Discovery of proqodine A derivatives with antitumor activity targeting NAD(P)H: quinone oxidoreductase 1 and nicotinamide phosphoribosyltransferase / 中国天然药物

NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavin protease highly expressed in various cancer cells. NQO1 catalyzes a futile redox cycle in substrates, leading to substantial reactive oxygen species (ROS) production. This ROS generation results in extensive DNA damage and elevated poly (ADP-ribose) polymerase 1 (PARP1)-mediated consumption of nicotinamide adenine dinucleotide (NAD+), ultimately causing cell death. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage synthesis pathway, emerges as a critical target in cancer therapy. The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD+ depletion. In this study, we designed, synthesized, and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT. Among these, compound T8 demonstrated potent antitumor properties. Specifically, T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT. This discovery offers a promising new molecular entity for advancing anticancer research.

Role of visfatin-intracellular Nampt axis in the progression of epithelial ovarian cancer / 西安交通大学学报(医学版)

【Objective】 To explore the role of visfatin-nicotinamide phosphoribosyl transferase （Nampt） axis in the progression of epithelial ovarian cancer （EOC） and its effect on the patients’ prognosis. 【Methods】 Immunohistochemical analysis was used to detect the expression of Nampt protein in tissues from epithelial ovarian cancer and normal ovary； ELISA was used to determine the level of visfatin in serum. Then the two were further analyzed to estimate their effects on clinicopathological characteristics and the EOC patients’ overall survival. 【Results】 The mean level of serum visfatin in these EOC patients was significantly elevated compared with that of the patients with benign ovarian tumors and normal population. ROC curve analysis showed that the area under curve （AUC） of serum visfatin for diagnosis of EOC was 0.744， with a cut-off value of 5.95 ng/mL. Serum visfatin of the EOC patients was related to T， N and FIGO stage （P<0.05）， and was positively correlated with CA125 （rs=0.389， P=0.001）. The rate of Nampt positive expression in tissues from EOC was significantly increased and correlated with FIGO stage and serum visfatin （P<0.05）. Nampt protein expression in EOC was positively correlated with serum visfatin level （rs=0.55， P<0.001）. The 1-year， 3-year and 5-year survival rate of these patients with EOC was 98.6%， 74.3% and 34.3%， respectively. Survival analysis demonstrated that the overall survival of these patients was related to T， N， FIGO stage， serum visfatin and Nampt expression in EOC， and both FIGO stage and Nampt expression were independent prognostic factors （P<0.05）. 【Conclusion】 The overall survival of these EOC patients was related to T， N， FIGO stage， serum visfatin and Nampt expression， and FIGO stage and Nampt expression are independent factors predicting the outcome. This highlights that visfatin-Nampt axis promotes the progression of epithelial ovarian cancer and affects the prognosis of EOC patients.

Effects of liver-specific Nampt knockout on ischemic stroke / 药学实践杂志

Objective Nicotinamide phosphoribosyltransferase (Nampt) is a new therapeutic target for ischemic stroke. The aim of this study was to investigate protective effect of liver-derived Nampt on ischemic stroke. Methods Liver-specific Nampt knockout mice were generated using the Cre/loxP system. NamptloxP/loxP mice were crossed with liver-specific Cre recombinase expression mice (Alb-Cre), and the progeny genotypes were identified by polymerase chain reaction. Body weight of knockout mice and control mice were measured. Nampt in liver and brain was determined by Western blot assay. Middle cerebral artery occlusion (MCAO), a classical ischemic stroke model, was generated in liver-specific Nampt knockout mice and control mice by electrocoagulation. After 24 h of modeling, neurological deficit scores of each group were evaluated and TTC staining was performed to determine the cerebral infarction volume. The level of plasma Nampt in each group was determined by ELISA. Results Liver-specific Nampt knockout mice with the genotype of NamptloxP/loxPAlb-Cre were successfully constructed. The hepatic Nampt expression in knockout mice was significantly decreased by 74.2% compared to control mice, while there was no significant difference in the expression of brain Nampt protein between the knockout group and the control group. Specific knockout of liver Nampt gene expression had no effect on the body weight of mice. Under normal physiological conditions, there was no significant difference in plasma Nampt levels between liver-specific Nampt knockout mice and control mice of the same gender. 24 h after MCAO modeling, there were no significant differences in neurological deficit scores, cerebral infarct volume and plasma Nampt concentration between liver-specific Nampt knockout group and control group. Conclusion Liver-specific Nampt knockout mice are successfully constructed. Liver-derived Nampt has no significant protective effects on ischemic stroke.

