Pharmacological research最新文献_第2页

Formation of CSE-YAP complex drives FOXD3-mediated transition of neurotoxic astrocytes in Parkinson’s disease CSE-YAP 复合物的形成推动了 FOXD3 介导的帕金森病神经毒性星形胶质细胞的转变。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-11-14 DOI: 10.1016/j.phrs.2024.107507

Rong-Xin Zhu , Yue-Han Chen , Xian Xia , Ting Liu , Cong Wang , Lei Cao , Yang Liu , Ming Lu

Astrocytes, constituting the predominant glial cells in the brain, undergo significant morphological and functional transformations amidst the progression of Parkinson’s disease (PD). A majority of these reactive astrocytes display a neurotoxic phenotype, intensifying inflammatory responses. Nonetheless, the molecular underpinnings steering neurotoxic astrocyte reactivity during PD progression remain mostly uncharted. Here, we uncover the unique role of cystathionine γ-lyase (CSE) in shaping astrocyte reactivity, primarily channeling astrocytes towards a neurotoxic phenotype, thereby escalating neuroinflammation in PD. Single-cell sequencing data drawn from PD patients coupled with RNA sequencing data from MPP⁺-treated astrocytes, highlighted a marked positive association between increased expression of Cth, the gene that encodes CSE, and neurotoxic astrocyte reactivity. Employing genetic manipulation of Cth in astrocytes, we evidenced that CSE instigates a transition to a neurotoxic state in PD-afflicted astrocytes under in vitro and in vivo settings. Moreover, we identified a CSE-Yes-associated protein (YAP) complex within astrocytes via label-free mass spectrometry. An increased formation of the CSE-YAP complex was found to facilitate the expression of gene patterns tied to neurotoxic astrocytes, driven by the transcription factor, forkhead box protein D3 (FOXD3). Consequently, our work unveils valuable insights into the cell type-specific function of CSE in the brain, and presents FOXD3 as a novel transcription factor influencing astrocyte phenotypes in PD. These findings lay the groundwork for the development of potential strategies intended to manage conditions associated with neuroinflammation.

星形胶质细胞是大脑中最主要的胶质细胞，在帕金森病（PD）的进展过程中会发生显著的形态和功能转变。这些反应性星形胶质细胞大多具有神经毒性表型，加剧了炎症反应。然而，在帕金森病进展过程中引导神经毒性星形胶质细胞反应的分子基础大多仍是未知的。在这里，我们发现了胱硫醚γ-赖氨酸酶（CSE）在形成星形胶质细胞反应性中的独特作用，它主要引导星形胶质细胞向神经毒性表型发展，从而加剧了帕金森病的神经炎症。从帕金森氏症患者身上提取的单细胞测序数据与经 MPP+ 处理的星形胶质细胞的 RNA 测序数据突出表明，编码 CSE 的基因 Cth 的表达增加与神经毒性星形胶质细胞反应性之间存在明显的正相关。通过对星形胶质细胞中 Cth 的遗传操作，我们证明了 CSE 在体外和体内环境下促使帕金森病星形胶质细胞过渡到神经毒性状态。此外，我们还通过无标记质谱鉴定了星形胶质细胞中的 CSE-Yes-相关蛋白（YAP）复合物。研究发现，在转录因子叉头盒蛋白 D3（FOXD3）的驱动下，CSE-YAP 复合物的形成会促进与神经毒性星形胶质细胞相关的基因模式的表达。因此，我们的研究揭示了 CSE 在大脑中细胞类型特异性功能的宝贵见解，并提出 FOXD3 是影响帕金森病星形胶质细胞表型的新型转录因子。这些发现为开发旨在控制神经炎症相关病症的潜在策略奠定了基础。

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引用次数: 0

New TIPARP inhibitor rescues mitochondrial function and brain injury in ischemic stroke. 新型 TIPARP 抑制剂可挽救缺血性中风的线粒体功能和脑损伤。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-11-14 DOI: 10.1016/j.phrs.2024.107508

