作者: Leung, George Pak-Heng ; Chow, Franklin Wang-Ngai ; Li, Jing-Jing ; Kwan, Yiu-Wa ; Tsoi, Bun ; Wong, Chun-Chak ; Seto, Sai-Wang ; Kwok, Carsten Tsun-Ka

BACKGROUND:

Sclerostin (SOST) is traditionally regarded as an osteocyte-derived secreted glycoprotein that regulates bone mineralization. Recent studies reported that SOST is also released from non-skeletal sources, especially during inflammation. However, the cellular source and regulatory mechanisms governing SOST generation in inflammation remain unclear. This study investigated whether macrophages produce SOST in response to inflammatory stimuli and determined associated regulatory pathways.

METHODS:

The effect of lipopolysaccharide (LPS)-induced inflammation in SOST generation and its underlying regulatory mechanism was examined on mouse macrophage RAW 264.7 by western blot and immunofluorescent staining. Transfection with miR-92a-3p mimic and inhibitor were used to validate its role in SOST production. The role of NF-κB and TLR4 were studied using pharmacological inhibitors BAY 11-7085 and TAK242, respectively. The involvement of NF-κB and TLR4 in LPS-induced SOST production was further validated through nuclear NF-κB p65 immunoprecipitation and TLR4 small interfering RNA (siRNA) experiments, respectively.GW4869 and manumycin A (extracellular vesicles (EV) biogenesis inhibitors) were used to examine the associated of SOST and EV. Finally, SOST expression and characteristics of the isolated EV were assessed by Western blot and nanoparticle tracking analysis (NTA).

RESULTS:

LPS significantly induced SOST protein expression and secretion in RAW 264.7. MiR-92a-3p was upregulated by LPS stimulation in macrophages. Transfection of miR-92a-3p mimic increased SOST generation in RAW 264.7. Inhibition of TLR4 and NF-κB signalling pathways using pharmacological inhibitors significantly suppressed LPS-induced SOST in RAW 264.7. Similarly, TLR4 siRNA effectively suppressed LPS-induced SOST level. However, the LPS-induced upregulation of miR-92a-3p was only regulated by TLR4, but not by NF-κB. NF-κB was found to directly bind to the mouse sost promoter, thereby activating sost transcription. Additionally, SOST secretion was found predominantly associated with EV from LPS-stimulated cells, and inhibition of EV biogenesis suppressed SOST production in RAW 264.7 cells.

CONCLUSIONS:

In conclusion, our study showed, for the first time, that LPS induced SOST generation and secretion via TLR4/miR-92a-3p/PTEN/NF-κB singling pathway in murine macrophage RAW 264.7 cells. Moreover, we showed that SOST is secreted from the RAW 264.7 cells in the form of extracellular vesicle. This study identified macrophage as a novel source of SOST, highlighting its potential role in inflammatory diseases.

2025-08-01·CELLULAR SIGNALLING

MTDH∆7-mediated mTOR activation drives doxorubicin resistance in triple-negative breast cancer: Relevance of mTORC1 inhibition on chemosensitization

Article

作者: Kotamraju, Srigiridhar ; Neeli, Praveen Kumar ; Pulipaka, Sriravali ; Kumari, Sunita ; Chandra, Yogesh ; Sahoo, Shashikanta ; Annamaneni, Sandhya ; Kuncha, Madhusudana

Cancer chemoresistance poses a major hurdle in the management of several cancers, including breast cancer. Herein, we identified MTDH∆7, a splice variant of an oncogene, metadherin (MTDH), promotes doxorubicin (Dox)-induced chemoresistance in triple-negative breast cancer (TNBC) cells. Increased MTDH∆7 levels were positively correlated with the elevated levels of ABC transporters like ABCB1, ABCC1, and ABCG2, which in turn caused reduced intracellular Dox accumulation. Interestingly, everolimus, an mTORC1 inhibitor, potentiated Dox-induced cytotoxicity by inhibiting MTDH∆7-mediated increase in the aforementioned ABC transporters. Moreover, MTDH∆7 overexpression increased mTORC1 levels, possibly due to MTDH∆7-induced accentuation of mitochondrial respiration, ATP production, and AMPK inactivation. Mechanistically, enhanced phosphorylation of mTORC1 caused NF-κB-dependent activation of cAMP-regulatory element-binding protein (CREB). Further, activated CREB led to an increase in the levels of ABCB1, ABCC1, and ABCG2. Inhibition of either mTORC1 by everolimus or NF-κB by BAY-11-7082 or CREB by H89 reversed these effects and mitigated MTDH∆7-mediated Dox efflux. Accordingly, while Dox administration alone marginally caused tumor regression in SCID mice bearing LV.MTDH∆7-MDA-MB-231 cells, administration of everolimus greatly sensitized these mice to Dox-induced tumor regression. In agreement, intriguingly, a positive correlation was observed between elevated MTDH∆7, mTORC1 activation, and ABC transporters level in human breast cancer patient cohort tumor samples. Collectively, MTDH∆7, by promoting mTOR signaling causes breast cancer chemoresistance, and that targeting MTDH∆7-mTOR signaling axis effectively enhances chemosensitization.

2025-08-01·TOXICOLOGY

Cadmium induces the secretion of SASP factors regulated by MAPK and NF-κB signaling pathways in HEK293 cells: A possible mechanism of acute kidney damage induced by cadmium

Article

作者: Ren, Ziqi ; Liu, Zhicun ; Liu, Jianli ; Chen, Jiahe ; Ma, Huiping ; Qi, Ruiquan ; Liu, Haotian ; Zheng, Yuanchen

Cadmium (Cd) is a highly toxic environmental pollutant, which can accumulate in the kidney, induce cell damage and trigger inflammatory responses. However, the specific regulation mechanism of nephrotoxicity induced by Cd remains unclear. This study was conducted to investigate the toxic effects of Cd on human embryonic kidney 293 (HEK293) cells and explore its potential mechanisms. Cell viability was assessed with MTT assay. Reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) were evaluated through DCFH-DA staining and Rhodamine staining. Apoptosis was detected with Hoechst 33258 staining. The expression of the DNA damage biomarker 8-hydroxy-2'-deoxyguanosine (8-OHdG) was detected with the 8-OHdG ELISA kit. Senescence-associated secretory phenotype (SASP) factors and signaling pathways were analyzed by Western blot. The results showed that Cd exposure could induce oxidative stress and cellular inflammation. It could also impair MMP, contribute to cell apoptosis and activate MAPK and NF-κB signaling pathways. Finally, exposure to Cd triggered DNA damage and SASP production. However, NF-κB inhibitor BAY11-7082 and antioxidant NAC could inhibit these effects by suppressing NF-κB and MAPK signaling pathways. The present study revealed the specific mechanisms of Cd toxicity in HEK293 cells and provided useful information for elucidating the nephrotoxicity of Cd.

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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