Biomedicine & Pharmacotherapy最新文献_第3页

Butyrate modulates gut microbiota and anti-inflammatory response in attenuating cisplatin-induced kidney injury 丁酸盐调节肠道微生物群和抗炎反应，减轻顺铂引起的肾损伤

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2024-11-23 DOI: 10.1016/j.biopha.2024.117689

Wen-Jung Chen , Yng-Tay Chen , Jiunn-Liang Ko , Jian-Yuan Chen , Jun-Yao Zheng , Jiunn-Wang Liao , Chu-Chyn Ou

In our previous research, we reported that administering probiotics Lactobacillus reuteri and Clostridium butyricum (LCs) before cisplatin treatment effectively modifies structures of the gut microbiota and restore ecological balance and significantly increases butyrate levels, a process closely associated with reducing cisplatin-induced nephrotoxicity. This study aims to investigate further whether the elevation of metabolite butyrate in the gut, promoted by probiotics LCs, can effectively mitigate the nephrotoxic effects of cisplatin and the progression of renal senescence in rats. Results show that butyrate administration significantly improved kidney function and decreased renal fibrosis in a dose-dependent manner compared to the cisplatin group. Its effects were associated with reductions in inflammatory responses, evidenced by decreased levels of key inflammatory markers, including KIM-1, MPO, NOX2, F4/80, and TGF-β1, alongside increased production of the anti-inflammatory cytokine IL-10. Furthermore, the butyrate intervention ameliorated cisplatin-induced gut microbiota dysbiosis, preserving the structure and diversity of healthy microbial communities. Specifically, we observed a decrease in the abundance of Escherichia_Shigella and Blautia, alongside an increase in the abundance of the butyrate-producing genus Roseburia. Notably, Escherichia_Shigella exhibited a positive correlation with the pro-inflammatory factor MPO, while displaying a negative correlation with the anti-inflammatory cytokine IL-10. Butyrate also attenuated the cisplatin-induced expression of senescence markers p21 and p16 in kidney tissue. It alleviated the cisplatin-increased senescence-associated beta-galactosidase activity and reactive oxygen species production in SV40 MES-13 cells. These results indicate that butyrate, derived from the gut microbiota, may exert a protective effect against cisplatin-induced kidney damage by regulating microbiota balance and anti-inflammatory effects.

在之前的研究中，我们报道了在顺铂治疗前服用益生菌Lactobacillus reuteri和Clostridium butyricum（LCs）可有效改变肠道微生物群的结构，恢复生态平衡，并显著提高丁酸盐的水平，这一过程与减轻顺铂诱导的肾毒性密切相关。本研究旨在进一步探讨益生菌 LCs 促进肠道代谢物丁酸盐的升高是否能有效减轻顺铂的肾毒性效应和大鼠肾衰老的进程。结果表明，与顺铂组相比，丁酸盐能以剂量依赖的方式明显改善肾功能并减少肾纤维化。丁酸盐的作用与炎症反应的减少有关，主要炎症标志物（包括KIM-1、MPO、NOX2、F4/80和TGF-β1）水平的降低以及抗炎细胞因子IL-10产量的增加证明了这一点。此外，丁酸盐干预还能改善顺铂诱导的肠道微生物群失调，保护健康微生物群落的结构和多样性。具体来说，我们观察到石灰样肠杆菌（Escherichia_Shigella）和布劳氏菌（Blautia）的丰度下降，而丁酸菌属 Roseburia 的丰度上升。值得注意的是，志贺氏菌与促炎因子 MPO 呈正相关，而与抗炎细胞因子 IL-10 呈负相关。丁酸盐还能减轻顺铂诱导的肾组织中衰老标志物 p21 和 p16 的表达。它还减轻了顺铂增加的与衰老相关的 beta-半乳糖苷酶活性和 SV40 MES-13 细胞中活性氧的产生。这些结果表明，来自肠道微生物群的丁酸盐可通过调节微生物群平衡和抗炎作用，对顺铂诱导的肾损伤起到保护作用。

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引用次数: 0

Hydrocephalus: An update on latest progress in pathophysiological and therapeutic research 脑积水：病理生理学和治疗学研究的最新进展。

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2024-11-23 DOI: 10.1016/j.biopha.2024.117702

Faheem Anwar , Kuo Zhang , Changcheng Sun , Meijun Pang , Wanqi Zhou , Haodong Li , Runnan He , Xiuyun Liu , Dong Ming

Hydrocephalus is a severe and life-threatening disease associated with the imbalance of CSF dynamics and affects millions globally at any age, including infants. One cause of pathology that is wide-ranging is genetic mutations to post-traumatic injury. The most effective current pharmacological treatments provide only symptomatic relief and do not address the underlying pathology. At the same time, surgical procedures such as VP shunts performed in lower-income countries are often poorly tolerated due to insufficient diagnostic resources and suboptimal outcomes partially attributable to inferior materials. These problems are compounded by an overall lack of funding that keeps high-quality medical devices out of reach for all but the most developed countries and even among those states. There is a massive variance in treatment effectiveness. This review indicates the necessity for innovative and low-cost, accessible treatment strategies to close these gaps, focusing on current advances in novel therapies, including Pharmacological, gene therapy, and nano-based technologies, which are currently at different stages of clinical trial phases. This review provides an overview of pathophysiology, current treatments, and promising new therapeutic strategies for hydrocephalus.

