Biochemical pharmacology最新文献_第10页

AURKB and circAURKB_288aa enhance Esophageal cancer drug resistance through inducing abnormal centrosome separation AURKB和circAURKB_288aa通过诱导中心体异常分离增强食管癌耐药。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116691

Hongzhen Lv , Jing Zhou , Limin Qiu , Xiaozhu Tang , Cheng Huang

Esophageal cancer (EC) is one of the most fatal malignancies worldwide, with a dramatic increase in incidence in the western world occurring over the past few decades. Chromosome instability (CIN) is a major contributor to EC progression, drug resistance, relapse, and the development of intratumoral heterogeneity. This study revealed a striking elevation of AURKB expression in EC patients, with a strong correlation to poor clinical outcomes. AURKB overexpression promoted cellular proliferation and induced drug resistance in both cell culture and animal models. Conversely, genetic targeting of AURKB abrogated these effects. Mechanistically, enforced AURKB expression triggered CIN, a key driver of poor EC outcomes, primarily through CEP250 phosphorylation. Interestingly, we identified a novel circular form of AURKB (circAURKB_288aa) harboring the AURKB kinase domain and encoding a 288-amino acid protein. Elevated levels of circAURKB_288aa in EC peripheral blood samples mirrored poor patient outcomes and synergistically enhanced CIN alongside AURKB. Furthermore, EC cells were capable of secreting circAURKB_288aa, influencing tumor microenvironmental cells similarly to full-length AURKB protein. Notably, AURKB siRNA targeting the shared kinase domain of both AURKB and circAURKB_288aa significantly inhibited EC malignancy. Collectively, these findings establish AURKB and circAURKB_288aa as promising targets for EC prognosis and therapy.

食管癌（EC）是世界范围内最致命的恶性肿瘤之一，在过去的几十年里，西方世界的发病率急剧上升。染色体不稳定性（CIN）是EC进展、耐药、复发和肿瘤内异质性发展的主要因素。这项研究显示，在EC患者中，AURKB表达显著升高，与不良的临床结果有很强的相关性。在细胞培养和动物模型中，AURKB过表达促进细胞增殖并诱导耐药。相反，AURKB的基因靶向消除了这些影响。从机制上讲，强制的AURKB表达主要通过CEP250磷酸化触发CIN，这是EC预后不良的关键驱动因素。有趣的是，我们发现了一种新的圆形AURKB (circAURKB_288aa)，它包含AURKB激酶结构域，编码一个含有288个氨基酸的蛋白。EC外周血样本中circAURKB_288aa水平升高反映了患者预后不佳，并与AURKB协同增强了CIN。此外，EC细胞能够分泌circAURKB_288aa，影响肿瘤微环境细胞，类似于全长AURKB蛋白。值得注意的是，靶向AURKB和circAURKB_288aa的共享激酶结构域的AURKB siRNA显著抑制EC恶性肿瘤。总的来说，这些发现确定了AURKB和circAURKB_288aa是EC预后和治疗的有希望的靶点。

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引用次数: 0

JOSD2 promotes breast cancer metastasis by deubiquitinating and stabilizing SMAD4 JOSD2通过去泛素化和稳定SMAD4促进乳腺癌转移。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2025.116748

Jiamin Du , Jiao Wang , Fujing Ge , Hongrui Ma , Hongdao Zhu , Jiangxia Du , Fangjie Yan , Qiaojun He , Bo Yang , Tao Yuan , Hong Zhu

Breast cancer is one of the most common malignant tumors among women worldwide, and its high degree of metastasis significantly impacts treatment effectiveness leading to poor prognosis. The potential molecular mechanisms underlying breast cancer metastasis remain to be further elucidated. In this study, via database analysis, we revealed that the deubiquitinase josephin domain containing 2 (JOSD2) was abnormally amplified in patients with metastatic breast cancer, and was significantly negatively correlated with patient prognosis. By integrating data from the Gene Expression Omnibus (GEO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis, we found that the transforming growth factor beta (TGF-β) signaling pathway was significantly activated in breast cancer patients with increased JOSD2 expression. Further studies revealed that JOSD2 interacted with and stabilized SMAD family member 4 (SMAD4) by removing polyubiquitin chains. Inhibition of JOSD2 by RNA interference effectively inhibited the metastasis of breast cancer cells both in vitro and in vivo. In conclusion, our study not only reveals the role of JOSD2 in promoting breast cancer metastasis for the first time, but also indicates promising directions for the future development of deubiquitinase inhibitors, which could yield significant therapeutic benefits. Nevertheless, extensive research and development are required to fully realize this potential.