Yang Cai, Hongfeng Gu, Lu Li, Xue Liu, Ying Bai, Ling Shen, Bing Han, Yungen Xu, Honghong Yao

Ischemic stroke is a high-mortality disease that urgently requires new therapeutic strategies. Insufficient cerebral blood supply can induce poly (ADP-ribose) polymerase (PARP) activation and mitochondrial dysfunction, leading to tissue damage and motor dysfunction. We demonstrate that the expression of TCDD inducible PARP (TIPARP) is elevated in ischemic stroke patients and mice. Knockdown of Tiparp reduces brain infarction and promotes recovery of motor function in ischemic stroke mice. A rationally designed TIPARP inhibitor, XG-04-B1, promotes repair of brain injury and recovery of motor function in ischemic stroke mice. Mechanistically, XG-04-B1 increases neuronal plasticity and inhibits astrocyte activation in ischemic stroke mice. In addition, eukaryotic translation initiation factor 3 subunit B (EIF3B) is a direct target of TIPARP. TIPARP interacts with EIF3B through nucleoplasmic redistribution, leading to mitochondrial dysfunction. Knockdown of Tiparp and inhibition of TIPARP via XG-04-B1 restore mitochondrial homeostasis in ischemic stroke mice. Taken together, TIPARP activation contributes to mitochondrial dysfunction and subsequent brain injury, and is therefore a promising therapeutic target for stroke.

缺血性中风是一种死亡率很高的疾病，迫切需要新的治疗策略。脑供血不足可诱导多聚（ADP-核糖）聚合酶（PARP）活化和线粒体功能障碍，导致组织损伤和运动功能障碍。我们发现缺血性中风患者和小鼠体内 TCDD 诱导型 PARP（TIPARP）的表达升高。敲除 TIPARP 可减少脑梗塞，促进缺血性中风小鼠运动功能的恢复。合理设计的 TIPARP 抑制剂 XG-04-B1 能促进缺血性中风小鼠脑损伤的修复和运动功能的恢复。从机理上讲，XG-04-B1 增加了缺血性中风小鼠神经元的可塑性并抑制了星形胶质细胞的激活。此外，真核翻译起始因子 3 亚基 B（EIF3B）是 TIPARP 的直接靶标。TIPARP 通过核质重新分布与 EIF3B 相互作用，导致线粒体功能障碍。敲除 Tiparp 和通过 XG-04-B1 抑制 TIPARP 可恢复缺血性中风小鼠的线粒体稳态。综上所述，TIPARP 激活导致线粒体功能障碍和随后的脑损伤，因此是一种很有希望的中风治疗靶点。

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引用次数: 0

Pregnane X receptor activation promotes hematopoiesis during liver regeneration by inducing proliferation of hematopoietic stem and progenitor cells in mice 孕烷X受体激活通过诱导小鼠造血干细胞和祖细胞增殖，促进肝脏再生过程中的造血功能。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-11-08 DOI: 10.1016/j.phrs.2024.107504

Shuang Hu , Chenghua Wu , Dan Li , Xiaowen Jiang , Peng Wang , Guofang Bi , Hui Ouyang , Fengting Liang , Wenhong Zhou , Xiao Yang , Jian-Hong Fang , Huichang Bi