脑积水是一种与脑脊液动态失衡有关的严重疾病，危及生命，全球数百万人在任何年龄段都会受到影响，包括婴儿。病因广泛，包括基因突变和创伤后损伤。目前最有效的药物治疗只能缓解症状，并不能从根本上解决病理问题。与此同时，在低收入国家进行的 VP 分流术等外科手术往往由于诊断资源不足和部分由于劣质材料造成的效果不佳而难以被接受。除最发达的国家外，其他国家甚至是最发达的国家也无法获得高质量的医疗设备。治疗效果存在巨大差异。本综述指出，有必要采取创新、低成本、易获得的治疗策略来缩小这些差距，重点关注当前新型疗法的进展，包括药物疗法、基因疗法和纳米技术，这些疗法目前正处于临床试验的不同阶段。本综述概述了脑积水的病理生理学、目前的治疗方法和有前景的新治疗策略。

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引用次数: 0

A new perspective on targeting pulmonary arterial hypertension: Programmed cell death pathways (Autophagy, Pyroptosis, Ferroptosis) 针对肺动脉高压的新视角：细胞程序性死亡途径（自噬、凋亡、铁凋亡）。

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2024-11-23 DOI: 10.1016/j.biopha.2024.117706

Qingliang Ge , Tianqing Zhang , Jiangbiao Yu , Xuelin Lu , Sijie Xiao , Ting Zhang , Tao Qing , Zhenni Xiao , Liuting Zeng , Li Luo

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease characterized by elevated pulmonary vascular resistance, progressive increases in pulmonary artery pressures, ultimately leading to right-sided heart failure, and potentially mortality. Pulmonary vascular remodeling is pivotal in PAH onset and progression. While targeted drug therapies have notably ameliorated PAH prognosis, current medications primarily focus on vascular vasodilation, with limited ability to reverse pulmonary vascular remodeling fundamentally, resulting in suboptimal patient prognoses. Cellular death in pulmonary vasculature, once thought to be confined to apoptosis and necrosis, has evolved with the identification of pyroptosis, autophagy, and ferroptosis, revealing their association with vascular injury in PAH. These novel forms of regulated cellular death impact reactive oxygen species (ROS) generation, calcium stress, and inflammatory cascades, leading to pulmonary vascular cell loss, exacerbating vascular injury, and mediating adverse remodeling, inflammation, immune anomalies, and current emerging mechanisms (such as endothelial-mesenchymal transition, abnormal energy metabolism, and epigenetic regulation) in the pathogenesis of PAH. This review comprehensively delineates the roles of autophagy, pyroptosis, and ferroptosis in PAH, elucidating recent advances in their involvement and regulation of vascular injury. It juxtaposes their distinct functions in PAH and discusses the interplay of these programmed cell deaths in pulmonary vascular injury, highlighting the benefits of combined targeted therapies in mitigating pulmonary arterial hypertension-induced vascular injury, providing novel insights into targeted treatments for pulmonary arterial hypertension.

肺动脉高压（PAH）是一种严重的心血管疾病，其特点是肺血管阻力升高、肺动脉压力逐渐增加，最终导致右侧心力衰竭，并可能导致死亡。肺血管重塑是 PAH 发病和恶化的关键因素。虽然靶向药物疗法明显改善了 PAH 的预后，但目前的药物主要侧重于血管舒张，从根本上逆转肺血管重塑的能力有限，导致患者预后不佳。肺血管中的细胞死亡曾被认为仅限于细胞凋亡和坏死，但随着热噬、自噬和铁噬的发现，它们与 PAH 的血管损伤之间的关系也得到了发展。这些新形式的调节性细胞死亡会影响活性氧（ROS）的生成、钙应激和炎症级联反应，导致肺血管细胞丢失，加重血管损伤，并介导 PAH 发病机制中的不良重塑、炎症、免疫异常和当前新出现的机制（如内皮-间充质转化、能量代谢异常和表观遗传调控）。这篇综述全面阐述了自噬、热昏迷和铁昏迷在 PAH 中的作用，阐明了它们参与和调控血管损伤的最新进展。它并列了自噬在 PAH 中的不同功能，讨论了这些程序性细胞死亡在肺血管损伤中的相互作用，强调了联合靶向疗法在减轻肺动脉高压诱导的血管损伤方面的益处，为肺动脉高压的靶向治疗提供了新的见解。

