NAPRT

烟酰胺腺嘌呤二核苷酸(NAD+)是一种重要的辅因子，参与多种氧化还原反应，包括糖酵解、柠檬酸循环和氧化磷酸化。 烟酰胺腺嘌呤二核苷酸(NAD+)是一种重要的辅因子，参与多种氧化还原反应，包括糖酵解、柠檬酸循环和氧化磷酸化。此外，NAD+也是许多NAD+消耗酶的底物，如聚ADP核糖聚合酶(PAPS)、sirtuins和CD38，这些酶在DNA损伤修复、基因表达调控、细胞周期进展和细胞代谢中发挥重要作用。 据报道，癌细胞维持比正常细胞更高的NAD+浓度，以支持能量和大分子的快速产生，以及抵消过量的ROS产生。参与NAD+生物合成的各种酶，包括烟酰胺磷酸核糖基转移酶(NAMPT)和烟酸磷酸核糖基转移酶(NAPRT)，在多种癌症中异常上调，并被认为促进肿瘤的发生和癌症的进展。 此外，NAD+降低剂FK866和KPT-9274都是NAMPT的选择性抑制剂，已经进入早期临床试验，显示出很强的降低NAD+水平和诱导癌细胞凋亡的能力，表明NAD+耗竭在癌症治疗中具有巨大的潜力。 图片来源: https://doi.org/10.1038/s41418-023-01185-2 近日，来自北京大学健康科学中心的研究者们在Cell Death & Differentiation杂志上发表了题为“SLC25A51 promotes tumor growth through sustaining mitochondria acetylation homeostasis and proline biogenesis”的文章，该研究揭示了SLC25A51是一个有吸引力的抗癌靶点，并提供了一种新型的磷酸氟达拉滨与阿司匹林的药物组合，作为一种潜在的癌症治疗策略。 溶质载体家族25成员51(SLC25A51)是最近发现的哺乳动物线粒体NAD+转运蛋白。然而，SLC25A51在癌症等人类疾病中的作用仍未确定。在这里，研究者报告SLC25A51在多种癌症中上调，促进癌细胞增殖。 由于SIRT3功能障碍，SLC25A51基因缺失导致线粒体蛋白质乙酰化水平升高，导致作为生物合成关键酶的P5CS酶活性降低，并导致Pro含量降低。值得注意的是，研究者发现FDA批准的药物磷酸氟达拉滨能够与SLC25A51功能结合并抑制其功能，导致线粒体NAD+减少和蛋白质超乙酰化，这可能与阿司匹林进一步协同作用，以增强抗肿瘤效果。 阿司匹林与磷酸氟达拉滨协同抑制肿瘤生长 图片来源: https://doi.org/10.1038/s41418-023-01185-2 在本研究中，研究者揭示了SLC25A51的促肿瘤作用，通过激活SIRT3和维持线粒体的乙酰化动态平衡来促进癌细胞的增殖。研究者还表明，磷酸氟达拉滨是一种潜在的SLC25A51抑制剂，并可与阿司匹林协同抑制肿瘤生长。总之，本研究为癌症治疗提供了一个新的靶点，并发现了一种可能尽快投入临床使用的有效药物组合。（生物谷 Bioon.com） 参考文献 Yutong Li et al. SLC25A51 promotes tumor growth through sustaining mitochondria acetylation homeostasis and proline biogenesis. Cell Death Differ. 2023 Jul 7. doi: 10.1038/s41418-023-01185-2.

头颈部鳞状细胞癌(HNSCC)是全球第六大常见癌症。2020年新增病例近100万例。这种癌症是一组肿瘤，影响不同的解剖位置，包括口腔、舌头、咽部、喉部和唾液腺。其中90%的肿瘤起源于鳞状细胞。 头颈部鳞状细胞癌(HNSCC)是全球第六大常见癌症。2020年新增病例近100万例。这种癌症是一组肿瘤，影响不同的解剖位置，包括口腔、舌头、咽部、喉部和唾液腺。其中90%的肿瘤起源于鳞状细胞。 尽管HNSCC具有异质性，但根据其来源可分为两大类：人类乳头瘤病毒(HPV)阳性肿瘤和HPV阴性肿瘤，它们与长期饮酒和吸烟有关。尽管HNSCC治疗取得了进展，但肿瘤复发率和患者死亡率仍然很高。因此，寻找新的针对耐药肿瘤细胞的预后标志物和治疗方法是至关重要的。 图片来源: https://doi.org/10.1186/s13046-023-02631-2 近日，来自塞维利亚大学的研究者们在J Exp Clin Cancer Res杂志上发表了题为“NAD pool as an antitumor target against cancer stem cells in head and neck cancer”的文章，该研究揭示了NAMPT和NAPRT的共同抑制提高了抗肿瘤治疗的效果，表明NAD池中的减少对于防止肿瘤生长是重要的。 头颈部鳞状细胞癌(HNSCC)是一组影响不同解剖部位的异质性肿瘤。尽管存在这种异质性，HNSCC的治疗取决于肿瘤的解剖位置、TNM分期和可切除性。传统的化疗是基于铂衍生药物(顺铂、卡铂和奥沙利铂)、紫杉烷(多西紫杉醇、紫杉醇)和5-氟尿嘧啶。尽管HNSCC治疗取得了进展，但肿瘤复发率和患者死亡率仍然很高。因此，寻找针对耐药肿瘤细胞的新的预后标志物和治疗方法是至关重要的。 本研究工作表明，在HNSCC的CSC群体中存在不同的亚群，具有高表型可塑性。CD10、CD184和CD166可能与NAMPT一起鉴定这些CSC亚群中的一些亚群是这些亚群中弹性细胞的共同代谢基因。 研究者观察到，NAMPT的减少通过NAD池的耗尽导致肿瘤和干性特性、迁移能力和CSC表型的下降。然而，NAMPT抑制的细胞可以通过激活Preiss-Handler途径的NAPRT酶来获得耐药性。 研究者还发现，NAMPT抑制剂与NAPRT抑制剂联合给药对抑制肿瘤生长有协同作用。NAPRT抑制剂作为佐剂的使用提高了NAMPT抑制剂的疗效，并降低了这些抑制剂的剂量和毒性。因此，NAD池中的减少似乎在肿瘤治疗中具有疗效。体外试验证实了这一点，为细胞提供了抑制酶(NA、NMN或NAD)的产物，并恢复了它们的致瘤性和干性。 NAMPT表达降低会降低HNSCC细胞系的干性 图片来源: https://doi.org/10.1186/s13046-023-02631-2 本研究工作表明，在HNSCC的CSC群体中存在不同的亚群，具有高表型可塑性。CD10、CD184和CD166可能与NAMPT一起鉴定这些CSC亚群中的一些亚群是这些亚群中弹性细胞的共同代谢基因。 本研究观察到，NAMPT的减少通过NAD池的耗尽导致肿瘤和干性特性、迁移能力和CSC表型的下降。然而，NAMPT抑制的细胞可以通过激活Preiss-Handler途径的NAPRT酶来获得耐药性。最后，NAMPT和NAPRT的抑制都提高了治疗效率，表明NAD池的减少对于防止肿瘤生长非常重要。（生物谷 Bioon.com） 参考文献 Lola E. Navas et al. NAD pool as an antitumor target against cancer stem cells in head and neck cancer. J Exp Clin Cancer Res. 2023 Mar 3;42(1):55. doi: 10.1186/s13046-023-02631-2.