Liver regeneration is a complex process that involves the recruitment of bone marrow (BM)-derived hematopoietic stem and progenitor cells (HSPCs). Pregnane X receptor (PXR), also known as NR1I2, is an important regulator for liver enlargement and regeneration. However, the role of PXR activation in hematopoiesis during liver regeneration remains unclear. This study investigates the effects of PXR activation on HSPCs and hematopoiesis during liver regeneration, as well as the underlying mechanisms involved. Using a 70 % partial hepatectomy (PHx) on C57BL/6 wild-type (WT) and Pxr-null mice, we observed a significant correlation between the changes in HSPCs numbers in BM and the process of liver regeneration. PXR activation significantly increased the population of Lineage^- Sca-1⁺ c-Kit⁺ (LSK) cells in the BM, which are key HSPCs involved in hematopoiesis. Additionally, PXR activation increased serum levels of thrombopoietin (TPO) and erythropoietin (EPO), factors known to support HSPCs proliferation and hematopoiesis in the process of liver regeneration. PXR activation does not affect the hematopoietic function of normal mice. Furthermore, mice subjected to irradiation or busulfan-induced hematopoietic dysfunction exhibited impaired liver regeneration, which was alleviated by PXR activation. Importantly, in Pxr-null mice, the promotive effects of PXR activation on liver regeneration and increase of HSPCs were markedly diminished. Moreover, liver-specific Pxr silencing using AAV-Pxr shRNA attenuated the PXR activation-mediated liver regeneration and increase in BM LSK cells, confirming the critical role of hepatic PXR in hematopoiesis during liver regeneration. Collectively, these findings reveal that PXR activation promotes HSPCs proliferation and hematopoiesis during liver regeneration, providing new insights into the molecular mechanisms underlying the role of PXR in liver regeneration and hematopoiesis.

肝脏再生是一个复杂的过程，涉及骨髓（BM）衍生的造血干细胞和祖细胞（HSPCs）的招募。孕烷 X 受体（PXR）又称 NR1I2，是肝脏增大和再生的重要调节因子。然而，在肝脏再生过程中，PXR 在造血过程中的激活作用仍不清楚。本研究探讨了肝脏再生过程中 PXR 激活对 HSPCs 和造血的影响，以及相关的内在机制。通过对C57BL/6野生型（WT）和Pxr-null小鼠进行70%部分肝切除术（PHx），我们观察到BM中HSPCs数量的变化与肝脏再生过程之间存在显著的相关性。PXR 激活能明显增加 BM 中的 Lineage- Sca-1+ c-Kit+ (LSK) 细胞数量，这些细胞是参与造血的关键 HSPCs。此外，PXR 激活还能提高血清中血小板生成素（TPO）和促红细胞生成素（EPO）的水平。PXR 激活不会影响正常小鼠的造血功能。此外，受到辐照或丁胺磺胺诱导的小鼠造血功能障碍表现出肝脏再生受损，而 PXR 激活可减轻这种情况。重要的是，在 Pxr 缺失的小鼠中，PXR 激活对肝脏再生和 HSPCs 增加的促进作用明显减弱。此外，使用AAV-Pxr shRNA对肝脏特异性Pxr进行沉默可减轻PXR激活介导的肝脏再生和BM LSK细胞的增加，这证实了肝脏PXR在肝脏再生过程中造血的关键作用。总之，这些发现揭示了肝脏再生过程中PXR激活可促进HSPCs增殖和造血，为PXR在肝脏再生和造血过程中的分子机制提供了新的见解。

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引用次数: 0

Targeting gut microbiota as a therapeutic target in T2DM: A review of multi-target interactions of probiotics, prebiotics, postbiotics, and synbiotics with the intestinal barrier 将肠道微生物群作为 T2DM 的治疗靶点：综述益生菌、益生元、益后菌和合成益生菌与肠道屏障的多靶点相互作用。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-11-08 DOI: 10.1016/j.phrs.2024.107483

Keyu Chen , Han Wang , Xiaofei Yang , Cheng Tang , Guojie Hu , Zezheng Gao

The global epidemic of type 2 diabetes mellitus (T2DM) imposes a substantial burden on public health and healthcare expenditures, thereby driving the pursuit of cost-effective preventive and therapeutic strategies. Emerging evidence suggests a potential association between dysbiosis of gut microbiota and its metabolites with T2DM, indicating that targeted interventions aimed at modulating gut microbiota may represent a promising therapeutic approach for the management of T2DM. In this review, we concentrated on the multifaceted interactions between the gut microbiota and the intestinal barrier in the context of T2DM. We systematically summarized that the imbalance of beneficial gut microbiota and its metabolites may constitute a viable therapeutic approach for the management of T2DM. Meanwhile, the mechanisms by which gut microbiota interventions, such as probiotics, prebiotics, postbiotics, and synbiotics, synergistically improve insulin resistance in T2DM are summarized. These mechanisms include the restoration of gut microbiota structure, upregulation of intestinal epithelial cell proliferation and differentiation, enhancement of tight junction protein expression, promotion of mucin secretion by goblet cells, and the immunosuppressive functions of regulatory T cells (Treg) and M2 macrophages. Collectively, these actions contribute to the amelioration of the body's metabolic inflammatory status. Our objective is to furnish evidence that supports the clinical application of probiotics, prebiotics, and postbiotics in the management of T2DM.