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引用次数: 0

TNF signaling mediates lipopolysaccharide-induced lung epithelial progenitor cell responses in mouse lung organoids TNF 信号介导小鼠肺器官组织中脂多糖诱导的肺上皮祖细胞反应。

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2024-11-23 DOI: 10.1016/j.biopha.2024.117704

Dan Li , Rosa K. Kortekaas , Kelly B.I. Douglas , Wanda Douwenga , Ulrich L.M. Eisel , Barbro N. Melgert , Reinoud Gosens , Martina Schmidt

Bacterial respiratory infections are a major global health concern, often leading to lung injury and triggering lung repair mechanisms. Endogenous epithelial progenitor cells are crucial in this repair, yet the mechanisms remain poorly understood. This study investigates the response of lung epithelial progenitor cells to injury induced by lipopolysaccharide (LPS), a component of gram-negative bacteria, focusing on their regulation during lung repair. Lung epithelial cells (CD31^-CD45^-Epcam⁺) from wild-type and tumor necrosis factor (TNF) receptor 1/2 knock-out mice were co-cultured with wild-type fibroblasts. Organoid numbers and size were measured after 14 days of exposure to 100 ng/mL LPS. Immunofluorescence was used to assess differentiation (after 14 days), RNA sequencing analyzed gene expression changes (after 72 hours), and MTS assay assessed proliferative effects of LPS on individual cell types (after 24 hours). LPS treatment increased the number and size of wild-type lung organoids and promoted alveolar differentiation, indicated by more SPC⁺ organoids. RNA sequencing revealed upregulation of inflammatory and fibrosis-related markers, including Cxcl3, Cxcl5, Ccl20, Mmp13, and Il33, and enrichment of TNF-α signaling and epithelial-mesenchymal transition pathways. TNF receptor 1 deficiency inhibited LPS-induced progenitor cell activation and organoid growth. In conclusion, LPS enhances lung epithelial progenitor cell proliferation and differentiation via TNF receptor 1 signaling, highlighting potential therapeutic targets for bacterial lung injury.

细菌性呼吸道感染是全球关注的主要健康问题，通常会导致肺损伤并引发肺修复机制。内源性上皮祖细胞在这种修复机制中起着至关重要的作用，但人们对其机制仍知之甚少。本研究探讨了肺上皮祖细胞对革兰氏阴性细菌的一种成分脂多糖（LPS）诱导的损伤的反应，重点研究了它们在肺修复过程中的调控。野生型小鼠和肿瘤坏死因子（TNF）受体1/2基因敲除小鼠的肺上皮细胞（CD31-CD45-Epcam+）与野生型成纤维细胞共同培养。暴露于 100 ng/mL LPS 14 天后，测量类器官的数量和大小。免疫荧光用于评估分化（14 天后），RNA 测序分析基因表达变化（72 小时后），MTS 检测评估 LPS 对单个细胞类型的增殖效应（24 小时后）。LPS 处理增加了野生型肺组织细胞的数量和大小，促进了肺泡分化，表现为更多的 SPC+ 组织细胞。RNA 测序显示炎症和纤维化相关标记物（包括 Cxcl3、Cxcl5、Ccl20、Mmp13 和 Il33）上调，TNF-α 信号传导和上皮-间质转化通路丰富。TNF 受体 1 缺乏可抑制 LPS 诱导的祖细胞活化和类器官生长。总之，LPS通过TNF受体1信号增强肺上皮祖细胞的增殖和分化，突显了细菌性肺损伤的潜在治疗靶点。

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引用次数: 0

Recombinant soluble type I interferon receptor exerts antiviral activity by inducing proteins related to autophagy 重组可溶性 I 型干扰素受体通过诱导自噬相关蛋白发挥抗病毒活性。

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2024-11-21 DOI: 10.1016/j.biopha.2024.117678

Pablo Aliaga-Gaspar , Isabel Brichette-Mieg , MdM Fernández-Arjona , José Luis Rodríguez-Bada , Yolanda López-Moreno , Pedro Serrano-Castro , Oscar Fernández-Fernández , Nicolás Lundahl Ciano-Petersen , Begoña Oliver-Martos

The soluble type I IFN receptor (sIFNAR2) is produced by alternative splicing and is present in body fluids. Although it can modulate IFN-ß activity, its biological role remains unknown.

Methods

An in-silico study was conducted to compare the structure of recombinant human soluble IFNAR2 (r-sIFNAR2) with its native form. The antiviral activity of r-sIFNAR2, produced in BL21-bacteria and CHO cells, was tested using a cytopathic effect assay including appropriate controls. Viability and toxicity were assessed by MTT assays. Proteomic analysis using mass spectrometry was conducted in the A549/EMCV bioassay to elucidate the mechanism of action, and then it was validated by Western blot.

