Biochemical pharmacology最新文献_第8页

An organogold compound impairs Leishmania amazonensis amastigotes survival and delays lesion progression in murine cutaneous leishmaniasis: Mechanistic insights 一种有机金化合物损害亚马孙利什曼原虫的无鬃线虫存活并延缓小鼠皮肤利什曼病的病变进展：机制见解。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116716

Karen Minori , Fernanda R. Gadelha , Riccardo Bonsignore , Guillermo Moreno Alcántar , Josielle V. Fontes , Camilla Abbehausen , Mariana B.C. Brioschi , Lizandra Maia de Sousa , Sílvio R. Consonni , Angela Casini , Danilo C. Miguel

Leishmaniasis is one of the most important neglected diseases, classically characterized by three clinical forms that if left untreated can lead to skin lesions, lifelong scarring, or death depending on the parasite species. Unfortunately, treatment is unsatisfactory and the search for an improved therapy has been a priority. Gold compounds have emerged as promising candidates and among them, Au(I)bis-N-heterocyclic carbene (Au(BzTMX)₂) has stood out. We have shown that it alters the plasma membrane permeability of Leishmania amazonensis and L. braziliensis, with superior activity for L. amazonensis. Herein, we moved a step forward towards the elucidation of its mechanism of action in L. amazonensis axenic amastigotes in vitro and in vivo. After 24 h incubation, Au(BzTMX)₂ induced changes in safranin O uptake, reflecting the ultrastructural changes observed in mitochondria, especially cristae swelling, and oxygen consumption rates. Besides mitochondrial alterations, plasma membrane blebbing and the formation of multilamellar structures were also observed suggesting an autophagy-like process induction. In vivo, Au(BzTMX)₂ was capable of delaying lesion progression, decreasing the total ulcerated area and leading to a marked reduction in the parasite burden of infected BALB/c mice. Taking all into consideration, our results give support to the current knowledge of the importance of gold compounds in therapeutics and open new possibilities for leishmaniasis treatment.

利什曼病是最重要的被忽视疾病之一，其典型特征为三种临床形式，如果不加以治疗，可导致皮肤损伤、终身疤痕或死亡，具体取决于寄生虫种类。不幸的是，治疗并不令人满意，寻找一种改进的治疗方法一直是当务之急。金化合物是一个很有前途的候选化合物，其中金(I)双n杂环碳（Au(BzTMX)2）最为突出。结果表明，它能改变亚马孙利什曼原虫和巴西利什曼原虫的质膜通透性，其中对亚马孙利什曼原虫的活性更强。在此基础上，进一步阐明了其在亚马孙无性系中体外和体内的作用机制。孵育24 h后，Au(BzTMX)2诱导了红花素O摄取的变化，反映了线粒体超微结构的变化，特别是嵴肿胀和耗氧量的变化。除了线粒体改变外，还观察到质膜起泡和多层结构的形成，表明诱导了类似自噬的过程。在体内，Au(BzTMX)2能够延缓病变进展，减少总溃疡面积，并导致感染BALB/c小鼠的寄生虫负担显著减少。综上所述，我们的研究结果支持了目前关于金化合物在治疗中的重要性的认识，并为利什曼病的治疗开辟了新的可能性。

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引用次数: 0

The complex interplay between redox dysregulation and mTOR signaling pathway in cancer: A rationale for cancer treatment 癌症中氧化还原失调和mTOR信号通路之间的复杂相互作用：癌症治疗的基本原理。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116729

Christophe Glorieux , Cinthya Enríquez , Pedro Buc Calderon

The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that plays a critical role in regulating cellular processes such as growth, proliferation, and metabolism in healthy cells. Dysregulation of mTOR signaling and oxidative stress have been implicated in various diseases including cancer. This review aims to provide an overview of the current understanding of mTOR and its involvement in cell survival and the regulation of cancer cell metabolism as well as its complex interplay with reactive oxygen species (ROS). On the one hand, ROS can inhibit or activate mTOR pathway in cancer cells through various mechanisms. Conversely, mTOR signaling can induce oxidative stress in tumor cells notably due to the inhibition in the expression of antioxidant enzyme genes. Since mTOR is often activated and plays crucial role in cancer cell survival, the use of mTOR inhibitors, which often induce ROS accumulation, could be an interesting approach for cancer treatment. This review will address the advantages, disadvantages, combination strategies, and limitations associated with therapeutic modulation of mTOR signaling pathway in cancer treatment.

