Early divergent modulation of NLRP2′s and NLRP3′s inflammasome sensors vs. AIM2′s one by signals from Aβ·Calcium-sensing receptor complexes in human astrocytes

Article

作者: Dal Prà, Ilaria ; Chang, Shusen ; Yin, Meifang ; Gui, Li ; Chiarini, Anna ; Armato, Ubaldo

Alzheimer's disease (AD), the most prevalent human dementia, is driven by accruals of extracellular Aβ₄₂ senile patches and intracellular neurofibrillary tangles of hyperphosphorylated Tau (p-Tau) proteins. AD's concurrent neuroinflammation is prompted by innate immunity-related cytosolic protein oligomers named inflammasomes. Upon proper "first" (priming) and "second" (activating) signals, inflammasomes overproduce proinflammatory Interleukin (IL)-1β, and IL-18 while cleaving pyroptosis-promoting Gasdermin D's N-terminal fragments. Our earlier studies highlighted that in pure monocultures, exogenous Aβ_25-35-treated nonproliferating human cortical astrocytes (HCAs) made and released surpluses of endogenous Aβ₄₂-oligomers (-os) and p-Tau-os, just as alike-treated human cortical neurons did. Aβ_25-35-exposed HCAs also over-released NO, VEGFA, and IL-6. Aβ•CaSR (Aβ·Calcium-Sensing Receptor) complexes generated intracellular signals mediating all such neurotoxic effects since CaSR's negative allosteric modulators (aka NAMs or calcilytics, e.g., NPS2143) fully suppressed them. However, it had hitherto remained unexplored whether signals from Aβ·CaSR complexes also induced the early expression and/or activation of NOD-like 2 (NLRP2) and 3 (NLRP3) and of PYHIN absent in melanoma 2 (AIM2) inflammasomes in monocultured HCAs. To clarify this topic, we used in-situ-Proximity Ligation, qRT-PCR, double antibody arrays, immunoblots, and Caspase 1/4 enzymatic assays. Aβ·CaSR complexes quickly assembled on HCAs surface and issued intracellular signals activating Akt and JAK/STAT axes. In turn, the latter upregulated NLRP2 and NLRP3 PRRs (pattern recognition receptors) yet downregulated AIM2. These effects were specific, being significantly hindered by NPS2143 and inhibitors of PI3K (LY294002), AMPKα (Dorsomorphin), mTOR (Torin1), and JAK/TYK (Brepoticinib). A wide-spectrum inhibitor, Bay11-7082, intensified the Aβ·CaSR/Akt/JAK/STAT axis-driven opposite control of NLRP3's and AIM2's PRR proteins without affecting NLRP2 PRR upregulation. However, the said effects on the PRRs proteins vanished within 24-h. Moreover, Aβ·CaSR signals neither concurrently changed ASC, pro-IL-1β, and Gasdermin-D (holo- and fragments) protein levels and Caspases 1 and 4 enzymatic activities nor induced pyroptosis. Therefore, Aβ·CaSR cues acted as "first (priming) signals" temporarily increasing NLRP2 and NLRP3 PRRs expression without activating the corresponding inflammasomes. The neatly divergent modulation of NLRP3's vs. AIM2's PRR proteins by Aβ·CaSR cues and by Bay11-7082 suggests that, when bacterial or viral DNA fragments are absent, AIM2 might play "anti-inflammasomal" or other roles in HCAs. However, Bay11-7082's no effect on NLRP2 PRR overexpression also reveals that CaSR's downstream mechanisms controlling inflammasomes' sensors are quite complex in HCAs, and hence, given AD's impact on human health, well worth further studies.

2024-12-01·Environmental Pollution

Unravelling bisphenol A-induced hepatotoxicity: Insights into oxidative stress, inflammation, and energy dysregulation

Article

作者: Banerjee, Sambuddha ; Karmakar, Sampurna ; Maitra, Sudipta ; Das, Sriparna ; Mukherjee, Urmi ; Biswas, Subhasri