Results

The BL21-sIFNAR2 had a sequence identity of 83.6 % with the native form, showing variations only in terminal regions. BL21-sIFNAR2 and CHO-sIFNAR2 showed significantly higher percentage of cell viability compared to the viral control, similar to IFN-ß. Cell viability with BL21-sIFNAR2 was comparable to the cell control across all tested concentrations.

Proteomic analysis revealed an up regulation of pathways related with autophagy (macroautophagy, autophagy, pexophagy, and mitophagy) with an SQSTM1 overexpression that was then confirmed by Western Blot, especially after virus infection. However, pathways related to interferon signaling, and antiviral mechanisms mediated by IFN-stimulated genes were down-regulated.

Conclusion

r-sIFNAR2 exhibits significant antiviral activity regardless of the expression system used for its production and good safety profile, suggesting its use as a potential antiviral drug. Proteins related to autophagy are involved in the protection from the virus. This study highlights the biological relevance of soluble cytokine receptors as effectors so far overlooked.

可溶性 I 型 IFN 受体（sIFNAR2）是通过替代剪接产生的，存在于体液中。虽然它能调节 IFN-ß 的活性，但其生物学作用仍不清楚：方法：研究人员进行了一项体内研究，以比较重组人可溶性 IFNAR2（r-sIFNAR2）与其原生形式的结构。在 BL21-细菌和 CHO 细胞中产生的 r-sIFNAR2 的抗病毒活性通过细胞病理效应试验（包括适当的对照）进行了测试。活力和毒性通过 MTT 试验进行评估。在 A549/EMCV 生物测定中使用质谱进行了蛋白质组分析，以阐明其作用机制，然后通过 Western 印迹进行了验证：结果：BL21-sIFNAR2与原生型的序列一致性为83.6%，仅在末端区域存在差异。与病毒对照相比，BL21-sIFNAR2 和 CHO-sIFNAR2 的细胞存活率明显更高，与 IFN-ß 相似。在所有测试浓度下，BL21-sIFNAR2 的细胞存活率与细胞对照相当。蛋白质组分析表明，随着 SQSTM1 的过表达，与自噬相关的通路（大自噬、自噬、pexophagy 和 mitophagy）受到了上调，这一点随后通过 Western 印迹得到了证实，尤其是在病毒感染后。结论：无论使用哪种表达系统生产 r-sIFNAR2，它都具有显著的抗病毒活性和良好的安全性，这表明它可用作一种潜在的抗病毒药物。与自噬相关的蛋白质参与了病毒防护。这项研究强调了可溶性细胞因子受体作为效应因子的生物学相关性，而这种效应因子至今仍被忽视。

{"title":"Recombinant soluble type I interferon receptor exerts antiviral activity by inducing proteins related to autophagy","authors":"Pablo Aliaga-Gaspar , Isabel Brichette-Mieg , MdM Fernández-Arjona , José Luis Rodríguez-Bada , Yolanda López-Moreno , Pedro Serrano-Castro , Oscar Fernández-Fernández , Nicolás Lundahl Ciano-Petersen , Begoña Oliver-Martos","doi":"10.1016/j.biopha.2024.117678","DOIUrl":"10.1016/j.biopha.2024.117678","url":null,"abstract":"<div><div>The soluble type I IFN receptor (sIFNAR2) is produced by alternative splicing and is present in body fluids. Although it can modulate IFN-ß activity, its biological role remains unknown.</div></div><div><h3>Methods</h3><div>An in-silico study was conducted to compare the structure of recombinant human soluble IFNAR2 (r-sIFNAR2) with its native form. The antiviral activity of r-sIFNAR2, produced in BL21-bacteria and CHO cells, was tested using a cytopathic effect assay including appropriate controls. Viability and toxicity were assessed by MTT assays. Proteomic analysis using mass spectrometry was conducted in the A549/EMCV bioassay to elucidate the mechanism of action, and then it was validated by Western blot.</div></div><div><h3>Results</h3><div>The BL21-sIFNAR2 had a sequence identity of 83.6 % with the native form, showing variations only in terminal regions. BL21-sIFNAR2 and CHO-sIFNAR2 showed significantly higher percentage of cell viability compared to the viral control, similar to IFN-ß. Cell viability with BL21-sIFNAR2 was comparable to the cell control across all tested concentrations.</div><div>Proteomic analysis revealed an up regulation of pathways related with autophagy (macroautophagy, autophagy, pexophagy, and mitophagy) with an SQSTM1 overexpression that was then confirmed by Western Blot, especially after virus infection. However, pathways related to interferon signaling, and antiviral mechanisms mediated by IFN-stimulated genes were down-regulated.</div></div><div><h3>Conclusion</h3><div>r-sIFNAR2 exhibits significant antiviral activity regardless of the expression system used for its production and good safety profile, suggesting its use as a potential antiviral drug. Proteins related to autophagy are involved in the protection from the virus. This study highlights the biological relevance of soluble cytokine receptors as effectors so far overlooked.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117678"},"PeriodicalIF":6.9,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cellucalst enzyme-assisted extraction of Sargassum horneri enhances the immunomodulation by regulating TLR4/MyD88/NF-kB pathway in murine splenocytes with or without Concanavalin A Cellucalst 酶解辅助提取马尾藻角茴香可通过调节小鼠脾细胞中的 TLR4/MyD88/NF-kB 通路增强免疫调节作用，无论是否使用 Concanavalin A。