雷帕霉素（mTOR）的机制靶点是一种高度保守的丝氨酸/苏氨酸激酶，在调节健康细胞的生长、增殖和代谢等细胞过程中起关键作用。mTOR信号和氧化应激的失调与包括癌症在内的多种疾病有关。本文综述了目前对mTOR及其参与细胞存活、调节癌细胞代谢以及与活性氧（ROS）的复杂相互作用的认识。一方面，ROS可以通过多种机制抑制或激活癌细胞中的mTOR通路。相反，mTOR信号可以诱导肿瘤细胞氧化应激，主要是通过抑制抗氧化酶基因的表达。由于mTOR经常被激活并在癌细胞存活中起着至关重要的作用，因此使用mTOR抑制剂（通常会诱导ROS积累）可能是一种有趣的癌症治疗方法。本文将阐述mTOR信号通路在癌症治疗中的优势、劣势、联合策略和局限性。

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引用次数: 0

Corrigendum to “Verteporfin combined with ROCK inhibitor promotes the restoration of corneal endothelial cell dysfunction in rats” [Biochem. Pharmacol. 231 (2025) 116641] “维替波芬联合ROCK抑制剂促进大鼠角膜内皮细胞功能障碍的恢复”的更正[生物化学]。药物学杂志，2011(5):349 - 349。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116737

Xue Zhang , Hongling Liu , Chao Wan , Yijian Li , Chunge Ren , Jia Lu , Yong Liu , Yuli Yang

引用次数: 0

Corrigendum to “Natural fucoidans inhibit coronaviruses by targeting viral spike protein and host cell furin” [Biochem. Pharmacol. 215 (2023) 115688] “天然岩藻胶通过靶向病毒刺突蛋白和宿主细胞furin抑制冠状病毒”[生物化学]的勘误。药理学杂志，2015(5):391 - 391。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2025.116753

Cheng-Wei Yang , Hsing-Yu Hsu , Yue-Zhi Lee , Jia-Tsrong Jan , Sui-Yuan Chang , Yi-Ling Lin , Ruey-Bing Yang , Tai-Ling Chao , Jian-Jong Liang , Shu-Jing Lin , Chun-Che Liao , Chih-Shin Chang , Huey-Kang Sytwu , Ming-Shiu Hung , Chiung-Tong Chen , Shiow-Ju Lee

引用次数: 0

Implication of Let7b/AhR/ARNT/HMGB1/RAGE cascade in neuroplasticity disturbances induced by glucocorticoids and the promising reversible effect of 3,3 diindolymethane: Bidirectional crosstalk of Aryl hydrocarbon receptors Let7b/AhR/ARNT/HMGB1/RAGE级联在糖皮质激素诱导的神经可塑性障碍中的意义及3,3二吲哚甲烷的有希望的可逆作用：芳烃受体的双向串扰

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116692

Mai A. Abd-Elmawla , Asmaa A. ElMonier , Enas S. Gad , Haneen Y. Khidr , May A. Azzam

