteric modulators of the glucagon subfamily of GPCRs 异喹啉小分子配体是胰高血糖素亚家族 GPCR 的激动剂和探针依赖性异位调节剂。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-13 DOI: 10.1016/j.bcp.2024.116483

Class B1 G protein-coupled receptors (GPCRs) are peptide hormone receptors and well validated therapeutic targets, however development of non-peptide drugs targeting this class of receptors is challenging. Recently, a series of isoquinoline-based derivates were reported in the patent literature as allosteric ligands for the glucagon receptor subfamily, and two compounds, LSN3451217 and LSN3556672, were used to facilitate structural studies with the glucagon-like peptide-1 receptor (GLP-1R) and glucose dependent insulinotropic peptide receptor (GIPR) bound to orthosteric agonists. Here we pharmacologically characterized stereoisomers of LSN3451217 and LSN3556672, across the class B1 GPCR family. This revealed LSN3556672 isomers are agonists for the glucagon receptor (GCGR), GLP-1R, GIPR and the calcitonin receptor (CTR), albeit the degree of agonism varied at each receptor. In contrast, LSN3451217 isomers were more selective agonists at the GLP-1R, with lower potency at the GCGR and CTR and no activity at the GIPR. All compounds also modulated peptide-mediated cyclic adenosine monophosphate (cAMP) signaling at the GIPR, and to a lesser extent the GLP-1R, in a probe-dependent manner, with modest positive allosteric modulation observed for some peptides, and negligible effects observed with other peptides. In contrast neutral or weak negative/positive allosteric modulation was observed with peptides assessed at the GCGR and CTR. This study expands our knowledge on class B1 GPCR allosteric modulation and may have implications for future structural and drug discovery efforts targeting the class B1 GPCR subfamily.

B1 类 G 蛋白偶联受体(GPCRs)是肽类激素受体,也是经过充分验证的治疗靶点,然而开发针对该类受体的非肽类药物具有挑战性。最近,一系列基于异喹啉的衍生物作为胰高血糖素受体亚家族的异位配体出现在专利文献中,LSN3451217 和 LSN3556672 这两种化合物被用于促进胰高血糖素样肽-1 受体(GLP-1R)和葡萄糖依赖性胰岛素肽受体(GIPR)与正交激动剂结合的结构研究。在此,我们从药理学角度鉴定了 LSN3451217 和 LSN3556672 在 B1 类 GPCR 家族中的立体异构体。结果表明,LSN3556672 异构体是胰高血糖素受体 (GCGR)、GLP-1R、GIPR 和降钙素受体 (CTR) 的激动剂,尽管对每种受体的激动程度不同。相比之下,LSN3451217 异构体对 GLP-1R 的选择性更强,而对 GCGR 和 CTR 的效力较低,对 GIPR 没有活性。所有化合物还以探针依赖的方式调节 GIPR 上由肽介导的环磷酸腺苷(cAMP)信号转导,在较小程度上也调节 GLP-1R 信号转导,对某些肽可观察到适度的正异构调节,而对其他肽则可观察到可忽略不计的影响。相比之下,在 GCGR 和 CTR 上评估的肽则观察到中性或弱的负/正异位调节作用。这项研究拓展了我们对 B1 类 GPCR 异源调节的认识,并可能对未来针对 B1 类 GPCR 亚家族的结构和药物发现工作产生影响。
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引用次数: 0
Melatonin alleviates brain injury in copper-laden rats: Underlying benefits for Wilson’s disease 褪黑素可减轻铜负荷大鼠的脑损伤:对威尔逊氏病的潜在益处
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-13 DOI: 10.1016/j.bcp.2024.116490