2 型糖尿病（T2DM）在全球的流行给公共卫生和医疗保健支出造成了巨大负担，从而促使人们寻求具有成本效益的预防和治疗策略。新的证据表明，肠道微生物群及其代谢产物的失调与 T2DM 之间存在潜在联系，这表明旨在调节肠道微生物群的靶向干预措施可能是治疗 T2DM 的一种很有前景的方法。在这篇综述中，我们集中讨论了 T2DM 背景下肠道微生物群和肠屏障之间多方面的相互作用。我们系统地总结了有益肠道微生物群及其代谢产物的失衡可能是治疗 T2DM 的一种可行方法。同时，我们总结了益生菌、益生元、后益生元和合成益生元等肠道微生物群干预措施协同改善 T2DM 胰岛素抵抗的机制。这些机制包括恢复肠道微生物群结构、上调肠上皮细胞的增殖和分化、增强紧密连接蛋白的表达、促进鹅口疮细胞分泌粘蛋白，以及调节性 T 细胞（Treg）和 M2 巨噬细胞的免疫抑制功能。总之，这些作用有助于改善机体的代谢性炎症状态。我们的目标是提供支持临床应用益生菌、益生元和后益生元治疗 T2DM 的证据。

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引用次数: 0

Characterization of novel nitazene recreational drugs: Insights into their risk potential from in vitro µ-opioid receptor assays and in vivo behavioral studies in mice 新型硝基苯类娱乐性药物的特征：从体外μ-阿片受体测定和小鼠体内行为研究中洞察其潜在风险。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-11-07 DOI: 10.1016/j.phrs.2024.107503

Marthe M. Vandeputte , Grant C. Glatfelter , Donna Walther , Nathan K. Layle , Danielle M. St. Germaine , István Ujváry , Donna M. Iula , Michael H. Baumann , Christophe P. Stove

2-Benzylbenzimidazole derivatives or ‘nitazenes’ are increasingly present on the recreational drug market. Here, we report the synthesis and pharmacological characterization of 15 structurally diverse nitazenes that might be predicted to emerge or grow in popularity. This work expands the existing knowledge about 2-benzylbenzimidazole structure-activity relationships (SARs), while also helping stakeholders (e.g., forensic toxicologists, clinicians, policymakers) in their risk assessment and preparedness for the potential next generation of nitazenes. In vitro µ-opioid receptor (MOR) affinity was determined via competition radioligand (³[H]DAMGO) binding assays in rat brain tissue. MOR activation (potency and efficacy) was studied by means of a cell-based β-arrestin 2 recruitment assay. For seven nitazenes, including etonitazene, opioid-like pharmacodynamic effects (antinociception, locomotor activity, body temperature changes) were evaluated after subcutaneous administration in male C57BL/6 J mice. The results showed that all nitazenes bound to MOR with nanomolar affinities, and the functional potency of several of them was comparable to or exceeded that of fentanyl. In vivo, dose-dependent effects were observed for antinociception, locomotor activity, and body temperature changes in mice. SAR insights included the high opioid-like activity of methionitazene, iso-butonitazene, sec-butonitazene, and the etonitazene analogues 1-ethyl-pyrrolidinylmethyl N-desalkyl etonitazene and ethylene etonitazene. The most potent analogue of the panel across all functional assays was α’-methyl etonitazene. Taken together, through critical pharmacological evaluation, this work provides a framework for strengthened preparedness and risk assessments of current and future nitazenes that have the potential to cause harm to users.