Mechanisms of Dangua Recipe in Improving Glycolipid Metabolic Disorders Based on Transcriptomics / 中国结合医学杂志

OBJECTIVE@#To explore the mechanisms of Dangua Recipe (DGR) in improving glycolipid metabolism based on transcriptomics.@*METHODS@#Sprague-Dawley rats with normal glucose level were divided into 3 groups according to a random number table, including a conventional diet group (Group A), a DGR group (Group B, high-calorie diet + 20.5 g DGR), and a high-calorie fodder model group (Group C). After 12 weeks of intervention, the liver tissue of rats was taken. Gene sequence and transcriptional analysis were performed to identify the key genes related to glycolipid metabolism reflecting DGR efficacy, and then gene or protein validation of liver tissue were performed. Nicotinamide phosphoribosyl transferase (Nampt) and phosphoenolpyruvate carboxykinase (PEPCK) proteins in liver tissues were detected by enzyme linked immunosorbent assay, fatty acid synthase (FASN) protein was detected by Western blot, and fatty acid binding protein 5 (FABP5)-mRNA was detected by quantitative real-time polymerase chain reaction. Furthermore, the functional verification was performed on the diabetic model rats by Nampt blocker (GEN-617) injected in vivo. Hemoglobin A@*RESULTS@#Totally, 257 differential-dominant genes of Group A vs. Group C and 392 differential-dominant genes of Group B vs. Group C were found. Moreover, 11 Gene Ontology molecular function terms and 7 Kyoto Encyclopedia of Genes and Genomes enrichment pathways owned by both Group A vs. Group C and Group C vs. Group B were confirmed. The liver tissue target validation showed that Nampt, FASN, PEPCK protein and FABP5-mRNA had the same changes consistent with transcriptome. The in vivo functional tests showed that GEN-617 increased body weight, HbA@*CONCLUSION@#Nampt activation was one of the mechanisms about DGR regulating glycolipid metabolism.

NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

Nicotinamide phosphoribosyl transferase (NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation. However, therapeutic benefit of NAMPT enzymatic inhibitors appears very limited, likely due to the failure to intervene non-enzymatic functions of NAMPT. Herein, we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells (MDSCs) via a mechanism independent of its enzymatic activity. Using proteolysis-targeting chimera (PROTAC) technology, PROTAC A7 is identified as a potent and selective degrader of NAMPT, which degrades intracellular NAMPT (iNAMPT) via the ubiquitin-proteasome system, and in turn decreases the secretion of extracellular NAMPT (eNAMPT), the major player of the non-enzymatic activity of NAMPT. In vivo, PROTAC A7 efficiently degrades NAMPT, inhibits tumor infiltrating MDSCs, and boosts antitumor efficacy. Of note, the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on MDSCs. Together, our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment, and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT, pointing out a new direction for the development of NAMPT-targeted therapies.

Research on role of Nampt in regulating ERK1/2 in pathological myocardial hypertrophy / 中国药理学通报

Aim To investigate the role of Nampt in regulating ERK1/2 in cardiac hypertrophy and its mechanisms. Methods The primary neonatal rat cardiomyocytes were stimulated by phenylephrine (PE) (100 μmol · L

Tongluo Xingnao Effervescent Tablets ameliorates cognitive function of SAMP8 mice via Nampt/SIRT1/FOXO3 pathway / 中成药

AIM To investigate the effects of Tongluo Xingnao Effervescent Tablets (Chuanxiong Rhizoma,Angelicae sinensis Radix and Scutellariae Radix) on the learning and memory function in SAMP8 mice,and improvements in cognitive function.METHODS Morris water maze was used to evaluate the change of cognitive function in SAMP8 mice after they were treated with Tongluo Xingnao Effervescent Tablets for 60 d,and the activity of superoxide dismutase (SOD),the concentration of protein carbonyls (PC),the ratio of NAD +/NADH in brain tissue were detected by ELISA,the expression of Nampt,SIRT1 and FOXO3 in hippocampus were measured with immunohistochemical methods.RESULTS Tongluo Xingnao Effervescent Tablets shortened escape latency and obviously increased percentage of time in target quadrant in hidden platform test and increased the times entering the target quadrant in spatial probe test in SAMP8 mice.It evidently enhanced the activity of SOD,the ratio of NAD +/NADH and distinctly decreased the protein carbonyls level.Moreover,Tongluo Xingnao Effervescent Tablets could markedly up-regulate the expression of Nampt and SIRT1,but evidently down-regulate FOXO3 protein expression.CONCLUSION The experimental data show that Tongluo Xingnao Effervescent Tablets can enhance the cognitive function of SAMP8 through regulating Nampt/SIRT1/FOXO3 signal pathway.