Copper serves as an indispensable cofactor for all living organisms, and its excessive accumulation has been associated with a variety of diseases. Wilson’s disease (WD) serves as an illustrative example of copper toxicity in humans, frequently presenting with liver and/or neuropsychiatric symptoms. The current therapeutic drugs, penicillamine (PA) and zinc gluconate (ZnG), have constraints, and research on their combination efficacy remains insufficient. It has been reported that melatonin (MLT) plays a vital role in binding to transition metals and exhibits strong antioxidant capacity. To investigate the therapeutic efficacy of MLT and combined treatment, rats were randomly divided into the following seven groups: the control (Con) group, copper-laden model rat (Mod) group, PA-treated group, ZnG-treated group, MLT- treated group, PA-ZnG-treated group, and PA-MLT-treated group. Then potential mechanisms and targets were investigated using a combination of metabolomics and network pharmacology and verified by molecular docking and qPCR. The findings revealed that MLT and the combination significantly improved behavior, pathology and copper levels in copper-laden rats. The results of the metabolomics study showed that profoundly altered metabolites were identified, and alanine, aspartate and glutamate metabolism, pyruvate metabolism, citrate cycle (TCA cycle), and glycolysis/gluconeogenesis were explored. In addition, molecular docking showed that MLT had high binding affinity with key targets, and qPCR results revealed that MLT could reverse the mRNA expression of targets GOT2 and PKM2. It was concluded that MLT effectively improves brain injury in copper-laden rats, and this effect was linked with the altered features of the metabolite profiles.

铜是所有生物体不可或缺的辅助因子,铜的过度积累与多种疾病有关。威尔逊氏病(WD)是铜毒性在人类中的一个典型例子,经常出现肝脏和/或神经精神症状。目前的治疗药物青霉胺(PA)和葡萄糖酸锌(ZnG)有其局限性,对它们的综合疗效研究仍然不足。据报道,褪黑素(MLT)在与过渡金属结合方面发挥着重要作用,并具有很强的抗氧化能力。为了研究 MLT 和联合治疗的疗效,研究人员将大鼠随机分为以下七组:对照(Con)组、铜负荷模型大鼠(Mod)组、PA 治疗组、ZnG 治疗组、MLT 治疗组、PA-ZnG 治疗组和 PA-MLT 治疗组。然后结合代谢组学和网络药理学研究了潜在的机制和靶点,并通过分子对接和 qPCR 进行了验证。研究结果表明,MLT及其组合能明显改善铜负荷大鼠的行为、病理和铜水平。代谢组学研究结果表明,大鼠体内的代谢物发生了深刻的变化,丙氨酸、天冬氨酸和谷氨酸代谢、丙酮酸代谢、柠檬酸循环(TCA 循环)和糖酵解/葡萄糖生成都得到了探索。此外,分子对接显示 MLT 与关键靶点具有高结合亲和力,qPCR 结果显示 MLT 可逆转靶点 GOT2 和 PKM2 的 mRNA 表达。研究认为,MLT能有效改善铜负荷大鼠的脑损伤,而这一效果与代谢物谱特征的改变有关。
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引用次数: 0
The emergence of antidepressant drugs targeting GABAA receptors: A concise review 以 GABAA 受体为靶点的抗抑郁药物的出现:简明综述。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-13 DOI: 10.1016/j.bcp.2024.116481

Depression is among the most common psychiatric illnesses, which imposes a major socioeconomic burden on patients, caregivers, and the public health system. Treatment with classical antidepressants (e.g. tricyclic antidepressants and selective serotonine reuptake inhibitors), which primarily affect monoaminergic systems has several limitations, such as delayed onset of action and moderate efficacy in a relatively large proportion of depressed patients. Furthermore, depression is highly heterogeneus, and its different subtypes, including post-partum depression, involve distinct neurobiology, warranting a differential approach to pharmacotherapy. Given these shortcomings, the need for novel antidepressants that are superior in efficacy and faster in onset of action is fully justified. The development and market introduction of rapid-acting antidepressants has accelerated in recent years. Some of these new antidepressants act through the GABAergic system. In this review, we discuss the discovery, efficacy, and limitations of treatment with classic antidepressants. We provide a detailed discussion of GABAergic neurotransmission, with a special focus on GABAA receptors, and possible explanations for the mood-enhancing effects of GABAergic medications (in particular neurosteroids acting at GABAA receptors), and, ultimately, we present the most promising molecules belonging to this family which are currently used in clinical practice or are in late phases of clinical development.

