Advanced Science
·
2025
·
IF 14.1
Xinyi Lu,Pingping Jin,Qianyun Tang,Min Zhou,Hanjie Xu,Chen Su,Lei Wang,Feng Xu,Min Zhao,Yongxiang Yin,Jinqiu Zhang,Zhen Jia,Xinrui Peng,Jie Zhou,Lu Wang,Yan Chen,Min Wang,Min Yang,Daozhen Chen,Yu Chen
Cervical cancer (CC) is a major health threat to women, with immunotherapies targeting the programmed death receptor 1/programmed death ligand 1(PD-1/PD-L1) axis showing promise but encountering resistance in a significant patient population. This resistance has driven a critical quest to uncover the underlying mechanisms. This study uncovers a novel metabolic axis involving the nicotinamide adenine dinucleotide (NAD + ) salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) and the deacetylase Sirtuin 1 (SIRT1), which regulates PD-L1 expression and nuclear localization in CC. This axis may be a key factor contributing to the resistance observed in immunotherapy. This study reveals that PD-L1 overexpression in cancers is regulated by both transcriptional and post-transcriptional processes. Acetyl-proteomic analysis pinpoints SIRT1 as a central regulator in the deacetylation of histone H3 at lysines 27, which may influence PD-L1 subcellular distribution. This finding reveals the epigenetic control of immune checkpoint proteins by metabolic pathways, offering a new perspective on the regulation of PD-L1. The identification of the NAMPT/SIRT1 metabolic axis as a critical factor suggests that targeting this axis may enhance therapeutic responses.
研究领域:
肿瘤学
·
分子生物学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
VIEW
·
2025
·
IF 8.5
Youjia Zhang,Ming Chen,Yi Tian,Bo Qin,Xiaoxiao Chen,Yiwen Zhou,Jinhai Huang,Mei Yang,Xinghuai Sun,Yuan Lei,Yuhong Chen
Elevated intraocular pressure (IOP) is a critical risk factor for the development and progression of glaucoma. However, current treatments focus primarily on mechanical stress relief, neglecting the underlying issue of diminished cellular energy production in patients. In this study, we investigated the impact of NAD + reduction on IOP regulation and explored the potential of NAD + precursors as a therapeutic strategy. We investigated the role of NAD + metabolism in glaucoma and revealed decreased nicotinamide phosphoribosyltransferase (NAMPT) expression in both patients and the human trabecular meshwork (HTM) cell model. Supplementation with NAD + precursors, nicotinamide (NAM) or nicotinamide mononucleotide (NMN), provided protective effects in H 2 O 2 -treated HTM cells and reduced IOP in ocular hypertension mouse models by mitigating senescence, extracellular matrix accumulation, and oxidative stress. To optimize drug delivery, we engineered the NAM@CeMOF-2 nanozyme system, which achieved a maximum IOP reduction in Cav1 ⁻/⁻ mice following 7 days of treatment. This localized treatment improved bioavailability and reduced systemic side effects. These findings suggest that NAD + deficiency plays a role in glaucoma development and propose novel therapeutic targets for addressing cellular dysfunction in glaucoma.
研究领域:
医学
·
生物化学
·
眼科研究
✓ 已验证
产品关联
DOI
高影响因子
REDOX REPORT
·
2025
·
IF 7.4
Fang Cheng,Minzhu Zhao,Qi Wang,Hongli Xiong,Kai Yu,Chong Chen,Ying Zhu,Yemiao Chen,Jianbo Li
Objectives Doxorubicin (DOX) induces dose-dependent cardiotoxicity, primarily through oxidative stress and metabolic dysregulation. Although NAD+ deficiency has been implicated in cardiovascular pathology, its role in DOX-induced cardiotoxicity (DIC) remains poorly understood. This study investigated NAD+ metabolism dysregulation as a redox-sensitive mechanism in DIC pathogenesis.Methods Human cardiomyocytes (AC16), mouse atrial myocytes (HL-1), and C57BL/6 mice were used to establish the DIC model. The role and mechanism of NAD+ in DIC were investigated using a range of methods.Results Using integrated in vitro and in vivo models, we demonstrated that DOX induces myocardial oxidative damage accompanied by NAD+ depletion. Exogenous NAD+ supplementation mitigated the DOX-induced cardiomyocyte death and redox imbalance. Mechanistically, pharmacological CD38 inhibition with 78C or genetic silencing failed to restore the NAD+ pool, whereas nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3) overexpression, combined with nicotinamide mononucleotide (NMN) administration, effectively rescued NAD+ levels and attenuated oxidative stress. Computational and functional analyses identified FOXO1 as a transcriptional repressor of NMNAT3 following DOX exposure.Conclusion This study establishes the dysregulation of the FOXO1-NMNAT3 axis as a key mechanism underlying NAD+ depletion in DIC. Targeting this axis through NAD+ replenishment, particularly by activating NMNAT3, offers a novel redox-based therapeutic strategy against DIC.