Prolonged exposure to glucocorticoids (GC) disrupts neuronal architecture, hinders neuroplasticity, and triggers neuroinflammation. However, the precise underlying mechanisms have not been studied yet. The current study aimed to investigate the mechanisms of GC-induced neuroinflammatory effects by stimulating the miRNA let7b, aryl hydrocarbon receptor (AhR)/ARNT, HMGB1/RAGE, and other downstream targets. Rats were divided into 4 groups; control, GC (20 mg/kg, S.C.), 3,3′-diindolylmethane (DIM) 50 mg/kg/day, and donepezil (DNZ) 4 mg/kg/day for 21 days. Behavioral tests and histopathological investigations of cerebral cortex were done. Let7b, AhR, ARNT, and cytochrome A1A were estimated using qRT-PCR. HMGB1, RAGE, NQO1and NRF2 were estimated using ELISA, whereas GFAP and TNF-α by immunohistochemical analysis. Keap1 was estimated using Western technique. GSH and TBARS were assessed by colorimetric assay. In the current study, GC elevates the gene expressions of let7b, AhR, ARNT, and cytochrome A1A, along with the protein contents of HMGB1, RAGE, NQO1and NRF2. In addition, GC showed increased GFAP, TNF-α, and TBARS, together with decreased Keap1 and GSH. On the other side, DIM and DNZ reversed all the above-mentioned findings. Collectively, the study documents for the first time the effect of GC in upregulating let7b and activating the AhR/ARNT loop which subsequently stimulates RAGE/HMGB1 and NRF2/Keap1 cascade leading to stimulating further inflammatory and oxidative signaling pathways. Certainly, these effects are responsible for the behavioral fluctuations, the brain’s histological disruption, altered neuroplasticity, and neuroinflammation induced by GC. Moreover, DIM conquers GC-induced neuroinflammation due to its characteristic role in modulating AhR and its downstream targets.

长期暴露于糖皮质激素（GC）会破坏神经元结构，阻碍神经可塑性，并引发神经炎症。然而，确切的潜在机制尚未被研究。本研究旨在通过刺激miRNA let7b、芳烃受体(AhR)/ARNT、HMGB1/RAGE等下游靶点，探讨gc诱导神经炎症效应的机制。将大鼠分为4组；对照，GC(20 mg/kg， S.C.), 3,3'-二吲哚甲烷（DIM） 50 mg/kg/d，多奈哌齐（DNZ） 4 mg/kg/d，共21 d。进行行为学试验和大脑皮层组织病理学检查。使用qRT-PCR方法估计Let7b、AhR、ARNT和细胞色素A1A。ELISA法测定HMGB1、RAGE、nqo1、NRF2，免疫组化法测定GFAP、TNF-α。采用Western技术估计Keap1。用比色法测定GSH和TBARS。在本研究中，GC上调了let7b、AhR、ARNT和细胞色素A1A的基因表达，以及HMGB1、RAGE、nqo1和NRF2的蛋白含量。GFAP、TNF-α和TBARS升高，Keap1和GSH降低。另一方面，DIM和DNZ逆转了上述所有发现。总的来说，该研究首次证明了GC在上调let7b和激活AhR/ARNT环中的作用，该环随后刺激RAGE/HMGB1和NRF2/Keap1级联，从而刺激进一步的炎症和氧化信号通路。当然，这些影响是导致GC引起的行为波动、大脑组织破坏、神经可塑性改变和神经炎症的原因。此外，DIM由于其在调节AhR及其下游靶点方面的特殊作用，可以克服gc诱导的神经炎症。

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引用次数: 0

SIRT-2 inhibition by AK-7 orchestrates fibrotic cascades in airways through neuroimmune interaction via TRPA1, TRPM8 and TGF-β signalling AK-7对SIRT-2的抑制通过TRPA1、TRPM8和TGF-β信号传导的神经免疫相互作用调控气道纤维化级联反应。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116689

Vandana Yadav , Vinita Pandey , Pratikkumar Gaglani , Atul Srivastava , Soni , Subhashini