2-苄基苯并咪唑衍生物或 "硝氮烯 "越来越多地出现在娱乐性药物市场上。在此，我们报告了 15 种结构多样的硝氮类药物的合成和药理学特征，这些药物可能会出现或越来越受欢迎。这项工作拓展了现有的 2-苄基苯并咪唑结构-活性关系（SARs）知识，同时也有助于利益相关者（如法医毒理学家、临床医生、政策制定者）对潜在的下一代硝氮类药物进行风险评估并做好准备。在大鼠脑组织中通过竞争放射性配体（3[H]DAMGO）结合试验确定了体外μ-阿片受体（MOR）亲和力。通过基于细胞的 β-restin 2 招募试验研究了 MOR 的激活（效力和功效）。在雄性 C57BL/6 J 小鼠中皮下注射后，评估了包括依托尼他嗪在内的七种硝基苯类药物的类阿片药效学效应（抗痛觉、运动活动、体温变化）。结果表明，所有硝氮类药物都能以纳摩尔级的亲和力与 MOR 结合，其中几种硝氮类药物的药效与芬太尼相当，甚至超过芬太尼。在体内，对小鼠的抗痛觉、运动活动和体温变化都观察到了剂量依赖性效应。SAR 见解包括甲硫硝基苯、异丁硝基苯、仲丁硝基苯和乙烯硝基苯类似物 1-乙基吡咯烷甲基 N-去烷基乙烯硝基苯和乙烯乙烯硝基苯具有很高的阿片类活性。在所有功能测试中，α'-甲基依托尼他嗪是最有效的类似物。总之，通过关键的药理学评估，这项工作为加强对目前和未来有可能对使用者造成伤害的硝氮类药物的防范和风险评估提供了一个框架。

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引用次数: 0

Commentary on: MicroRNAs in Helicobacter pylori-infected gastric cancer: Function and clinical application 评论幽门螺杆菌感染胃癌中的微 RNA：功能和临床应用。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-11-07 DOI: 10.1016/j.phrs.2024.107500

Ya Liu, Zhao Zhao, Haibo Lei

引用次数: 0

Cortistatin exerts an immunomodulatory and neuroprotective role in a preclinical model of ischemic stroke 皮质素在缺血性中风临床前模型中发挥免疫调节和神经保护作用。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-11-07 DOI: 10.1016/j.phrs.2024.107501

J. Castillo-González , L. Buscemi , P. Vargas-Rodríguez , I. Serrano-Martínez , I. Forte-Lago , M. Caro , M. Price , P. Hernández-Cortés , L. Hirt , E. González-Rey

Ischemic stroke is the result of a permanent or transient occlusion of a brain artery, leading to irreversible tissue injury and long-term sequelae. Despite ongoing advancements in revascularization techniques, stroke remains the second leading cause of death worldwide. A comprehensive understanding of the complex and interconnected mechanisms, along with the endogenous mediators that modulate stroke responses is essential for the development of effective interventions. Our study investigates cortistatin, a neuropeptide extensively distributed in the immune and central nervous systems, known for its immunomodulatory properties. With neuroinflammation and peripheral immune deregulation as key pathological features of brain ischemia, cortistatin emerges as a promising therapeutic candidate. To this aim, we evaluated its potential effect in a well-established middle cerebral artery occlusion (MCAO) preclinical stroke model. Our findings indicated that the peripheral administration of cortistatin at 24 h post-stroke significantly reduced neurological damage and enhanced recovery. Importantly, cortistatin-induced neuroprotection was multitargeted, as it modulated the glial reactivity and astrocytic scar formation, facilitated blood-brain barrier recovery, and regulated local and systemic immune dysfunction. Surprisingly, administration of cortistatin at immediate and early post-stroke time points proved to be not beneficial and even detrimental. These results emphasize the importance of understanding the spatio-temporal dynamics of stroke pathology to develop innovative therapeutic strategies with appropriate time windows. Premature interruption of certain neuroinflammatory processes might inadvertently compromise neuroprotective mechanisms. In summary, our study highlights cortistatin as a novel pleiotropic therapeutic approach against ischemic stroke, offering new treatment options for patients who undergo early revascularization intervention but unsuccessful recovery.