Bisphenol A (BPA), a prevalent plastic monomer and endocrine disruptor, negatively impacts metabolic functions. This study examines the chronic effects of eco-relevant BPA concentrations on hepatotoxicity, focusing on redox balance, inflammatory response, cellular energy sensors, and metabolic homeostasis in male Swiss albino mice. Chronic BPA exposure resulted in reactive oxygen species (ROS) accumulation, altered hepatic antioxidant defense, lipid peroxidation, and NOX4 expression, leading to reduced cell viability. Additionally, BPA exposure significantly upregulated hepatic pro-inflammatory cytokine genes (Tnf-α, Il-1β, Il-6), NOS2, and arginase II, correlating with increased TLR4 expression, NF-κB phosphorylation, and a dose-dependent decrease in IκBα levels. BPA-induced NF-κB nuclear localization and inflammasome activation (NLRP3, cleaved caspase-1, IL-1β) established an inflammatory milieu. Perturbations in hepatic AMPKα phosphorylation, SIRT1, and PGC-1α, along with elevated p38 MAPK phosphorylation and ERα expression, indicated BPA-induced energy dysregulation. Furthermore, increased PLA2G4A, COX1, COX2, and PTGES2 expression in BPA-treated liver correlated with hyperlipidemia, hepatic FASN expression, steatosis, and visceral adiposity, likely due to disrupted energy sensors, oxidative stress, and inflammasome activation. Elevated liver enzymes (ALP, AST, ALT) and apoptotic markers indicated liver damage. Notably, N-acetylcysteine (NAC) priming reversed BPA-induced hepatocellular ROS accumulation, NF-κB-inflammasome activation, and intracellular lipid accumulation, while upregulating cellular energy sensors and attenuating ERα expression, suggesting NAC's protective effects against BPA-induced hepatotoxicity. Pharmacological inhibition of the NF-κB/NLRP3 cascade in BAY11-7082 pretreated, or NLRP3 immunodepleted hepatocytes reversed BPA's negative impact on SIRT1/p-AMPKα/PGC-1α and intracellular lipid accumulation, providing mechanistic insights into BPA-induced metabolic disruption.

2024-12-01·Molecular Biology Reports

The endonuclease FEN1 mediates activation of STAT3 and facilitates proliferation and metastasis in breast cancer

Article

作者: Yu, Lin ; Wu, Benmeng ; Liu, Jingjing ; Huang, Xiaoshan ; Lan, Ting ; Zhu, Miaolin ; Wu, Min ; Zhu, Yaqin

BACKGROUNDThe metastasis accounts for most deaths from breast cancer (BRCA). Understanding the molecular mechanisms of BRCA metastasis is urgently demanded. Flap Endonuclease 1 (FEN1), a pivotal factor in DNA metabolic pathways, contributes to tumor growth and drug resistance, however, little is known about the role of FEN1 in BRCA metastasis.METHODS AND RESULTSIn this study, FEN1 expression and its clinical correlation in BRCA were investigated using bioinformatics, showing being upregulated in BRCA samples and significant relationships with tumor stage, node metastasis, and prognosis. Immunohistochemistry (IHC) staining of local BRCA cohort indicated that the ratio of high FEN1 expression in metastatic BRCA tissues rose over that in non-metastatic tissues. The assays of loss-of-function and gain-of-function showed that FEN1 enhanced BRCA cell proliferation, migration, invasion, xenograft growth as well as lung metastasis. It was further found that FEN1 promoted the aggressive behaviors of BRCA cells via Signal Transducer and Activator of Transcription 3 (STAT3) activation. Specifically, the STAT3 inhibitor Stattic thwarted the FEN1-induced enhancement of migration and invasion, while the activator IL-6 rescued the decreased migration and invasion caused by FEN1 knockdown. Additionally, overexpression of FEN1 rescued the inhibitory effect of nuclear factor-κB (NF-κB) inhibitor BAY117082 on phosphorylated STAT3. Simultaneously, the knockdown of FEN1 attenuated the phosphorylation of STAT3 promoted by the NF-κB activator tumor necrosis factor α (TNF-α).CONCLUSIONSThese results indicate a novel mechanism that NF-κB-driven FEN1 contributes to promoting BRCA growth and metastasis by STAT3 activation.