Chronic obstructive pulmonary diseases (COPD) is characterized by airflow limitation, chronic inflammation and airway remodeling (AR) in airways and lung parenchyma. AR, a lung response, involves mucus production, airflow issues, and structural changes. It is exacerbated by neurogenic inflammation from activated sensory nerves, highlighting the interplay between neuronal and immune regulation in COPD. Sirtuins play a crucial role in lung remodeling, with SIRT-2 being the least studied. Present study explores how SIRT-2 regulates neurogenic inflammation and fibrosis in experimental BALB/c mice with cigarette smoke-induced COPD. Mice from each group, except the control, were exposed to CS for 60 days and AK-7 (100ug/kg and 200ug/kg) was administered intranasally. The study evaluated lung injury and inflammation marked by increased Cortisol, ACTH, COX-2 and LDH in COPD group with its attenuation by SIRT-2 inhibition. Additionally, CS exposure exhibited neurogenic inflammation represented by activated TPRV1 and TRPM8, elevated neuromediators levels (dopamine, acetylcholine, substance P, serotonin) and their respective receptors which were mitigated by AK-7. CS exposure enhanced fibrosis by targeting the fibrotic cascade, enhancing MMP-9, total collagen, hydroxyproline, and upregulating αSMA, MUC5AC, TGF-β, PKA, GATA-3, FOXO3, and STAT-6. SIRT-2 inhibition effectively reversed all these factors suppressing fibrosis further supported by downregulated SIRT-2 expression and histopathological studies where collagen deposition and mucus production were also attenuated by AK-7. Molecular docking revealed strong binding affinity of certain protein such as COX-2, D5DR and 5HT with AK-7. Overall, targeting SIRT-2 to modulate neuro-immune interplay presents a promising therapeutic approach for addressing AR in COPD.

慢性阻塞性肺疾病（COPD）以气道和肺实质的气流受限、慢性炎症和气道重塑（AR）为特征。AR是一种肺部反应，包括粘液产生、气流问题和结构改变。由激活的感觉神经引起的神经源性炎症加重了慢性阻塞性肺病，突出了慢性阻塞性肺病中神经元和免疫调节之间的相互作用。Sirtuins在肺重塑中起着至关重要的作用，其中SIRT-2被研究得最少。本研究探讨了SIRT-2如何调节实验性BALB/c小鼠香烟烟雾诱导的COPD的神经源性炎症和纤维化。除对照组外，各组小鼠暴露于CS 60 天，AK-7 （100ug/kg和200ug/kg）经鼻给药。本研究评估COPD组以皮质醇、ACTH、COX-2和LDH升高为特征的肺损伤和炎症，并通过抑制SIRT-2来减弱。此外，CS暴露表现出神经源性炎症，表现为激活的TPRV1和TRPM8，升高的神经介质水平（多巴胺，乙酰胆碱，P物质，血清素）及其各自的受体，AK-7减轻。CS暴露通过靶向纤维化级联，增强MMP-9、总胶原蛋白、羟脯氨酸，上调αSMA、MUC5AC、TGF-β、PKA、GATA-3、FOXO3和STAT-6来增强纤维化。SIRT-2抑制有效地逆转了所有这些抑制纤维化的因素，这进一步得到了SIRT-2表达下调和组织病理学研究的支持，AK-7也减弱了胶原沉积和粘液产生。分子对接显示COX-2、D5DR、5HT等蛋白与AK-7具有较强的结合亲和力。总的来说，靶向SIRT-2调节神经免疫相互作用是解决COPD中AR的一种有希望的治疗方法。

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引用次数: 0

Novel-designed antimicrobial peptides with dual antimicrobial and anti-inflammatory actions against Cutibacterium acnes for acne vulgaris therapy 新设计的抗菌肽具有双重抗菌和抗炎作用对抗痤疮表皮杆菌治疗寻常痤疮。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116708

Hyun Kim , Ju Hye Jang , Ha Rang Kim , Ju Hyun Cho

Acne vulgaris is a prevalent skin condition among adolescents, primarily instigated by over-colonization and subsequent inflammation triggered by Cutibacterium acnes. Although topical and oral antibiotics are standard treatments, they often lead to the proliferation of antibiotic-resistant bacteria and are associated with undesirable side effects. Antimicrobial peptides (AMPs) are considered a promising solution to these challenges. In this study, we aimed to develop novel short AMPs to combat C. acnes. By comparing sequences and abstracting the distribution of residue types of established AMPs, we derived a sequence template. Using this template, we crafted novel anti-C. acnes peptides comprising 13 amino acid residues. To enhance their potential therapeutic application, we designed a series of peptides by varying the number and position of the tryptophan residues. Among these peptides, DAP-7 and DAP-10 demonstrated potent antimicrobial activity against both antibiotic-susceptible and -resistant strains of C. acnes, with minimal cytotoxicity. The antimicrobial action of these peptides was attributed to their ability to target the bacterial membrane, resulting in permeabilization and rupture. Moreover, DAP-7 and DAP-10 effectively reduced the expression of pro-inflammatory cytokines induced by C. acnes and remained stable for up to 12 h after exposure to proteases found in acne lesions. Notably, DAP-7 decreased the C. acnes colonies on the ears and significantly alleviated C. acnes-induced ear swelling in a mouse model. Our findings suggest that the DAP-7 and DAP-10 peptides hold promise as candidates for developing a new acne vulgaris treatment.