抑郁症是最常见的精神疾病之一,给患者、护理人员和公共卫生系统带来了沉重的社会经济负担。传统抗抑郁剂(如三环类抗抑郁剂和选择性血清素再摄取抑制剂)主要影响单胺能系统,但其治疗存在一些局限性,如起效延迟,对相对较大比例的抑郁症患者疗效一般。此外,抑郁症具有高度异质性,其不同的亚型(包括产后抑郁症)涉及不同的神经生物学,因此需要采取不同的药物治疗方法。鉴于这些缺陷,我们完全有理由需要疗效更好、起效更快的新型抗抑郁药物。近年来,快速起效抗抑郁药的开发和上市速度加快。其中一些新型抗抑郁药通过 GABA 能系统发挥作用。在这篇综述中,我们将讨论传统抗抑郁药的发现、疗效和治疗局限性。我们详细讨论了GABA能神经递质,特别关注GABAA受体,以及GABA能药物(尤其是作用于GABAA受体的神经类固醇)增强情绪效果的可能解释,最后,我们介绍了属于这一家族的最有前途的分子,这些分子目前已用于临床实践或处于临床开发的后期阶段。
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引用次数: 0
Alamandine, a protective component of the renin-angiotensin system, reduces cellular proliferation and interleukin-6 secretion in human macrophages through MasR–MrgDR heteromerization 肾素-血管紧张素系统的保护成分阿拉曼丁通过 MasR-MrgDR 异构化减少人巨噬细胞的细胞增殖和白细胞介素-6 的分泌。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-10 DOI: 10.1016/j.bcp.2024.116480

Alamandine (ALA) exerts protective effects similar to angiotensin (Ang) (1–7) through Mas-related G protein-coupled receptor type D receptor (MrgDR) activation, distinct from Mas receptor (MasR). ALA induces anti-inflammatory effects in mice but its impact in human macrophages remains unclear. We aimed to investigate the anti-inflammatory effects of ALA in human macrophages. Interleukin (IL)-6 and IL-1β were measured by ELISA in human THP-1 macrophages and human monocyte-derived macrophages exposed to lipopolysaccharide (LPS). Consequences of MasR–MrgDR heteromerization were investigated in transfected HEK293T cells. ALA decreased IL-6 and IL-1β secretion in LPS-activated THP-1 macrophages. The ALA-induced decrease in IL-6 but not in IL-1β was prevented by MasR blockade and MasR downregulation, suggesting MasR–MrgDR interaction. In human monocyte-derived M1 macrophages, ALA decreased IL-1β secretion independently of MasR. MasR–MrgDR interaction was confirmed in THP-1 macrophages, human monocyte-derived macrophages, and transfected HEK293T cells. MasR and MrgDR formed a constitutive heteromer that was not influenced by ALA. ALA promoted Akt and ERK1/2 activation only in cells expressing MasR–MrgDR heteromers, and this effect was prevented by MasR blockade. While Ang-(1–7) reduced cellular proliferation in MasR −but not MrgDR- expressing cells, ALA antiproliferative effect was elicited in cells expressing MasR–MrgDR heteromers. ALA also induced an antiproliferative response in THP-1 cells and this effect was abolished by MasR blockade, reinforcing MasR–MrgDR interaction. MasR–MrgDR heteromerization is crucial for ALA-induced anti-inflammatory and antiproliferative responses in human macrophages. This study broaden our knowledge of the protective axis of the RAS, thus enabling novel therapeutic approaches in inflammatory-associated diseases.