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2024-11-20 DOI: 10.1016/j.biopha.2024.117673

Jiwon Yang , Hyo Jin Kim , Kalahe Hewage Iresha Nadeeka Madushani Herath , Youngheun Jee

Sargassum horneri (S. horneri) is an edible species of large brown algae inhabiting along the coasts of northeastern Asia. The study focuses on the impact of celluclast enzyme extract of S. hoeneri (SHC) on various immune cell populations in splenocytes including granulocytes, macrophages, dendritic cells, and T lymphocytes. SHC alone increased the population of granulocytes and macrophages and the secretion of M1 macrophage-derived cytokines (TNF-α, IL-22), and M2 macrophage-derived cytokines (IL-4, IL-10). Interestingly, however, SHC suppressed the concanavalin A (Con A)-expanded populations of macrophages, dendritic cells, granulocytes, T and B cells, and Con A-promoted secretion of M1-macrophage derived cytokines (IFN-γ, IL-1β, TNF-α, IL-17, IL-22) and M2-macrophage derived cytokines (IL-4, IL-10, IL-13, TGF-β). SHC further restrained the Th1, Th2, and Th17 cell responses through attenuating the expression of respective transcription factors T-bet, Gata3, and Rorγt. The anti-inflammatory property of SHC is highlighted through its influence on cytokine production, particularly in the NF-κB pathway, and the attenuation of Toll-like receptor (TLR) signaling. The results reveal that SHC acts as both an immunostimulator and an inhibitor of hyperimmune reactions, showcasing its potential therapeutic applications in conditions involving dysregulated immune responses such as autoimmune diseases and inflammatory disorders. This positions SHC as a promising candidate for the development of functional ingredients with diverse applications encompassing the realms of food, pharmaceuticals, and cosmetics.

马尾藻（Sargassum horneri，S. horneri）是一种可食用的大型褐藻，栖息于亚洲东北部沿海地区。本研究的重点是马尾藻细胞核酶提取物（SHC）对脾细胞中各种免疫细胞群（包括粒细胞、巨噬细胞、树突状细胞和 T 淋巴细胞）的影响。单用 SHC 可增加粒细胞和巨噬细胞的数量，增加 M1 巨噬细胞衍生细胞因子（TNF-α、IL-22）和 M2 巨噬细胞衍生细胞因子（IL-4、IL-10）的分泌。但有趣的是，SHC 可抑制巨噬细胞、树突状细胞、粒细胞、T 细胞和 B 细胞的共振素 A（Con A）扩增，以及 Con A 促进的 M1-巨噬细胞衍生细胞因子（IFN-γ、IL-1β、TNF-α、IL-17、IL-22）和 M2-巨噬细胞衍生细胞因子（IL-4、IL-10、IL-13、TGF-β）的分泌。SHC 通过抑制转录因子 T-bet、Gata3 和 Rorγt 的表达，进一步抑制 Th1、Th2 和 Th17 细胞的反应。SHC 对细胞因子（尤其是 NF-κB 通路中的细胞因子）产生的影响以及对 Toll 样受体（TLR）信号转导的抑制作用凸显了 SHC 的抗炎特性。研究结果表明，SHC 既是一种免疫刺激剂，也是一种高免疫反应抑制剂，显示了它在自身免疫性疾病和炎症性疾病等免疫反应失调情况下的潜在治疗用途。这使得 SHC 成为开发功能性成分的理想候选物质，其应用领域涵盖食品、药品和化妆品等多个领域。

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引用次数: 0

Population pharmacokinetics of unfractionated heparin and multivariable analysis of activated clotting time in patients undergoing radiofrequency ablation of atrial fibrillation 心房颤动射频消融术患者体内非分叶肝素的群体药代动力学和活化凝血时间的多变量分析。

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2024-11-20 DOI: 10.1016/j.biopha.2024.117700

Celine Konecki , François Lesaffre , Sophie Guillou , Catherine Feliu , Florine Dubuisson , Moad Labdaoui , Laurent Faroux , Zoubir Djerada

Introduction

Atrial fibrillation (AF) increases cardiovascular morbidity and mortality. To reduce thrombosis and bleeding risks, and due to high variability of unfractionated heparin (UFH) effect, activated clotting time (ACT) is used during radiofrequency catheter ablation (RFCA) of AF to guide UFH dose. This study aimed to develop a population PK-PD model and perform multivariable analysis in order to identify the most significant covariates associated with interindividual variability of UFH.