乳腺癌是世界范围内女性最常见的恶性肿瘤之一，其转移程度高，严重影响治疗效果，导致预后不良。乳腺癌转移的潜在分子机制仍有待进一步阐明。本研究通过数据库分析发现，转移性乳腺癌患者脱泛素酶josephin结构域2 （JOSD2）异常扩增，且与患者预后呈显著负相关。通过整合Gene Expression Omnibus （GEO）数据库数据和京都基因与基因组百科全书（KEGG）信号通路富集分析，我们发现JOSD2表达升高的乳腺癌患者转化生长因子β (TGF-β)信号通路显著激活。进一步的研究表明，JOSD2通过去除多泛素链与SMAD家族成员4 （SMAD4）相互作用并稳定SMAD4。RNA干扰抑制JOSD2在体内和体外均能有效抑制乳腺癌细胞的转移。总之，我们的研究不仅首次揭示了JOSD2在促进乳腺癌转移中的作用，也为未来去泛素酶抑制剂的开发指明了有希望的方向，这些抑制剂可能会产生显著的治疗效益。然而，要充分发挥这一潜力，还需要进行广泛的研究和开发。

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引用次数: 0

SMURF1 leads to the β-catenin signaling-mediated progression of esophageal squamous carcinoma by losing PATZ1-induced CCNG2 transcription SMURF1通过丢失patz1诱导的CCNG2转录，导致β-catenin信号介导的食管鳞状癌进展。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116688

Lingling Chen , Jie Tang , Yunli Chang , Dongyun Hang , Jieru Ji , Guoyu Chen

Cyclin G2 (CCNG2), a known inhibitor of cell cycle progression, has been identified as a suppressor for the canonical β-catenin pathway. This study explores the impact of CCNG2 on β-catenin activity and malignant characteristics of esophageal squamous cell carcinoma (ESCC) cells, and the mechanism behind CCNG2 dysregulation. In ESCC tissues and cells, CCNG2 was under-expressed and associated with poor clinical outcomes, whereas β-catenin showed an opposite trend. Inducing CCNG2 overexpression in ESCC cells led to a reduction in β-catenin levels, which in turn suppressed proliferation, cell cycle progression, migration, invasion, stemness, and tumorigenesis. Additionally, it enhanced the cytotoxicity and proliferation of T cells in co-culture systems. However, these beneficial effects were negated by the Wnt signaling agonist BML-284. Furthermore, PATZ1 was found as a transcription factor promoting CCNG2 transcription. However, the PATZ1 protein in ESCC cells was degraded by SMURF1. Silencing of SMURF1 restored CCNG2 expression and inhibited β-catenin, thereby suppressing the malignant phenotype of ESCC cells and reducing T cell exhaustion. Yet, these effects were blocked by further silencing of PATZ1. In summary, this research demonstrates that SMURF1 activates β-catenin signaling by suppressing the PATZ1/CCNG2 axis, thereby promoting the progression of ESCC.

细胞周期蛋白G2 （CCNG2）是一种已知的细胞周期进程抑制剂，已被确定为典型β-catenin通路的抑制因子。本研究探讨CCNG2对食管鳞状细胞癌（ESCC）细胞β-catenin活性和恶性特征的影响，以及CCNG2失调的机制。在ESCC组织和细胞中，CCNG2低表达且与较差的临床结果相关，而β-catenin则呈现相反的趋势。在ESCC细胞中诱导CCNG2过表达导致β-catenin水平降低，从而抑制增殖、细胞周期进展、迁移、侵袭、干性和肿瘤发生。此外，它还增强了共培养系统中T细胞的细胞毒性和增殖能力。然而，这些有益作用被Wnt信号激动剂BML-284所抵消。此外，还发现PATZ1是促进CCNG2转录的转录因子。然而，ESCC细胞中的PATZ1蛋白被SMURF1降解。沉默SMURF1恢复CCNG2表达，抑制β-catenin，从而抑制ESCC细胞的恶性表型，减少T细胞衰竭。然而，这些作用通过进一步沉默PATZ1而被阻断。综上所述，本研究表明SMURF1通过抑制PATZ1/CCNG2轴激活β-catenin信号通路，从而促进ESCC的进展。