阿拉曼定(ALA)通过激活与马斯受体(MasR)不同的马斯相关 G 蛋白偶联受体 D 型受体(MrgDR),发挥类似于血管紧张素(Ang)(1-7)的保护作用。ALA 可诱导小鼠产生抗炎作用,但其对人类巨噬细胞的影响仍不清楚。我们的目的是研究 ALA 在人类巨噬细胞中的抗炎作用。我们用酶联免疫吸附法测定了暴露于脂多糖(LPS)的人 THP-1 巨噬细胞和人单核细胞衍生巨噬细胞中的白细胞介素(IL)-6 和 IL-1β。在转染的 HEK293T 细胞中研究了 MasR-MrgDR 异构化的后果。ALA 可减少 LPS 激活的 THP-1 巨噬细胞中 IL-6 和 IL-1β 的分泌。阻断 MasR 和下调 MasR 可阻止 ALA 诱导的 IL-6 而非 IL-1β 的减少,这表明 MasR-MrgDR 相互作用。在源于人单核细胞的 M1 巨噬细胞中,ALA 可减少 IL-1β 的分泌,而与 MasR 无关。在 THP-1 巨噬细胞、人单核细胞衍生的巨噬细胞和转染的 HEK293T 细胞中证实了 MasR-MrgDR 相互作用。MasR 和 MrgDR 形成了不受 ALA 影响的组成型异构体。只有在表达 MasR-MrgDR 异构体的细胞中,ALA 才会促进 Akt 和 ERK1/2 的活化,阻断 MasR 可阻止这种效应。虽然 Ang-(1-7) 在表达 MasR 的细胞中减少了细胞增殖,但在表达 MasR-MrgDR 异构体的细胞中却没有减少,但 ALA 在表达 MasR-MrgDR 异构体的细胞中产生了抗增殖效应。ALA 还能诱导 THP-1 细胞产生抗增殖反应,MasR 阻断后这种效应消失,从而加强了 MasR-MrgDR 的相互作用。MasR-MrgDR 异源化对 ALA 诱导的人类巨噬细胞抗炎和抗增殖反应至关重要。这项研究拓宽了我们对 RAS 保护轴的认识,从而为治疗炎症相关疾病提供了新的治疗方法。
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引用次数: 0
Trimetazidine attenuates Ischemia/Reperfusion-Induced myocardial ferroptosis by modulating the Sirt3/Nrf2-GSH system and reducing Oxidative/Nitrative stress 曲美他嗪通过调节 Sirt3/Nrf2-GSH 系统和减少氧化/硝化应激,减轻缺血/再灌注诱导的心肌铁蛋白沉积。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-10 DOI: 10.1016/j.bcp.2024.116479

Ferroptosis is a newly defined mode of cellular demise. The increasing investigation supports that ferroptosis is a crucial factor in the complex mechanisms of myocardial ischemia–reperfusion (I/R) injury. Hence, targeting ferroptosis is a novel strategy for treating myocardial injury. Although evidence suggests that trimetazidine (TMZ) is potentially efficacious against myocardial injury, the exact mechanism of this efficacy is yet to be fully elucidated. This study aimed to determine whether TMZ can act as a ferroptosis resistor and affect I/R-mediated myocardial injury. To this end, researchers have constructed in vitro and in vivo models of I/R using H9C2 cardiomyocytes, primary cardiomyocytes, and SD rats. Here, I/R mediated the onset of ferroptosis in vitro and in vivo, as reflected by excessive iron aggregation, GSH depletion, and the increase in lipid peroxidation. TMZ largely reversed this alteration and attenuated cardiomyocyte injury. Mechanistically, we found that TMZ upregulated the expression of Sirt3. Therefore, we used si-Sirt3 and 3-TYP to interfere with Sirt3 action in vitro and in vivo, respectively. Both si-Sirt3 and 3-TYP partly mitigated the inhibitory effect of TMZ on I/R-mediated ferroptosis and upregulated the expression of Nrf2 and its downstream target, GPX4-SLC7A11. These results indicate that TMZ attenuates I/R-mediated ferroptosis by activating the Sirt3-Nrf2/GPX4/SLC7A11 signaling pathway. Our study offers insights into the mechanism underlying the cardioprotective benefits of TMZ and establishes a groundwork for expanding its potential applications.