Methods

Electronic medical records from 668 patients undergoing RFCA were analyzed, including relevant covariates. The relationship between UFH dose and ACT and the impact of the main covariates were characterized using a mixed-effect PK-PD model. Multivariable analysis was then used to identify predictors of ACT 15 minutes after UFH administration (ACT15).

Results

A two-compartment PK model with linear elimination and a direct Emax PD model with a baseline and sigmoidicity best described the observed ACT values. Pretreatment with dabigatran, warfarin, or fluindione significantly influenced baseline ACT. Pretreatment with vitamin K antagonists or low molecular weight heparin explained Emax variability. The multivariable model identified baseline ACT, initial UFH dose, and previous anticoagulant as the main predictors of ACT15. Model evaluation through resampling and external validation showed accurate ACT15 predictions.

Conclusion

This study presents the first population PK-PD model characterizing the relationship between UFH doses and ACT during RFCA, along with multivariable analysis. Additionally, predictive calculators for ACT15 and UFH dose based on patient and procedural characteristics were developed, enhancing personalized anticoagulation management during RFCA.

导言：心房颤动（房颤）会增加心血管疾病的发病率和死亡率。为了降低血栓形成和出血风险，同时由于非分叶肝素（UFH）效果的高变异性，在房颤射频导管消融术（RFCA）中使用活化凝血时间（ACT）来指导 UFH 剂量。本研究旨在建立一个人群 PK-PD 模型并进行多变量分析，以确定与 UFH 的个体间变异相关的最重要的协变量：分析了668名接受RFCA治疗的患者的电子病历，包括相关的协变量。采用混合效应 PK-PD 模型分析了 UFH 剂量和 ACT 之间的关系以及主要协变量的影响。然后利用多变量分析确定了UFH给药15分钟后ACT（ACT15）的预测因素：结果：具有线性消除作用的二室 PK 模型和具有基线和正交性的直接 Emax PD 模型最能描述观察到的 ACT 值。达比加群、华法林或氟啶酮的预处理对基线ACT有显著影响。维生素 K 拮抗剂或低分子量肝素的预处理可解释 Emax 变异。多变量模型确定基线 ACT、初始 UFH 剂量和既往抗凝剂是 ACT 的主要预测因素15。通过重新取样和外部验证对模型进行的评估显示，ACT15预测准确：本研究首次提出了描述 RFCA 期间 UFH 剂量与 ACT 之间关系的人群 PK-PD 模型，并进行了多变量分析。此外，还根据患者和手术特征开发了 ACT15 和 UFH 剂量的预测计算器，从而加强了 RFCA 期间的个性化抗凝管理。

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引用次数: 0

Induction of Ca2+-dependent autophagy and concurrent lysosomal alkalinization underlies the cytotoxic effects of NNC-55–0396 on glioblastoma cells NNC-55-0396对胶质母细胞瘤细胞的细胞毒性作用是诱导Ca2+依赖性自噬和同时溶酶体碱化的基础。

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2024-11-20 DOI: 10.1016/j.biopha.2024.117690

Anna Visa, Maria Casals, Lía Alza, Judit Herreros , Carles Cantí

Diverse agents targeting (macro)autophagy, a critical metabolic stress response in cancer cells, have been proposed for cancer therapy. In previous studies, we showed that NNC-55–0396 (NNC) induces glioblastoma cell death by activating the Unfolded Protein Response (UPR) of ER stress and increasing cytosolic Ca²⁺ levels. Here, we report that NNC affects both ends of the autophagy process, causing extensive cytoplasmic vacuolation. Our results show that: (1) NNC induces autophagy downstream of UPR and Ca²⁺ signaling pathways, thus silencing IRE1α/JNK1 or inhibiting Ca²⁺/IP₃R signaling prevents NNC-induced vacuolation. (2) Silencing ATG5 delays cell death, indicating that autophagy induction plays a role in NNC's cytotoxic effects. (3) NNC and other Ca²⁺-mobilizing agents transcriptionally upregulate p62/SQSTM1, an autophagosome cargo receptor, highlighting a role for this protein in the response to NNC. (4) Studies using tandem fluorescent-tagged LC3 and electron microscopy, however, further reveal that NNC blocks late-stage autophagy that leads to enlarged degradative compartments accumulating ubiquitin-tagged cargoes. (5) Finally, NNC impedes pro-cathepsin-B processing, an effect that is reversed with a weak acid co-treatment, suggesting that lysosomal dysfunction due to increased intraluminal pH is the underlying cause of the autophagy blockade. Together, these findings underscore a multi-level dysregulation of autophagy that contributes to NNC's anti-tumoral effects.