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引用次数: 0

The function and mechanism of clinical trial agent CPI-613 in multiple myeloma 临床试验药物CPI-613治疗多发性骨髓瘤的作用及机制。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116717

Haiqin Wang , Yibin Zhang , Yu Jiang , Ruohong Xiang , Han Gong , Yanfei Gong , Hao Xu , Zekang Ma , Yifang Xie , Yu Zhu , Bin Hu , Xiao He , Jing Liu , Ji Zhang , Xiaojuan Xiao

Multiple myeloma (MM) is an incurable malignant hematological neoplasm characterized by clonal proliferation of plasma cells accumulating in the bone marrow. Currently, the treatment of MM is usually based on a multi-drug combination strategy, and the remission rates of MM patients have been greatly improved. However, MM is still not immune to drug resistance and recurrence and is an incurable tumor. In this study, a comprehensive screen of the TCA cycle identified oxoglutarate dehydrogenase (OGDH) and pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) as the most clinically relevant genes in MM, highlighting their potential as therapeutic targets. CPI-613, a novel non-redox-active lipoic acid analog that causes mitochondrial metabolism dysfunction by targeting OGDH and PDHA1, is currently in clinical trials in a variety of malignancies. In our study, CPI-613 was found to inhibit the proliferation of MM cells, and its combination with bortezomib (BTZ) produced a significant inhibitory effect at lower doses. In addition, CPI-613 can disrupt various mitochondrial functions, such as disrupting mitochondrial morphology, reducing oxidative phosphorylation, decreasing 5′- adenylate triphosphate production, and increasing reactive oxygen species, which ultimately leads to cell death mediated by the intrinsic apoptotic pathway in vitro. Furthermore, we found CPI-613 significantly inhibited tumor growth and induced intrinsic apoptosis in the MM mouse xenograft model. This study reveals the mechanism and effect of CPI-613 in MM, which suggests that CPI-613 may be a new drug option for the clinical treatment of MM, but further clinical trials are needed for evaluation.

多发性骨髓瘤（MM）是一种无法治愈的恶性血液肿瘤，其特征是积聚在骨髓中的浆细胞克隆性增殖。目前，治疗 MM 通常采用多种药物联合治疗的策略，MM 患者的缓解率已大大提高。然而，MM仍无法避免耐药和复发，是一种无法治愈的肿瘤。本研究对TCA循环进行了全面筛选，发现氧戊二酸脱氢酶（OGDH）和丙酮酸脱氢酶E1亚基α1（PDHA1）是MM中与临床最相关的基因，凸显了它们作为治疗靶点的潜力。CPI-613是一种新型非氧化还原活性硫辛酸类似物，可通过靶向OGDH和PDHA1导致线粒体代谢功能障碍，目前正在对多种恶性肿瘤进行临床试验。在我们的研究中发现，CPI-613 可抑制 MM 细胞的增殖，与硼替佐米（BTZ）联用在较低剂量时也能产生显著的抑制作用。此外，CPI-613还能破坏线粒体的多种功能，如破坏线粒体形态、降低氧化磷酸化、减少5'-腺苷酸三磷酸酯的产生、增加活性氧等，最终导致体外固有凋亡途径介导的细胞死亡。此外，我们还发现 CPI-613 在 MM 小鼠异种移植模型中能显著抑制肿瘤生长并诱导细胞内在凋亡。这项研究揭示了CPI-613在MM中的作用机制和效果，这表明CPI-613可能是临床治疗MM的一种新药选择，但还需要进一步的临床试验进行评估。

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引用次数: 0

Runcaciguat activates soluble guanylyl cyclase via the histidine essential for heme binding and nitric oxide activation Runcaciguat通过组氨酸激活可溶性胍基环化酶，组氨酸是血红素结合和一氧化氮激活所必需的。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2025.116739

Theresa Wittrien , Anne Rühle , Christin Elgert , Ilka Mathar , Peter Sandner , Sönke Behrends