寻常痤疮是青少年中普遍存在的一种皮肤状况，主要是由痤疮表皮杆菌引发的过度定植和随后的炎症引起的。虽然局部和口服抗生素是标准的治疗方法，但它们经常导致抗生素耐药细菌的增殖，并伴有不良副作用。抗菌肽（AMPs）被认为是解决这些挑战的有希望的解决方案。在这项研究中，我们的目标是开发新的短AMPs来对抗痤疮。通过对已建立的AMPs序列进行比较，提取其残基类型分布，推导出一个序列模板。利用这个模板，我们制作了新的抗c。含有13个氨基酸残基的痤疮肽。为了提高其潜在的治疗应用，我们通过改变色氨酸残基的数量和位置设计了一系列肽。在这些肽中，DAP-7和DAP-10显示出对抗生素敏感和耐药菌株的有效抗菌活性，并且具有最小的细胞毒性。这些肽的抗菌作用归因于它们靶向细菌膜的能力，导致渗透和破裂。此外，DAP-7和DAP-10有效降低了痤疮C. acnes诱导的促炎细胞因子的表达，并在暴露于痤疮病变中发现的蛋白酶后保持稳定长达12 h。值得注意的是，DAP-7减少了痤疮C.菌落在耳上，显著减轻了痤疮C.引起的小鼠耳肿胀。我们的研究结果表明，DAP-7和DAP-10肽有望开发一种新的寻常性痤疮治疗方法。

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引用次数: 0

Sleep deprivation alters hepatic UGT1A9 and propofol metabolism in mice 睡眠剥夺改变小鼠肝脏UGT1A9和异丙酚代谢。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116713

Zhiqian Yan , Linna Ha , Hui Chen , YiFei Xiao , Min Chen , Baojian Wu , Haiman Xu , Dong Dong

Sleep deprivation (SD) causes circadian misalignment, and circadian clock disruption is associated with metabolic diseases such as obesity, insulin resistance, and diabetes. However, the underlying mechanism for SD-induced circadian clock disruption as well as metabolic enzyme changes is still lacking. Here, we developed SD sensitizes mice with disrupted circadian rhythms to demonstrate the regulation role and mechanism of SD in UDP-glucuronosyltransferases (UGTs) expression and the metabolism of corresponding substrates. We found that UGT Family 1 Member A9 (UGT1A9) expression was significantly decreased in the liver of SD mice, which led to an elevation exposure and prolonged anesthesia effect of propofol, which was attributed to the decreased metabolism. Meanwhile, SD down-regulated basic helix-loop-helix ARNT like 1 (BMAL1) and its target clock genes period circadian clock (Per), cryptochrome circadian regulator (Cry), and nuclear receptor subfamily 1 group D member 1 (Rev-erb) expression in mice. Furthermore, the positive regulation of UGTIA9 mRNA and protein levels by Bmal1 was confirmed in hepatocyte-specific Bmal1-knockout mice (Bmal1-hkO) and Bmal1-overexpressed AML-12 cells. At last, through a combination of promoter analysis, luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay, it was conducted that Bmal1 regulates Ugtla9 expression by directly binding the −864 bp E-box in Ugtla9 promotor or indirectly acting on the Rev-erbα- differentiated embryo chondrocyte 2 (Dec2) axis. In conclusion, our findings suggested that SD can lead to altered drug disposition and effects in vivo, and Bmal1 plays a crucial role in the crosstalk between SD-induced circadian clock disruption and drug metabolism. It initiates a new direction for the understanding of drug efficacy and toxicity changes in SD conditions and provides a scientific basis for improving the rationality of drug use.