自噬是癌细胞中一种关键的代谢应激反应，针对自噬的多种药物已被提出用于癌症治疗。在之前的研究中，我们发现NNC-55-0396（NNC）通过激活ER应激的折叠蛋白反应（UPR）和增加细胞膜Ca2+水平诱导胶质母细胞瘤细胞死亡。在这里，我们报告了 NNC 影响自噬过程的两端，导致广泛的细胞质空泡化。我们的研究结果表明(1) NNC 在 UPR 和 Ca2+ 信号通路下游诱导自噬，因此沉默 IRE1α/JNK1 或抑制 Ca2+/IP3R 信号可防止 NNC 诱导的空泡化。(2）沉默 ATG5 可延缓细胞死亡，表明自噬诱导在 NNC 的细胞毒性效应中发挥作用。(3) NNC 和其他 Ca2+ 动物质转录上调自噬体货物受体 p62/SQSTM1，突出了该蛋白在对 NNC 的反应中的作用。(4）然而，使用串联荧光标记 LC3 和电子显微镜进行的研究进一步揭示，NNC 会阻碍后期自噬，导致降解区扩大，积累泛素标记的货物。(5) 最后，NNC 阻碍了前胰蛋白酶-B 的处理，而弱酸联合处理可逆转这种效应，这表明溶酶体功能障碍是导致腔内 pH 值升高的根本原因，也是自噬受阻的根本原因。这些发现共同强调了自噬的多层次失调，它是 NNC 抗肿瘤作用的原因之一。

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引用次数: 0

Prenatal THC exposure drives sex-specific alterations in spatial memory and hippocampal excitatory/inhibitory balance in adolescent rats 产前接触四氢大麻酚会导致青春期大鼠的空间记忆和海马兴奋/抑制平衡发生性别特异性改变。

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2024-11-20 DOI: 10.1016/j.biopha.2024.117699

Valentina Castelli , Gianluca Lavanco , Giuseppe Tringali , Cesare D’Amico , Salvatore Feo , Martina Di Bartolomeo , Claudio D’Addario , Martin Kuchar , Anna Brancato , Carla Cannizzaro

The interaction between the main psychotropic ingredient of Cannabis, Δ⁹- tetrahydrocannabinol (THC), with the endogenous cannabinoid system (ECS) is a critical and underrated issue that deserves utmost attention. The ECS, indeed, contributes to the formation and regulation of excitatory and inhibitory (E/I) neuronal networks that in the hippocampus underly spatial memory. This study explored sex-specific consequences of prenatal exposure to THC in hippocampus-dependent memory and the underlying cellular and molecular contributors of synaptic plasticity and E/I homeostasis. Sprague Dawley dams were exposed to THC (2 mg/kg) or vehicle, from gestational day 5–20. The adolescent progeny of both sexes was tested for: spatial memory retrieval and flexibility in the Barnes Maze; mRNA expression of relevant players of hippocampal synaptic plasticity; density of cholecystokinin-positive basket cells (CCK+BCs) – a major subtype of hippocampal inhibitory interneurons; mRNA expression of the excitatory and inhibitory synaptic proteins neuroligins (Nlgns), as a proxy of synaptic efficiency. Our results show a sex-specific disruption in spatial memory retrieval and flexibility, a male-specific decrease in CCK+BCs density and increase in the expression of markers of neuroplasticity, and consistent changes in the expression of Nlgn-1 and 3 isoforms. Despite a delay in memory retrieval, flexibility of memory was spared in prenatally-THC-exposed female offspring as well as most of the markers of neuroplasticity; a sex-specific increase in CCK+BCs density, and a consistent expression of Nlgn-3 was observed. The current results highlight a major vulnerability to prenatal exposure to THC on memory processing in the male progeny, and sex-specific alterations in the E/I balance and synaptic plasticity.

大麻的主要精神药物Δ⁹- 四氢大麻酚（THC）与内源性大麻素系统（ECS）之间的相互作用是一个关键且被低估的问题，值得高度重视。事实上，ECS 有助于兴奋性和抑制性（E/I）神经元网络的形成和调节，而这些网络在海马中是空间记忆的基础。本研究探讨了产前暴露于四氢大麻酚对海马依赖性记忆的性别特异性影响，以及突触可塑性和E/I平衡的潜在细胞和分子促进因素。从妊娠第 5-20 天开始，Sprague Dawley 母鼠暴露于 THC（2 毫克/千克）或药物。对雌雄胎儿的青春期后代进行了以下测试：巴恩斯迷宫中的空间记忆检索和灵活性；海马突触可塑性相关参与者的 mRNA 表达；胆囊收缩素阳性篮细胞（CCK+BCs）--海马抑制性中间神经元的一个主要亚型--的密度；兴奋性和抑制性突触蛋白神经ligins（Nlgns）的 mRNA 表达，作为突触效率的代表。我们的研究结果表明，空间记忆检索和灵活性的中断具有性别特异性，CCK+BCs 密度的降低和神经可塑性标志物表达的增加具有男性特异性，Nlgn-1 和 3 异构体的表达也发生了一致的变化。尽管产前暴露于四氢大麻酚的雌性后代的记忆检索延迟，但其记忆的灵活性以及大多数神经可塑性标志物都没有受到影响；观察到CCK+BCs密度的增加具有性别特异性，Nlgn-3的表达也具有一致性。目前的研究结果凸显了产前暴露于四氢大麻酚对雄性后代记忆处理的主要脆弱性，以及E/I平衡和突触可塑性的性别特异性改变。