Soluble guanylyl cyclase (sGC) is a well-established pharmacological target for the treatment of acute angina pectoris, pulmonary hypertension and heart failure. Histidine 105 in the heme binding pocket of sGC is a crucial residue for heme binding and natural enzyme activation by NO. It was assumed that the heme-free sGC mutants α₁/β₁H105F and α₁/β₁H105A were valuable research tools for studying NO independent sGC activators. These mutants have been used in drug screening and animal models. We confirm that the first generation of sGC activators cinaciguat and BAY 60-2770 activate the α₁/β₁H105F and α₁/β₁H105A mutants. In contrast, we show that the second generation sGC activators runcaciguat and BAY 543 only activate heme-free sGC when the β₁H105 residue is present. By testing runcaciguat in β₁ H105F knock-in mice, we confirm this histidine-dependency in vivo. We propose a novel classification of sGC activators, distinguishing between the histidine-dependent activators runcaciguat and BAY 543 and the histidine-independent activators cinaciguat, BAY 60-2770 and BI 703704. The histidine-dependency of some of the sGC activators provides a compelling rationale for a re-evaluation of previous research and drug development programs based on sGC histidine mutants. Whether the classification of sGC activators based on the activation mechanism also makes a therapeutic difference needs to be clarified in the future.

可溶性胍基环化酶（sGC）是治疗急性心绞痛、肺动脉高压和心力衰竭的有效药物靶点。sGC血红素结合口袋中的组氨酸105是血红素结合和天然酶被NO激活的关键残基。我们认为无血红素sGC突变体α1/β1H105F和α1/β1H105A是研究NO独立sGC激活剂的有价值的研究工具。这些突变体已用于药物筛选和动物模型。我们证实第一代sGC激活剂cinaciguat和BAY 60-2770可以激活α1/β1H105F和α1/β1H105A突变体。相反，我们发现第二代sGC活化剂runcaciguat和BAY 543仅在β1H105残基存在时才能激活无血红素的sGC。通过在β 1h105f敲入小鼠中测试runcaciguat，我们在体内证实了这种组氨酸依赖性。我们提出了一种新的sGC激活剂分类方法，将依赖组氨酸的激活剂runcaciguat和BAY 543与不依赖组氨酸的激活剂cinaciguat， BAY 60-2770和BI703704区分开来。一些sGC激活剂的组氨酸依赖性为重新评估先前基于sGC组氨酸突变体的研究和药物开发计划提供了令人信服的理由。基于激活机制的sGC激活剂分类是否也会对治疗产生影响，还需要在未来进一步明确。

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引用次数: 0

Therapeutic evaluation of glycoprotein hormone β5/α2 in reducing obesity and metabolic dysfunctions in genetically obese ob/ob mice 糖蛋白激素β5/α2在减轻遗传性肥胖ob/ob小鼠肥胖和代谢功能障碍中的治疗评价。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116710

Aijun Qian , Gengmiao Xiao , Zhuang Li , Yunping Mu , Xiaohong Liu , Xue Tian , Jianqin Yang , Allan Z. Zhao , Fanghong Li

The escalating obesity epidemic poses serious public health challenges, requiring the development of effective therapeutic strategies. In this study, we aimed to determine if recombinant glycoprotein hormone β5 (GPHB5) protein, particularly in the hybrid form with glycoprotein hormone α2 (GPHA2) (recombinant corticotroph-derived glycoprotein hormone, rCGH), can alleviate obesity in the genetically obese mice, ob/ob. Six-week-old male ob/ob mice were intraperitoneally injected for four weeks with rCGH (10 mg/kg) treatment. Body weight, fat mass and lean mass as well as energy expenditure were evaluated. Blood samples were collected to assess circulating concentrations of triiodothyronine (T3) and thyroxine (T4). Glucose and insulin tolerance tests were also conducted. rCGH significantly decreased body weight and fat mass, stimulated energy expenditure without alterations in food consumption, induced lipolysis and browning of white adipose tissue (WAT) by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway. The treatment with the recombinant protein also led to marked reduction in hepatic steatosis, improved glucose tolerance and insulin sensitivity, and reduced triglycerides (TG), and total cholesterol (T-CHO) levels in ob/ob mice. In conclusion, rCGH attenuated obesity and alleviated metabolic syndromes in ob/ob mice, and it may represent a promising polypeptide-based drug candidate in treating obesity and obesity-related complications without interfering energy intake.