项与 BAY-11-7083 相关的新闻（医药）

2022-08-04

·生物制药小编

信达已入局|AKT抑制剂能否成为乳腺癌PD-1联用新宠？

乳腺癌作为高居女性恶性肿瘤的发病率和死亡率首位，尽管现在不少疗法对于乳腺癌已经有了对应治疗方法，但有介于部分疗法仍有毒性等问题，癌前病变作为乳腺癌发生发展的重要阶段，干预乳腺癌前病变，阻断其向乳腺癌发展，是目前防治乳腺癌的研究关键。图：乳腺癌肿瘤微环境其中，程序性死亡分子(PD)-1 / PD-1配体(PD-L1)信号通路介导形成的免疫抑制微环境是乳腺癌变细胞赖以生存的基础，对促进乳腺癌发生发展、逃避免疫监视等方面起着重要作用。此外，磷脂酰肌醇3-激酶/蛋白激酶BPI3K/AKT通路是乳腺癌中最频繁改变的信号通路之一，50%的HR阳性乳腺癌和约25%的TNBC存在PI3K/AKT通路的过度激活，主要来自HR阳性肿瘤的PIK3CA突变和TNBC（三阴乳腺癌）的PTEN缺失。PI3K作为联系胞外信号与细胞应答效应的桥梁分子，在一系列上游或旁路信号分子的影响下，作用于AKT及其下游信号分子，控制乳腺癌变中至关重要的细胞生物学过程，包括细胞增殖、凋亡、细胞周期、血管形成等。研究发现，PI3K/ AKT信号通路通过影响癌变免疫微环境中CD8 +T细胞的活性及癌变细胞PD-L1的表达参与癌变免疫抑制微环境的形成，进而促进肿瘤发生发展，如果阻断PI3K/AKT信号通路，可下调癌变细胞表面PD-L1表达，解除患者的免疫抑制状态，促进患者机体免疫功能恢复，提高患者抗肿瘤固有的免疫效应。PD-1 / PD-L1与PI3K/ AKT交联PD-1表达于乳腺癌变周围浸润的CD8 +T淋巴细胞表面，PD-L1异常高表达于乳腺癌变细胞表面，PD-1与PD-L1特异性结合后，通过PD-1胞质区的免疫受体酪氨酸转换基序(ITSM)募集磷酸酶(SHP)-2，能够引起下游蛋白激酶PI3K的去磷酸化，抑制下游AKT通路的活化，进而抑制CD8 +T细胞的正常活化、增殖及细胞因子的分泌,促进活化的CD8 + T细胞凋亡，介导癌变细胞逃避 CD8 +T细胞的杀伤,最终实现癌变细胞的免疫逃逸。图：PD-1 / PD-L1 与 PI3K/AKT信号通路在乳腺癌变免疫微环境中的协同作用此外，研究还表明，肿瘤来源的骨髓间充质干细胞通过直接的受体-配体相互作用激活B细胞中的PI3K/AKT/NF-κB通路，以及MDSC培育的PD-1−PD-L1+Bregs抑制T细胞免疫反应，从而导致肿瘤进展。采用抗PD-1抗体、LY294002和BAY 11-7085可以逆转MDSC培育的B细胞介导的T细胞免疫反应的抑制。因此，干扰PD-1/PD-L1轴和激活PI3K/AKT/NF-κB通路的免疫疗法可以恢复肿瘤中的免疫功能障碍。图：乳腺癌中MDSCs对B细胞调节的示意图目前开发的AKT抑制剂目前，尽管尚未有一款AKT抑制剂获批上市，有两类AKT抑制剂正在开发中，分别为ATP竞争性抑制剂和变构抑制剂。其中ATP竞争性抑制剂与AKT的活性位点结合，阻断ATP结合；而变构抑制剂与Pleckstrin同源性结构域结合，阻止AKT磷酸化和活化。尽管AKT抑制剂在具有特定遗传改变的肿瘤中具有引人注目的抗肿瘤活性，但是AKT复杂的细胞功能和潜在反馈信号的激活限制了AKT作为单一药物的功效。且由于药物毒性。基于AKT途径和联合治疗的机制见解设计的临床试验将提供AKT抑制剂更好的临床前景，并充分发挥这些化合物的潜力。事实上，无论有无化疗，大量的研究正在调查AKT抑制剂和免疫治疗剂之间的关系。一项Ib期试验(CO40151/NCT03800836)取得了令人鼓舞的结果，该试验联合应用ipatasertib、PD-L1抗体 (atezolizumab)和化疗药物(阿霉素加环磷酰胺、紫杉醇或纳米颗粒-白蛋白结合紫杉醇)作为转移性TNBC的一线治疗。114名患者的最新结果显示，不管PD-L1表达和预后如何，患者的ORR为54 %( 95%可信区间44–63 %)，中位PFS为7.2个月(95%可信区间5.5–7.4个月)。小编总结考虑到信达已经与来凯医药展开PD-1抗体与AKT抑制剂的联合临床，AKT抑制剂迈向上市的道路可能要通过联合临床，或开发下一代毒性更弱的AKT抑制剂。参考来源：1.李德辉,苏伊璠．PD-1/PD-L1与PI3K/AKT交叉对话与乳腺癌变免疫微环境[J]．中国老年学杂志,2022,42(1):215-2182.Liu M, Wei F, Wang J, Yu W, Shen M, Liu T, Zhang D, Wang Y, Ren X, Sun Q. Myeloid-derived suppressor cells regulate the immunosuppressive functions of PD-1-PD-L1+ Bregs through PD-L1/PI3K/AKT/NF-κB axis in breast cancer. Cell Death Dis. 2021 May 9;12(5):465. doi: 10.1038/s41419-021-03745-1. PMID: 33967272; PMCID: PMC8107179.3.Shariati M, Meric-Bernstam F. Targeting AKT for cancer therapy. Expert Opin Investig Drugs. 2019 Nov;28(11):977-988. doi: 10.1080/13543784.2019.1676726. Epub 2019 Oct 12. PMID: 31594388; PMCID: PMC6901085.4.Martorana F, Motta G, Pavone G, Motta L, Stella S, Vitale SR, Manzella L and Vigneri P (2021) AKT Inhibitors: New Weapons in the Fight Against Breast Cancer?. Front. Pharmacol. 12:662232. doi: 10.3389/fphar.2021.662232

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100 项与 BAY-11-7083 相关的药物交易

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