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引用次数: 0

Chronic metabolic effects of novel gut-oriented small-molecule GPR119 agonists in diet-induced obese mice 新型肠道导向小分子 GPR119 激动剂对饮食诱导肥胖小鼠的慢性代谢影响。

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2024-11-19 DOI: 10.1016/j.biopha.2024.117675

Mohan Patil , Dinesh Thapa , Leon N. Warne , Ricky R. Lareu , Elena Dallerba , Jerome Lian , Massimiliano Massi , Rodrigo Carlessi , Marco Falasca

The pharmacological activation of G-protein coupled receptor-119 (GPR119) modulates glucose, energy, and hepatic lipid homeostasis in type-2 diabetes (T2D). We developed synthetic small-molecule GPR119 agonists targeting gastrointestinal receptors. This study investigates the chronic metabolic effects of lead candidates, ps297 and ps318, individually and in combination with sitagliptin, a dipeptidyl peptidase-IV (DPP-IV) inhibitor, in high-fat diet (HFD)-induced obese (DIO) mice. In a 10-week dose-escalation protocol, DIO mice were orally treated with the investigational agents alone (10–90 mg/kg/day) and in combination with sitagliptin (20 mg/kg/day). Weekly body weight, food intake, and random blood glucose levels were monitored during the treatment phase. Post-treatment, an intraperitoneal glucose tolerance test (ipGTT), estimation of plasma biomarkers and haematological assessment were conducted. The treatment’s effect on hepatic steatosis was studied by estimating liver biomarkers and histological examinations. Ten-week sitagliptin combination therapy with the investigational entities restored incretins, insulin, and other metabolic hormonal secretions, accompanied by improved glucose homeostasis and retarded weight gain. Interestingly, monotherapy with investigational agents improved liver health by reducing liver weight, liver enzymes, and inflammation. Hepatic effects were further enhanced by co-administration of sitagliptin, evident by amelioration in hepatic steatosis endpoints such as liver weight, plasma liver enzyme concentrations, hepatic triglycerides (TG), total cholesterol (CHO), hydroxyproline content, and cytokine levels. Histopathological investigations confirmed regression in hepatic steatosis in the combination groups. These findings demonstrate the therapeutic potential of novel gut-oriented GPR119 agonists in combination with a DPP-IV inhibitor to ameliorate metabolic dysfunction-associated steatohepatitis (MASH), warranting further mechanistic investigations.

药理激活 G 蛋白偶联受体-119（GPR119）可调节 2 型糖尿病（T2D）患者的葡萄糖、能量和肝脏脂质平衡。我们开发了针对胃肠道受体的合成小分子 GPR119 激动剂。本研究调查了候选药物ps297和ps318单独使用或与二肽基肽酶-IV（DPP-IV）抑制剂西格列汀联用对高脂饮食（HFD）诱导肥胖（DIO）小鼠的慢性代谢影响。在一项为期 10 周的剂量递增方案中，DIO 小鼠口服单用（10-90 毫克/千克/天）和与西他列汀（20 毫克/千克/天）合用的研究药物。在治疗阶段，每周监测体重、食物摄入量和随机血糖水平。治疗后进行腹腔内葡萄糖耐量试验（ipGTT）、血浆生物标志物评估和血液学评估。通过评估肝脏生物标志物和组织学检查，研究了治疗对肝脏脂肪变性的影响。为期十周的西他列汀与研究药物的联合治疗恢复了胰岛素、胰岛素和其他代谢激素的分泌，同时改善了葡萄糖稳态，延缓了体重增加。有趣的是，研究药物单药治疗可通过减轻肝脏重量、降低肝酶和炎症来改善肝脏健康。联合应用西他列汀可进一步增强对肝脏的影响，肝脏重量、血浆肝酶浓度、肝甘油三酯 (TG)、总胆固醇 (CHO)、羟脯氨酸含量和细胞因子水平等肝脏脂肪变性终点指标均有所改善。组织病理学检查证实，联合用药组的肝脏脂肪变性有所减轻。这些研究结果表明，新型肠道导向 GPR119 激动剂与 DPP-IV 抑制剂联用具有改善代谢功能障碍相关性脂肪性肝炎（MASH）的治疗潜力，值得进一步进行机理研究。

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引用次数: 0