不断升级的肥胖流行病构成了严重的公共卫生挑战，需要制定有效的治疗策略。在这项研究中，我们旨在确定重组糖蛋白激素β5 （GPHB5）蛋白，特别是与糖蛋白激素α2 (GPHA2)（重组促肾上腺皮质激素衍生糖蛋白激素，rCGH）的杂交形式，是否可以减轻遗传性肥胖小鼠的肥胖，ob/ob。6周龄雄性ob/ob小鼠腹腔注射rCGH(10 mg/kg) 4周。评估了体重、脂肪质量和瘦质量以及能量消耗。采集血液样本评估三碘甲状腺原氨酸（T3）和甲状腺素（T4）的循环浓度。葡萄糖和胰岛素耐量试验也进行了。rCGH通过激活环磷酸腺苷(cAMP)/蛋白激酶A （PKA）信号通路，显著降低体重和脂肪量，在不改变食物消耗的情况下刺激能量消耗，诱导脂肪分解和白色脂肪组织（WAT）褐变。重组蛋白治疗还显著降低了ob/ob小鼠的肝脂肪变性，改善了葡萄糖耐量和胰岛素敏感性，降低了甘油三酯（TG）和总胆固醇（T-CHO）水平。综上所述，rCGH减轻了ob/ob小鼠的肥胖和代谢综合征，它可能是一种有前途的多肽药物，可以在不干扰能量摄入的情况下治疗肥胖和肥胖相关并发症。

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引用次数: 0

Berberine enhances autophagic flux to alleviate ischemic neuronal injury by facilitating N-ethylmaleimide-sensitive factor-mediated fusion of autophagosomes with lysosomes 小檗碱通过促进 N-乙基马来酰亚胺敏感因子介导的自噬体与溶酶体融合，增强自噬通量以缓解缺血性神经元损伤。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116715

Wenting Zhuang , Zhiwen Huang , Liling Yu, Meilin Yu, Hongyun He, Yihao Deng

Our previous study demonstrated that Berberine (BBR) significantly enhances autophagic flux, alleviating ischemic neuronal injury by restoring autolysosomal function, but how BBR augmented autolysosomal functions remained elusive. N-ethyl-maleimide sensitive factor (NSF) is considered as a major ATPase to reactivate soluble NSF attachment protein receptors (SNAREs), which directly mediate autophagosome-lysosome fusion. However, NSF was dramatically inactivated by ischemia to hamper membrane-membrane fusion, leading to autophagic/lysosomal dysfunction in neurons. This study was to investigate whether BBR-ameliorated autophagic flux was exerted by reinforcing NSF activity, which subsequently boosted autophagosome-lysosome fusion in ischemic neurons. Rat model of ischemic stroke and neuronal ischemia model of HT22 cells were prepared by middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD), respectively. BBR was intraperitoneally administrated with 100 mg/Kg/d for 3 days before MCAO and was treated with 90 μM in HT22 neurons for 12 h, respectively. The results illustrated that NSF activity was markedly reinforced to facilitate autophagosome-lysosome fusion in penumbral cells and OGD HT22 neurons by BBR treatment. Consequently, the ischemia-created autophagic/lysosomal dysfunction was greatly restored to alleviate ischemic injury. Thereafter, NSF activity in OGD HT22 neurons was altered by transfection with NSF-overexpressing lentiviruses and siRNA-mediated knockdown, respectively. The data showed that BBR-enhanced autophagic flux and it-induced neuroprotection were greatly counteracted by NSF knockdown. By contrast, NSF overexpression synergistically boosted autophagosome-lysosome fusion and further attenuated neuronal death upon BBR treatment. Therefore, our study indicates that BBR-conferred neuroprotection against ischemic stroke is induced through facilitating autophagosome-lysosome fusion, by which enhancing autophagic flux in ischemic neurons.