研究领域:
心血管病理学
·
分子生物学
·
药理学
·
氧化应激
·
代谢调控
·
转化医学
·
药物毒性
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYTICAL BIOCHEMISTRY
·
2024
·
IF 2.6
Mengyu Jiang,Li Li,Yuan Jin,Liuliu Lu,Zhenchen Lu,Wangjie Lv,Xiaoqun Wang,Lei Di,Zhicheng Liu
Sepsis is a life-threatening condition characterized by organ dysfunction resulting from a dysregulated host response to infection. Dysregulated tryptophan (TRP) metabolites serve as significant indicators for endogenous immune turnovers and abnormal metabolism in the intestinal microbiota during sepsis. Therefore, a high coverage determination of TRP and its metabolites in sepsis is beneficial for the diagnosis and prognosis of sepsis, as well as for understanding the underlying mechanism of sepsis development. However, similar structures in TRP metabolites make it challenging for separation and metabolite identification. Here, high-performance liquid chromatography coupled with a diode array detector (HPLC-DAD) was developed to determine TRP metabolites in rat serum. The first-order derivative spectrophotometry of targeted metabolites in the serum was investigated and proved to be promising for chromatographic peak annotation across different columns and systems. The established method separating the targeted metabolites was optimized and validated to be sensitive and accurate. Application of the method revealed dysregulated TRP metabolites, associated with immune disorders and NAD + metabolism in both the host and gut flora in septic rats. Our findings indicate that the derivative spectrophotometry-assisted method enhances metabolite identifications for the chromatographic systems based on DAD detectors and holds promise for precision medicine in sepsis.
研究领域:
分析化学
·
免疫学
·
代谢组学
·
微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
·
2024
·
IF 5.7
Peiling Wu,Wenjie Wang,Chuan Huang,Le Sun,Xiaoli Wu,Lijia Xu,Peigen Xiao
Background TRY-NAD metabolic network includes TRY (tryptophan), 5-HT (5-hydroxytryptamine), KYN (kynurenine), and NAD (nicotinamide adenine dinucleotide) pathway, which plays a significant role in neurological diseases and ageing. It is important to monitor these metabolites for studying the pathological anatomy of disease and treatment of responses evaluation. Although previous studies have reported quantitative methods for several metabolites in the network, the bottlenecks of simultaneously quantifying the whole metabolic network are their similar structures, diverse physico-chemical properties, and instability. Standardized protocols for the whole metabolic network are still missing, which hinders the in-depth study of TRY-NAD metabolic network in laboratory research and clinical screening. Results We developed a LC-MS/MS method for quantifying 28 metabolites in the TRY-NAD network simultaneously. Optimization was done for the mass spectral parameters, chromatographic conditions and sample pretreatment process. The developed method was fully validated in terms of standard curves, sensitivity, carryover, recovery, matrix effect, accuracy, precision, and stability. The pretreatment of 30 samples only takes 90 minutes, and the LC-MS/MS running time of one sample is only 13 minutes. With this method, we bring to light the chaos of global TRY-NAD metabolic network in sleep deprivation mice for the first time, including serum, clotted blood cells, hippocampus, cerebral cortex, and liver. NAD pathway levels in brain and blood decreased, whereas the opposite happened in the liver. The 5-HT pathway decreased and the concentration of KYN increased significantly in the brain. The concentration of many metabolites in KYN pathway (NAD + de novo synthesis pathway) increased in the liver. Significance This method is the first time to determine the metabolites of KYN, 5-HT and NAD pathway at the same time, and it is found that TRY-NAD metabolic network will be disordered after sleep deprivation. This work clarifies the importance of the pH of the extraction solution, the time and temperature control in pretreatment in standardized protocols building, and overcoming the problems of inconsistent sample pretreatment, separation, matrix effect interference and potential metabolite degradation. This method exhibits great prospects in providing more information on metabolic disturbances caused by sleep deprivation as well as neurological diseases and ageing.
研究领域:
分析化学
·
神经科学
·
药理学
·
生物化学
·
临床研究
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）