睡眠剥夺（SD）会导致昼夜节律失调，而昼夜节律紊乱与肥胖、胰岛素抵抗和糖尿病等代谢性疾病有关。然而，SD 诱导昼夜节律紊乱以及代谢酶变化的内在机制仍然缺乏研究。在此，我们培养了昼夜节律紊乱的SD致敏小鼠，以证明SD对UDP-葡萄糖醛酸转移酶（UGTs）表达和相应底物代谢的调节作用和机制。我们发现，SD小鼠肝脏中UGT家族1号成员A9（UGT1A9）的表达明显降低，导致丙泊酚的暴露量升高和麻醉效应延长，这与代谢降低有关。同时，SD下调了小鼠体内碱性螺旋环螺旋ARNT样1（BMAL1）及其靶时钟基因周期昼夜节律钟（Per）、隐色素昼夜节律调节因子（Cry）和核受体亚家族1 D群成员1（Rev-erb）的表达。此外，在肝细胞特异性 Bmal1 基因敲除小鼠（Bmal1-hkO）和 Bmal1 基因表达的 AML-12 细胞中，证实了 Bmal1 对 UGTIA9 mRNA 和蛋白水平的正向调控。最后，通过启动子分析、荧光素酶报告实验和染色质免疫沉淀（ChIP）实验，研究发现Bmal1通过直接结合Ugtla9启动子中的-864 bp E-box或间接作用于Rev-erbα-分化胚胎软骨细胞2（Dec2）轴来调控Ugtla9的表达。总之，我们的研究结果表明，SD可导致体内药物处置和效应的改变，而Bmal1在SD诱导的昼夜节律紊乱和药物代谢之间的串扰中起着至关重要的作用。该研究为了解SD条件下药物疗效和毒性变化开辟了新方向，为提高药物使用的合理性提供了科学依据。

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引用次数: 0

Transcriptomic data integration and analysis revealing potential mechanisms of doxorubicin resistance in chondrosarcoma cells 转录组数据整合和分析揭示了软骨肉瘤细胞中阿霉素耐药的潜在机制。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116733

Jui-Chieh Chen , Ming-Shan Chen , Shin-Kuang Jiang , Chi-Yang Eaw , Yu-Jiao Han , Chih-Hsin Tang

Chondrosarcoma is a type of bone cancer that originates from cartilage cells. In clinical practice, surgical resection is the primary treatment for chondrosarcoma, but chemotherapy becomes essential for patients with metastasis or tumors in surgically inaccessible sites. However, drug resistance often leads to treatment failure. Tumor microenvironment proteins modulate intercellular communication, contributing to drug resistance. Doxorubicin (Dox) is a common chemotherapeutic agent.

The present study aimed to establish Dox-resistant chondrosarcoma cells and compare their secretome with parental cells using antibody arrays. Results showed significantly heightened secretion of hepatocyte growth factor (HGF). Knockdown of both HGF and its receptor MET increased Dox sensitivity in chondrosarcoma cells. Treatment of chondrosarcoma cells with conditioned media (CM) from cells secreting high levels of HGF resulted in MET activation. Additionally, the expression levels of HGF and MET were significantly elevated in chondrosarcoma tissues compared to normal cartilage tissues, as confirmed by analysis of GEO database. RNA sequencing and Gene Set Enrichment Analysis (GSEA) elucidated the mechanism involving HGF. Additionally, genes with log fold change > 1 underwent bioinformatics analysis using the ShinyGO web server. The results from both GSEA and ShinyGO analyses corroborate each other, indicating the significance of HGF in cellular signal transduction, regulation of cell motility, developmental processes, immune-inflammatory responses, and functions related to blood and neural systems.

In summary, highly secreted HGF can activate signaling pathways through its receptor MET, particularly Ras and Akt activation, enhancing drug resistance in chondrosarcoma cells. The present study may guide the development of novel therapeutic strategies targeting HGF, ultimately improving treatment outcomes and prognosis for malignant chondrosarcoma patients.