铁蜕变是一种新定义的细胞死亡模式。越来越多的研究证实,铁蜕变是心肌缺血再灌注(I/R)损伤复杂机制中的一个关键因素。因此,靶向铁蛋白沉积是治疗心肌损伤的一种新策略。虽然有证据表明曲美他嗪(TMZ)对心肌损伤有潜在疗效,但其确切的疗效机制尚未完全阐明。本研究旨在确定曲美他嗪是否能作为铁变态反应阻滞剂影响 I/R 介导的心肌损伤。为此,研究人员使用 H9C2 心肌细胞、原代心肌细胞和 SD 大鼠构建了体外和体内 I/R 模型。在这里,I/R 在体外和体内介导了铁变态反应的发生,表现为铁的过度聚集、GSH 的耗竭和脂质过氧化的增加。TMZ 在很大程度上逆转了这种改变,减轻了心肌细胞损伤。从机理上讲,我们发现 TMZ 上调了 Sirt3 的表达。因此,我们使用 si-Sirt3 和 3-TYP 分别在体外和体内干扰 Sirt3 的作用。si-Sirt3和3-TYP都部分减轻了TMZ对I/R介导的铁变态反应的抑制作用,并上调了Nrf2及其下游靶标GPX4-SLC7A11的表达。这些结果表明,TMZ通过激活Sirt3-Nrf2/GPX4/SLC7A11信号通路,减轻了I/R介导的铁细胞凋亡。我们的研究深入揭示了 TMZ 具有心脏保护作用的机制,并为扩大其潜在应用奠定了基础。
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引用次数: 0
Endothelial Birc3 promotes renal fibrosis through modulating Drp1-mediated mitochondrial fission via MAPK/PI3K/Akt pathway 内皮细胞 Birc3 通过 MAPK/PI3K/Akt 通路调节 Drp1 介导的线粒体裂变,从而促进肾脏纤维化。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-10 DOI: 10.1016/j.bcp.2024.116477

Renal fibrosis serves as the shared pathway in chronic kidney disease (CKD) progression towards end-stage renal disease (ESRD). Endothelial-mesenchymal transition (EndMT) is a vital mechanism leading to the generation of myofibroblasts, thereby contributing to the advancement of fibrogenesis. Baculoviral IAP Repeat Containing 3(Birc3) was identified as a crucial inhibitor of cell death and a significant mediator in inflammatory signaling and immunity. However, its involvement in the development of renal interstitial fibrosis via EndMT still needs to be clarified. Herein, elevated levels of Birc3 expression along with EndMT-associated alterations, including increased α-smooth muscle actin (α-SMA) levels and decreased CD31 expression, were observed in fibrotic kidneys of Unilateral Ureteral Obstruction (UUO)-induced mouse models and transforming growth factor-β (TGF-β)-induced EndMT in Human Umbilical Vein Endothelial Cells (HUVECs). Functionally, Birc3 knockdown inhibited EndMT and mitochondrial fission mediated by dynamin-related protein 1 (Drp1) both in vivo and in vitro. Mechanistically, endothelial Birc3 exacerbated Drp-1-induced mitochondrial fission through the MAPK/PI3K/Akt signaling pathway in endothelial cell models stimulated TGF-β. Collectively, these findings illuminate the mechanisms and indicate that targeting Birc3 could offer a promising therapeutic strategy to improve endothelial cell survival and mitigate the progression of CKD.