缺血性中风是脑动脉永久性或短暂性闭塞的结果，会导致不可逆转的组织损伤和长期后遗症。尽管血管重建技术不断进步，中风仍是全球第二大死亡原因。全面了解复杂且相互关联的机制以及调节中风反应的内源性介质对于开发有效的干预措施至关重要。我们的研究调查了一种广泛分布于免疫系统和中枢神经系统的神经肽--可的松，它以其免疫调节特性而闻名。神经炎症和外周免疫失调是脑缺血的主要病理特征，因此可体素成了一种很有希望的候选疗法。为此，我们在一个成熟的大脑中动脉闭塞（MCAO）临床前中风模型中评估了可的松的潜在作用。我们的研究结果表明，中风后 24 小时经外周给药可的松可显著减轻神经损伤并促进恢复。重要的是，可的松诱导的神经保护是多靶点的，因为它调节了神经胶质的反应性和星形胶质细胞瘢痕的形成，促进了血脑屏障的恢复，并调节了局部和全身的免疫功能紊乱。令人惊讶的是，在脑卒中后即刻和早期时间点服用可的松并无益处，甚至有害。这些结果表明，了解中风病理的时空动态对于开发具有适当时间窗口的创新治疗策略非常重要。过早中断某些神经炎症过程可能会无意中损害神经保护机制。总之，我们的研究强调了可的松是一种新型的多效应治疗缺血性中风的方法，为接受早期血管重建干预但恢复不成功的患者提供了新的治疗选择。

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引用次数: 0

Chrysophanol: A promising natural compound in cancer therapy – Mechanistic insights and future perspectives Chrysophanol：一种在癌症治疗中大有可为的天然化合物--机理认识与未来展望。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-11-07 DOI: 10.1016/j.phrs.2024.107502

Dehong Liu , Kun Zhu , Tao Guo , Yao Xiao , Meijing Wang , Yanxin Guan , Junjun Li , Degui Chang , Xujun Yu

Cancer continues to be a leading cause of death worldwide, highlighting the urgent need for the development of new therapeutic strategies. Chrysophanol, a naturally occurring anthraquinone compound, has demonstrated significant potential in cancer treatment due to its diverse biological activities. This review delves into the mechanisms through which chrysophanol exerts its anti-cancer effects, including the induction of cell cycle arrest, promotion of apoptosis, regulation of autophagy, and initiation of necrosis across various cancer cell lines. Additionally, the review discusses chrysophanol's impact on inhibiting cancer cell invasion and metastasis and its role in modulating chemotherapy sensitivity. Despite the promising therapeutic potential of chrysophanol, challenges such as poor water solubility, low bioavailability, and safety concerns remain. Comprehensive clinical trials are essential to validate its efficacy and safety. This review emphasizes chrysophanol as a promising candidate for cancer therapy and underscores the necessity for further research to fully harness its therapeutic potential.

癌症仍然是导致全球死亡的主要原因，因此迫切需要开发新的治疗策略。蛹虫草酚是一种天然的蒽醌化合物，由于其具有多种生物活性，在癌症治疗方面已显示出巨大的潜力。本综述深入探讨了金丝桃醇发挥其抗癌作用的机制，包括诱导细胞周期停滞、促进细胞凋亡、调节自噬和引发各种癌细胞株的坏死。此外，综述还讨论了菊醇对抑制癌细胞侵袭和转移的影响，以及它在调节化疗敏感性方面的作用。尽管菊醇具有良好的治疗潜力，但仍存在水溶性差、生物利用率低和安全性问题等挑战。全面的临床试验对于验证其疗效和安全性至关重要。这篇综述强调了菊醇是一种很有希望的癌症治疗候选药物，并强调了进一步研究以充分利用其治疗潜力的必要性。

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引用次数: 0

Erratum to "Age-related macular degeneration (AMD) is a detrimental eye disease, and the most common cause of visual loss in many countries around the world" [Pharmacol. Res. 208 (2024) 107402]. 对 "老年性黄斑变性（AMD）是一种有害的眼病，也是世界上许多国家最常见的视力丧失原因 "的勘误 [Pharmacol. Res. 208 (2024) 107402]。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-11-06 DOI: 10.1016/j.phrs.2024.107470