我们之前的研究表明，小檗碱（Berberine， BBR）可显著增强自噬通量，通过恢复自溶酶体功能来减轻缺血性神经元损伤，但BBR如何增强自溶酶体功能尚不清楚。n -乙基马来酰亚胺敏感因子（NSF）被认为是重新激活可溶性NSF附着蛋白受体（SNAREs）的主要atp酶，其直接介导自噬体与溶酶体的融合。然而，缺血导致NSF显著失活，阻碍膜-膜融合，导致神经元自噬/溶酶体功能障碍。本研究旨在探讨bbr改善的自噬通量是否通过增强NSF活性来发挥作用，从而促进缺血神经元的自噬体-溶酶体融合。采用大脑中动脉闭塞法（MCAO）和氧糖剥夺法（OGD）分别制备大鼠缺血性卒中模型和HT22细胞神经元缺血模型。在MCAO前3 天，BBR腹腔灌胃100 mg/Kg/d， HT22神经元灌胃90 μM，灌胃12 h。结果表明，BBR处理显著增强了半影细胞和OGD HT22神经元的NSF活性，促进了自噬体与溶酶体的融合。因此，缺血造成的自噬/溶酶体功能障碍大大恢复，减轻缺血损伤。随后，通过转染过表达NSF的慢病毒和sirna介导的敲低分别改变了OGD HT22神经元中NSF的活性。数据显示，bbr增强的自噬通量及其诱导的神经保护作用被NSF敲低大大抵消。相比之下，NSF过表达协同促进了自噬体-溶酶体融合，并进一步减轻了BBR治疗后神经元的死亡。因此，我们的研究表明，bbr对缺血性卒中的神经保护作用是通过促进自噬体与溶酶体的融合，从而增强缺血神经元的自噬通量而诱导的。

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引用次数: 0

Estrogenic actions of alkaloids: Structural characteristics and molecular mechanisms 生物碱的雌激素作用：结构特征和分子机制。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116645

Ryoiti Kiyama , Yuko Wada-Kiyama

This comprehensive review of estrogenic alkaloids reveals that although the number is small, they exhibit a wide range of structures, biosynthesis pathways, mechanisms of action, and applications. Estrogenic alkaloids belong to different classes, different biosynthetic pathways, different estrogenic actions (estrogenic/synergistic, anti-estrogenic/antagonistic, biphasic, and acting as a selective estrogen receptor modulator or SERM), different receptor-initiated signaling pathways, different ways of modulations of estrogen action, and different applications. The future applications of estrogenic alkaloids, such as those for diagnostics, drug development, and therapeutics, are considered with the help of new databases containing comprehensive descriptions of their relationships and more elaborate artificial intelligence-based prediction technologies. Structure-activity studies reveal the significance of the nitrogen atom for their structural and functional diversity, which may help support their broader applications. Based on the summary of previous reports, estrogenic alkaloids have significant potential for future applications.

这篇关于雌激素生物碱的综述揭示，虽然雌激素生物碱的数量不多，但它们的结构、生物合成途径、作用机制和应用范围却十分广泛。雌激素生物碱属于不同的类别、不同的生物合成途径、不同的雌激素作用（雌激素/协同作用、抗雌激素/拮抗作用、双相作用以及作为选择性雌激素受体调节剂或 SERM）、不同的受体启动信号传导途径、不同的雌激素作用调节方式以及不同的应用。雌激素生物碱的未来应用，如诊断、药物开发和治疗，将借助包含对其关系的全面描述的新数据库和更复杂的基于人工智能的预测技术来考虑。结构-活性研究揭示了氮原子对其结构和功能多样性的重要性，这可能有助于支持其更广泛的应用。根据以往报告的总结，雌激素生物碱在未来的应用中具有巨大的潜力。

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引用次数: 0

Multi-target anti-MRSA mechanism and antibiotic synergistic effect of marine alkaloid Ascomylactam A in vitro and in vivo against clinical MRSA strains 海洋生物碱Ascomylactam A体外和体内抗MRSA多靶点机制及抗生素协同作用。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116697

Ke-Yue Wu , Fei-Hua Yao , Xu-Meng Ren , Xu-Dong Hang , Yue-Fan Bai , Shu-Hua Qi

Methicillin-resistant Staphylococcus aureus (MRSA), as a kind of multi-drug resistant bacteria, often causes serious sanitary infection problems. Marine fungi are seen as a promising source of lead compounds for antibiotics. In this research, the antibacterial activity, antibiotic synergistic effect and mechanism of the alkaloid Ascomylactam A (AsA) derived from the marine fungus Microascus sp. SCSIO 41821 were investigated in vivo and in vitro. Antibacterial assays showed that AsA had excellent antibacterial activity and inhibition of biofilm formation against MRSA SC41993, and exhibitted synergistic antibacterial effects with clinical antibiotics. Transcriptomics revealed the potential mechanism that AsA affected the formation of MRSA biofilm, cell wall synthesis and virulence through LytSR, VraSR, ArgAC and KdpDE two-component system (TCS). In addition, by treatment with AsA, it was found that AdhE protein was a potential target for oxidative stress and lipid peroxidation in MRSA, and the resistance of MRSA was reversed by regulating some genes. In vivo experiments showed that AsA combined with gentamicin sulfate (GMS) had a better therapeutic effect than alone against clinical MRSA USA300, especially in the heart. In this study, the antibacterial mechanism of decahydrofluorene-class alkaloids was preliminarily investigated, supporting the potence of AsA as a promising therapeutic agent to combat MASA infections.