肾脏纤维化是慢性肾脏病(CKD)向终末期肾脏病(ESRD)发展的共同途径。内皮-间质转化(EndMT)是导致肌成纤维细胞生成的重要机制,从而促进了纤维化的发生。含IAP重复序列的杆状病毒3(Birc3)被认为是细胞死亡的重要抑制剂,也是炎症信号转导和免疫的重要介质。然而,它通过内膜生长因子参与肾间质纤维化的发展仍有待明确。在本文中,在单侧输尿管梗阻(UUO)诱导的小鼠模型的纤维化肾脏和转化生长因子-β(TGF-β)诱导的人脐静脉内皮细胞(HUVECs)中,观察到Birc3表达水平升高以及与EndMT相关的改变,包括α-平滑肌肌动蛋白(α-SMA)水平升高和CD31表达降低。从功能上讲,Birc3 基因敲除在体内和体外均可抑制由动态相关蛋白 1(Drp1)介导的内膜种植和线粒体裂变。从机制上讲,在内皮细胞模型中,内皮 Birc3 通过 MAPK/PI3K/Akt 信号通路刺激 TGF-β,加剧了 Drp-1 诱导的线粒体裂解。总之,这些研究结果阐明了这些机制,并表明以 Birc3 为靶点可以提供一种很有前景的治疗策略,以改善内皮细胞的存活率并缓解 CKD 的进展。
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引用次数: 0
The ‘ABC’ of split-nanoluciferase HIF heterodimerization bioassays: Applications, Benefits & Considerations 分体荧光素酶 HIF 异源二聚体生物测定的 "ABC":应用、益处和注意事项。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-10 DOI: 10.1016/j.bcp.2024.116478

Hypoxia-inducible factors (HIF) are interesting targets for multiple therapeutic indications. While HIF activation is desired for the treatment of anemia-related and ischemic diseases, HIF inhibition is of tremendous interest to anti-cancer drug development. Different signaling events within the HIF pathway are being targeted by drug discovery programs, with a special interest in HIF-selective (possibly also HIF1/2 isoform-selective) compounds. In this study, we applied recently developed cell-based split-nanoluciferase HIF heterodimerization assays to study the effects of compounds, targeting HIF activity by various mechanisms of action. This study shows that the application of similar or diverse assay protocols allows to detect various influences on HIF heterodimerization as a key signaling event in the oxygen sensing pathway: increased HIF heterodimerization (roxadustat, MG-132), decreased HIF heterodimerization (PX-478, ibuprofen) and direct (HIF isoform-selective) heterodimerization inhibiting effects (PT-2385). Changes in treatment time and in the assay protocol allowed to assess direct and indirect effects on HIFα-HIFβ heterodimerization. In addition to the evaluation of applications of these new bioassays regarding pharmacological characterizations, benefits and considerations are discussed related to the use of cellular, luminescent-based bioassays. Briefly, benefits include the bidirectional nature of the biological readout, the upstream mechanism of detection, the differentiation between HIF1 and HIF2 effects and the simulation of various conditions. Specific and general considerations include cell-based, technical and disease/drug-related aspects (e.g., non-specific effects, color interference). In summary, the versatility of these bioassays offers benefits in widespread applications regarding drug discovery and pharmacological characterization of various therapeutics, applying either the same or optimized experimental protocols.