­­­­­Researchers have unraveled key physiological mechanisms to pave the way for the discovery of novel therapeutics XI'AN, China, March 23, 2023 /PRNewswire/ -- As the search for high-quality pharmaceutical drugs continues, researchers spend countless hours discovering the underlying mechanisms of drug action, thus expediting the drug discovery process. A recent example includes the discovery of the broad-spectrum anti-inflammatory effects of inosine, a nucleoside found in transfer RNAs, by researchers in China. These findings were made available online on 22 October 2022 and published in Volume 13, Issue 1 of Journal of Pharmaceutical Analysis (JPA) on 1st January 2023. Corresponding author, Yue Gao says, "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storms constitute the primary cause of COVID-19 progression, severity, criticality, and death. Glucocorticoid and anti-cytokine therapies are frequently administered to treat COVID-19 but have limited clinical efficacy in severe and critical cases." While attempting to develop effective treatment modalities for COVID-19, the researchers found that inosine downregulated the inflammation-promoting interleukin (IL)-6, upregulated the anti-inflammatory IL-10, and improved acute inflammatory lung injury. Their study suggests that inosine appreciably improved survival in mice infected with SARS-CoV-2 and hindered TANK-binding kinase 1 (TBK1) phosphorylation by binding stimulator of interferon genes and glycogen synthase kinase-3b. It also inhibited the activation and nuclear translocation of the downstream transcription factors, interferon regulatory factor and nuclear factor kappa B, and downregulated IL-6 in the sera and lung tissues of mice infected with lipopolysaccharide, H1N1, or SARS-CoV-2. Dr. Gao further adds, "Inosine is potentially an excellent broad-spectrum anti-inflammatory agent. Our study empirically demonstrated that inosine administration improved survival in severe SARS-CoV-2 infection through its immunomodulatory effects." The researchers concluded that inosine therapy may exert distinct anti-inflammatory effects in patients with severe COVID-19, and identified TBK1 as a promising target for inhibiting cytokine storms and for mitigating acute inflammatory lung injury. In another instance, Gu et al. demonstrated that compounds inhibiting disruptor of telomeric silencing-1-like (DOT1L) diminished the demethylation of histone H3 lysine 79 and inhibited the malignant behavior of uveal melanoma (UM) cells. This novel discovery can facilitate the development of the next generation of therapeutics targeting UM. As the author Xiang Gu, observes, "Our research reveals a novel targetable DOT1L-nicotinate phosphoribosyltransferase oncogenic mechanism, broadening the current understanding of UM therapies." Similarly, Li and colleagues identified squalene epoxidase as a promising therapeutic target for combating drug-induced hepatotoxicity. The author Zhiqi Li says, "We elucidate the hepatotoxicity mechanism of Paris polyphylla, commonly used in traditional herbal medicines, and provide a reference for its safe clinical use. These results may help to modify the structure of related chemical components responsible for the toxicity of polyphyllin 1, the active ingredient of Paris polyphylla, and make its clinical use safer by reducing its toxicity." In addition, Guo and co-authors demonstrated the promising antitumor efficacy of the supramolecular nanoreactor "DOC@TA-Fe3+" in a mouse model of colorectal cancer. The nanoreactor developed by the team rapidly accumulated at the tumor site following injection via the tail vein, attesting to its rapid transportability to the tumor tissue. Author Min Mu says, "The nanoreactor provides a new strategy for drug delivery and provides a reference for clinical research." Collectively, these cutting-edge studies pave the way for the identification of novel pathophysiological pathways, strongly boosting the process of drug discovery. Reference Title of original paper: Inosine: A broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation Journal: Journal of Pharmaceutical Analysis DOI: Contact: Mengjie Wang +86-29-82657423 355966@email4pr.com