软骨肉瘤是一种起源于软骨细胞的骨癌。在临床实践中，手术切除是软骨肉瘤的主要治疗方法，但对于转移或手术无法到达部位的肿瘤患者，化疗是必不可少的。然而，耐药往往导致治疗失败。肿瘤微环境蛋白调节细胞间通讯，促进耐药。阿霉素（Dox）是一种常用的化疗药物。本研究旨在建立dox抗性软骨肉瘤细胞，并使用抗体阵列将其分泌组与亲本细胞进行比较。结果显示肝细胞生长因子（HGF）分泌明显增加。抑制HGF及其受体MET可增加软骨肉瘤细胞对Dox的敏感性。用分泌高水平HGF的细胞的条件培养基（CM）治疗软骨肉瘤细胞导致MET激活。此外，与正常软骨组织相比，软骨肉瘤组织中HGF和MET的表达水平显著升高，这一点通过GEO数据库的分析得到了证实。RNA测序和基因集富集分析（GSEA）阐明了与HGF有关的机制。此外，使用ShinyGO web服务器对具有log fold变化 > 1的基因进行生物信息学分析。GSEA和ShinyGO分析的结果相互证实，表明HGF在细胞信号转导、细胞运动调节、发育过程、免疫炎症反应以及与血液和神经系统相关的功能中具有重要意义。综上所述，高分泌的HGF可以通过其受体MET激活信号通路，特别是Ras和Akt的激活，增强软骨肉瘤细胞的耐药性。本研究可能指导开发针对HGF的新型治疗策略，最终改善恶性软骨肉瘤患者的治疗效果和预后。

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引用次数: 0

Advancements in understanding the role and mechanism of sirtuin family (SIRT1-7) in breast cancer management sirtuin家族（SIRT1-7）在乳腺癌治疗中的作用及机制研究进展

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2025.116743

Deepak Sharma , Muthukumaran Panchaksaram , Rajiniraja Muniyan

Breast cancer (BC) is the most prevalent type of cancer in women worldwide and it is classified into a few distinct molecular subtypes based on the expression of growth factor and hormone receptors. Though significant progress has been achieved in the search for novel medications through traditional and advanced approaches, still we need more efficacious and reliable treatment options to treat different types and stages of BC. Sirtuins (SIRT1-7) a class III histone deacetylase play a major role in combating various cancers including BC. Studies reveal that each sirtuin has a unique and well-balanced biology, indicating that it regulates a variety of biological processes that result in the initiation, progression, and metastasis of BC. SIRT also plays a major role in numerous vital biological functions, including apoptosis, axonal protection, transcriptional silencing, DNA recombination and repair, fat mobilization, and aging. As per the current demand, we wish to outline the structural insights into sirtuin’s catalytic site, substantial variations among all SIRT types, and their mechanism in BC management. Additionally, this review will focus on the application of SIRT modulators along with their clinical significance, hurdles, and future perspective to develop successful SIRT-based drug candidates to conquer the BC problem.

乳腺癌（BC）是全世界女性中最常见的癌症类型，根据生长因子和激素受体的表达，它被分为几个不同的分子亚型。尽管在通过传统和先进方法寻找新型药物方面取得了重大进展，但我们仍然需要更有效和可靠的治疗方案来治疗不同类型和阶段的BC。Sirtuins （SIRT1-7）是III类组蛋白去乙酰化酶，在对抗包括BC在内的多种癌症中发挥重要作用。研究表明，每种sirtuin都具有独特且平衡良好的生物学特性，表明它调节了导致BC发生、进展和转移的多种生物学过程。SIRT还在许多重要的生物学功能中发挥重要作用，包括细胞凋亡、轴突保护、转录沉默、DNA重组和修复、脂肪动员和衰老。根据目前的需求，我们希望概述sirtuin催化位点的结构见解，所有SIRT类型之间的实质性差异，以及它们在BC管理中的机制。此外，本文将重点介绍SIRT调节剂的应用及其临床意义、障碍和未来发展前景，以成功开发基于SIRT的候选药物来克服BC问题。

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引用次数: 0