低氧诱导因子(HIF)是多种治疗适应症的有趣靶点。激活 HIF 是治疗贫血相关疾病和缺血性疾病的理想方法,而抑制 HIF 则是抗癌药物开发的巨大兴趣所在。HIF 通路中的不同信号事件正成为药物研发计划的目标,其中对 HIF 选择性(也可能是 HIF1/2 同工酶选择性)化合物特别感兴趣。在这项研究中,我们应用了最近开发的基于细胞的裂殖核素酶 HIF 异源二聚体测定法来研究化合物的作用,通过各种作用机制来靶向 HIF 活性。这项研究表明,应用类似或不同的检测方案可以检测出对作为氧传感途径中关键信号事件的 HIF 异源二聚化的各种影响:HIF 异源二聚化增加(roxadustat、MG-132)、HIF 异源二聚化减少(PX-478、布洛芬)以及直接(HIF 同工酶选择性)异源二聚化抑制作用(PT-2385)。通过改变处理时间和检测方案,可以评估对 HIFα-HIFβ 异源二聚化的直接和间接影响。除了评估这些新生物测定在药理学特征方面的应用外,还讨论了使用基于细胞发光的生物测定的好处和注意事项。简而言之,好处包括生物读数的双向性、检测的上游机制、HIF1 和 HIF2 效应的区分以及各种条件的模拟。具体和一般考虑因素包括基于细胞、技术和疾病/药物相关方面(如非特异性效应、颜色干扰)。总之,这些生物测定的多功能性为药物发现和各种治疗药物的药理学特征描述提供了广泛的应用优势,可应用相同或优化的实验方案。
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引用次数: 0
Zn(II) enhances the antimicrobial effect of chloroxine and structural analogues against drug-resistant ESKAPE pathogens in vitro Zn(II) 可增强氯氧嘧啶和结构类似物在体外对耐药性 ESKAPE 病原体的抗菌效果。
IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-10 DOI: 10.1016/j.bcp.2024.116482

The emerging antibiotic-resistant bacteria, especially the “ESKAPE” pathogens, pose a continuous threat to global health. In this study, we explored metalloantibiotics as promising therapeutics and innovative antimicrobial agents. The role of metal in the antimicrobial activity of chloroxine (5,7-dichloro-8-hydroxyquinoline), as a metalloantibiotic, was investigated by minimal inhibit concentration (MIC) assay and a series of assays, including growth curve, time-killing, and UV–visible spectroscopy and PAR (4-(2-pyridylazo)-resorcinol) competition assays. Both chloroxine and its structural analogues exhibited increased antibacterial potency against Gram-positive bacteria compared to Gram-negative bacteria. The introduction of exogenous manganese or zinc ions significantly boosted chloroxine’s antibacterial efficacy against Gram-negative bacteria, including the notorious ESKAPE pathogens. However, the enhanced antibacterial activity induced by zinc ions could be negated in the presence of copper or ferrous iron ions, as well as changes in oxygen availability, highlighting the involvement of proton motive force, oxidative and antioxidative systems. Notably, chloroxine effectively inhibited the enzymatic activity of superoxide dismutase (SOD). In addition, chloroxine could reverse polymyxin and carbapenem resistance in E. coli in vitro. Therefore, these results suggested that chloroxine with zinc ions are promising therapeutics and antibiotics potentiator to combat multidrug-resistant ESKAPE pathogens.

新出现的抗生素耐药细菌,尤其是 "ESKAPE "病原体,对全球健康构成了持续威胁。在这项研究中,我们探讨了金属抗生素作为有前景的治疗药物和创新抗菌剂的可能性。通过最小抑菌浓度(MIC)测定法和一系列测定法,包括生长曲线、时间杀灭、紫外可见光谱和 PAR(4-(2-吡啶偶氮)-间苯二酚)竞争测定法,研究了金属在作为金属抗生素的氯氧(5,7-二氯-8-羟基喹啉)抗菌活性中的作用。与革兰氏阴性菌相比,氯氧及其结构类似物对革兰氏阳性菌的抗菌效力都有所提高。引入外源锰离子或锌离子后,氯氧吡啶对革兰氏阴性细菌(包括臭名昭著的 ESKAPE 病原体)的抗菌效力明显增强。然而,锌离子诱导的抗菌活性增强在铜离子或亚铁离子存在以及氧气供应变化的情况下会被抵消,这凸显了质子动力、氧化和抗氧化系统的参与。值得注意的是,氯氧有效地抑制了超氧化物歧化酶(SOD)的酶活性。此外,氯氧还能在体外逆转大肠杆菌对多粘菌素和碳青霉烯的耐药性。因此,这些结果表明,含锌离子的氯氧化物是一种很有前景的治疗剂和抗生素增效剂,可用于抗耐多药 ESKAPE 病原体。
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Biochemical pharmacology
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