Torben Lykke Sørensen

引用次数: 0

The ketogenic diet modulates tumor-associated neutrophil polarization via the AMOT-YAP/TAZ axis to inhibit colorectal cancer progression 生酮饮食通过 AMOT-YAP/TAZ 轴调节肿瘤相关中性粒细胞极化，从而抑制结直肠癌的进展。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-11-05 DOI: 10.1016/j.phrs.2024.107494

Xiuwei Mi , Yudong Duan , Jiying Sun , Qingliang Tai , Huihui Yao , Lijun Meng , Xiaoshan Yang , Xinyu Shi , Bo Shi , Junjie Chen , Liang Sun , Diyuan Zhou , Sheng Xiao , Yizhou Yao , Songbing He

Despite significant advances in the diagnosis and treatment of colorectal cancer (CRC), the prognosis for late-stage patients remains poor, highlighting the urgent need for new preventive and therapeutic strategies. Recent studies have focused on the ketogenic diet (KD) and its metabolite, β-hydroxybutyrate (BHB), for their tumor-suppressive effects and modulation of inflammatory responses. Using the azoxymethane (AOM) / dextran sulfate sodium (DSS)-induced mouse CRC model, we found that the ketogenic diet and BHB inhibit pro-tumor N2-type tumor-associated neutrophils (TANs) while promoting the polarization of TANs towards the anti-tumor N1 type. This shift in TANs polarization affects tumor growth and metastasis. The underlying mechanism involves BHB acting on the intracellular receptor histone deacetylases 3 (HDAC3), which modulates the activation of the AMOT-YAP/TAZ axis, leading to the inhibition of pro-carcinogenic factor transcription and release. Moreover, clinical cohort data corroborate these findings, showing that CRC patients with elevated BHB levels have significantly lower rates of lymph node involvement, which is associated with a higher infiltration ratio of anti-carcinogenic N1-type TANs in the tumor microenvironment (TME). These results suggest that BHB levels could serve as a prognostic biomarker for CRC. In conclusion, our findings indicate that BHB derived from KD regulates TANs polarization in CRC via the HDAC3-AMOT-YAP/TAZ axis, effectively inhibiting tumor growth and metastasis. These insights establish a novel theoretical basis for employing the KD in the treatment of CRC and for developing cancer adjuvant immunotherapy strategy based on the polarization of neutrophils.

尽管结直肠癌（CRC）的诊断和治疗取得了重大进展，但晚期患者的预后仍然很差，这凸显了对新的预防和治疗策略的迫切需求。最近的研究主要集中在生酮饮食（KD）及其代谢产物β-羟基丁酸盐（BHB）上，因为它们具有抑制肿瘤和调节炎症反应的作用。利用偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导的小鼠 CRC 模型，我们发现生酮饮食和 BHB 可抑制亲肿瘤的 N2 型肿瘤相关中性粒细胞（TANs），同时促进 TANs 向抗肿瘤的 N1 型极化。这种 TANs 极化的转变会影响肿瘤的生长和转移。其基本机制是 BHB 作用于细胞内受体组蛋白去乙酰化酶 3（HDAC3），后者可调节 AMOT-YAP/TAZ 轴的激活，从而抑制促癌因子的转录和释放。此外，临床队列数据也证实了这些发现，显示 BHB 水平升高的 CRC 患者淋巴结受累率明显较低，这与肿瘤微环境（TME）中抗癌 N1 型 TANs 的浸润比例较高有关。这些结果表明，BHB 水平可作为 CRC 的预后生物标志物。总之，我们的研究结果表明，来自 KD 的 BHB 可通过 HDAC3-AMOT-YAP/TAZ 轴调节 CRC 中 TANs 的极化，从而有效抑制肿瘤的生长和转移。这些发现为利用 KD 治疗 CRC 以及开发基于中性粒细胞极化的癌症辅助免疫疗法策略奠定了新的理论基础。

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引用次数: 0