Overexpression of Nampt induced cardiac hypertrophy by activating NF-κB / 中国药理学通报

Aim To examine the effect of Nampt over-expression on cardiac hypertrophy,and elucidate the role of NF-κB.Methods The cultured neonatal car-diomyocytes were pretreated with 100 μmol · L-1 PE or transfected with Nampt.The mRNA and protein ex-pression of Nampt were determined by Real-time PCR and Western blot respectively.The cardiomyocyte hy-pertrophy was monitored by measuring cell-surface area and the mRNA levels of ANP and BNP,which were biomarkers of hypertrophic response.Moreover,we te-sted the effects of Nampt on NF-κB-dependent tran-scription activity through luciferase reporter gene as-says.Results Nampt overexpression significantly in-creased cardiomyocyte surface area and the mRNA ex-pression of ANP and BNP.In addition,Nampt overex-pression could markedly increase NF-κB-dependent transcription activity. Moreover, when p65 was knocked down,cardiomyocytes with Nampt overexpres-sion could not induce cardiac hypertrophy.Conclusion Overexpression of Nampt induces cardiac hypertro-phy by increasing NF-κB-dependent transcription activ-ity.

The research progress on NAMPT in malignant tumors / 实用肿瘤学杂志

Nicotinamide phosphoribosyltransferase( NAMPT) is the rate-limiting enzyme that catalyzes the first step in Nicotinamide adenine dinucleotide( NAD) biosynthesis and regulates biological processes such as metab-olism,growth and apoptosis of cells.In the past few years,a large number of studies have found that expression level of NAMPT is increased in a variety of malignancies,which is associated with the progression and treatment of malig-nant tumors.The research of the mechanism of NAMPT in malignant tumors and molecule inhibitors of the NAMPT have brought new hope and prospect for the treatment of malignant tumors.This article makes a brief review of NAMPT research status in malignant tumors.

Target and drug research for stroke treatment / 中国药理学与毒理学杂志

As the first most common cause of death in China,stroke has become a public health problem that seriously affects national economy and people′s livelihood. Unfortunately,only 3% to 5% of stroke patients receive tissue plasminogen activator(tPA)treatment,the only pharmacological therapy ap?proved for ischemic stroke,and no drug is available for hemorrhagic stroke. Therefore,there is an ur?gent need to develop new drugs for stroke therapy. Despite the awareness that neuroprotective agents could be a common strategy for the treatment of both ischemic and hemorrhagic stroke,numerous neu?roprotective agents have showed failure in clinical trials. Combined with the current therapeutic strategies and drug development of stroke,this paper elaborated the stroke injury mechanisms and corresponding clinical drug research targeting excitotoxicity,oxidative and nitrosative stress,and inflammation. From a new perspective,this paper has proposed a novel therapeutic strategy targeting inherent defense mechanisms against stroke,with nicotinamide phosphoribosyltransferase(Nampt)- nicotinamide ade?nine dinucleotide defense system as an example to present our experimental evidence that Nampt can serve as an anti-stroke target and nicotinamide mononucleotide as an anti-stroke agent under development. It is hoped that the bottleneck of stroke therapy can be overcome with unremitting efforts so as to reduce the financial burden and mental stress,and bring benefits to people around the world.

The advance of Nampt in gliomas / 实用肿瘤学杂志

Nampt is a rate -limiting enzyme in the mammalian salvaging pathway for the synthesis of NAD that is involved in cell metabolism and proliferation .In recent years,growing research has elucidated that Nampt is correlated to various malignant tumors .It has a complex functions including regulation of energy metabo-lism and genome instability,promotion of proliferation and angiogenesis ,tumor-promoting inflammation and a-voidance of immune destruction .Recent reports indicate that Nampt is highly expressed in gliomas ,and it is close-ly related to the proliferation ,migration,invasion and prognosis of gliomas ,which will provide a new target for the glioma research and therapy .