耐甲氧西林金黄色葡萄球菌（MRSA）是一种多重耐药细菌，经常引起严重的卫生感染问题。海洋真菌被视为抗生素先导化合物的一个有希望的来源。本研究对海洋真菌Microascus sp. SCSIO 41821中提取的生物碱Ascomylactam A （AsA）的体内外抑菌活性、增效作用及机制进行了研究。抑菌试验表明，AsA对MRSA SC41993具有良好的抑菌活性和抑制生物膜的形成，与临床抗生素具有协同抑菌作用。转录组学揭示了AsA通过LytSR、VraSR、ArgAC和KdpDE双组分系统（TCS）影响MRSA生物膜形成、细胞壁合成和毒力的潜在机制。此外，通过AsA处理，发现AdhE蛋白是MRSA氧化应激和脂质过氧化的潜在靶点，并通过调节部分基因逆转MRSA的耐药性。体内实验表明，AsA联合硫酸庆大霉素（GMS）对临床MRSA USA300的治疗效果优于单用，尤其是对心脏的治疗效果更好。本研究对十氢芴类生物碱的抗菌机制进行了初步研究，支持AsA作为一种有前景的治疗AsA感染的药物的潜力。

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引用次数: 0

Exosomes as carriers to stimulate an anti-cancer immune response in immunotherapy and as predictive markers 外泌体作为免疫治疗中刺激抗癌免疫反应的载体和预测标志物。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2024.116699

Lili Nie , Jingru Ma , Yang Yu , Ying Tao , Zhidu Song , Jian Li

During this era of rapid advancements in cancer immunotherapy, the application of cell-released small vesicles that activate the immune system is of considerable interest. Exosomes are cell-derived nanovesicles that show great promise for the immunological treatment of cancer because of their immunogenicity and molecular transfer capacity. Recent technological advancements have enabled the identification of functional functions that exosome cargoes perform in controlling immune responses. Exosomes are originated specifically from immune cells and tumor cells and they show unique composition patterns directly related to the immunotherapy against cancer. Exosomes can also deliver their cargo to particular cells, which can affect the phenotypic and immune-regulatory functions of those cells. Exosomes can influence the course of cancer and have therapeutic benefits by taking part in several cellular processes; as a result, they have the dual properties of activating and restraining cancer. Exosomes have tremendous potential for cancer immunotherapy; they may develop into the most powerful cancer vaccines and carriers of targeted antigens and drugs. Comprehending the potential applications of exosomes in immune therapy is significant for regulating cancer progression. This review offers an analysis of the function of exosomes in immunotherapy, specifically as carriers that function as diagnostic indicators for immunological activation and trigger an anti-cancer immune response. Moreover, it summarizes the fundamental mechanism and possible therapeutic applications of exosome-based immunotherapy for human cancer.

在这个癌症免疫治疗快速发展的时代，细胞释放的小泡激活免疫系统的应用引起了相当大的兴趣。外泌体是细胞衍生的纳米囊泡，由于其免疫原性和分子转移能力，在癌症的免疫治疗中显示出巨大的前景。最近的技术进步已经能够识别外泌体货物在控制免疫反应方面的功能。外泌体起源于免疫细胞和肿瘤细胞，它们具有独特的组成模式，与癌症的免疫治疗直接相关。外泌体也可以将它们的货物运送到特定的细胞，这可以影响这些细胞的表型和免疫调节功能。外泌体可以影响癌症的进程，并通过参与几个细胞过程而具有治疗益处；因此，它们具有激活和抑制癌症的双重特性。外泌体在癌症免疫治疗中具有巨大的潜力；它们可能会发展成为最强大的癌症疫苗和靶向抗原和药物的载体。了解外泌体在免疫治疗中的潜在应用对调节癌症进展具有重要意义。本文综述了外泌体在免疫治疗中的功能，特别是作为免疫激活诊断指标和引发抗癌免疫反应的载体。此外，综述了基于外泌体的免疫治疗人类癌症的基本机制和可能的治疗应用。

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引用次数: 0