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.
Humans ; NAD/metabolism* ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism* ; Nicotinamide Phosphoribosyltransferase/metabolism* ; Cytokines/metabolism* ; Quinones ; Oxidoreductases

BACKGROUND: Systemic inflammation in psoriasis causes insulin resistance and cardiovascular diseases. Adipokines are adipose-tissue-derived factors that are involved in metabolic processes. It is thought that these adipokines are associated with the development of psoriasis. OBJECTIVE: The purpose of this study was to determine the changes in adipokine levels, insulin resistance, hypertension, and dyslipidemia over a 12-week period. METHODS: The study comprised 35 psoriasis patients and 50 controls. Blood samples were obtained twice from the patients, one sample at the start and one at the end of a 12-week follow-up period. The following parameters were assessed in both groups: serum fasting glucose, fasting insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR) index, serum lipids, adiponectin, leptin, resistin, chemerin, omentin, vaspin, visfatin, retinol-binding protein 4, and high-sensitivity C-reactive protein (hs-CRP) levels; blood pressure; body mass index; and the psoriasis area severity index (PASI) scores. RESULTS: The patients showed an improvement in the PASI score and a significant decrease in serum hs-CRP, omentin, and chemerin values. Moreover, at the start of the follow-up, the psoriasis patients had significantly lower levels of adiponectin and visfatin and significantly higher levels of vaspin and resistin than those of the control group. Visfatin levels correlated negatively with low-density lipoprotein (LDL) and cholesterol, while vaspin and omentin levels correlated positively with diastolic blood pressure. Decreased adiponectin levels correlated negatively with diastolic blood pressure and LDL. CONCLUSION: Plasma levels of adipokines might be useful for evaluating the disease activity of psoriasis and its comorbidities.
Adipokines* ; Adiponectin ; Blood Pressure ; Body Mass Index ; C-Reactive Protein ; Cardiovascular Diseases ; Cholesterol ; Comorbidity ; Dyslipidemias* ; Fasting ; Follow-Up Studies ; Glucose ; Homeostasis ; Humans ; Hypertension* ; Inflammation ; Insulin Resistance* ; Insulin* ; Leptin ; Lipoproteins ; Metabolism ; Nicotinamide Phosphoribosyltransferase ; Plasma ; Psoriasis* ; Resistin

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD(+), essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA (TSA) and β-lapachone (β-lap) induced a rapid depletion of NAD(+) pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death. Compared with TSA or β-lap treatment alone, co-treatment with FK866 induced a more dramatic depletion of NAD(+), repression of SIRT1 activity, and thereby the increased accumulation of acetylated FOXO1 and the activation of apoptotic pathway. In conclusion, the results from the present study support that NAMPT inhibition can synergize with NQO1 activation to induce apoptotic cell death, thereby providing a new rationale for the development of combinative therapeutic drugs in combating non-small lung cancer.
Abietanes ; pharmacology ; Apoptosis ; drug effects ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; enzymology ; genetics ; physiopathology ; Cell Line, Tumor ; Cytokines ; antagonists & inhibitors ; genetics ; metabolism ; Enzyme Inhibitors ; pharmacology ; Humans ; NAD ; metabolism ; NAD(P)H Dehydrogenase (Quinone) ; genetics ; metabolism ; Naphthoquinones ; pharmacology ; Nicotinamide Phosphoribosyltransferase ; antagonists & inhibitors ; genetics ; metabolism

OBJECTIVEInterferon-γ (IFN-γ) plays an important role in apoptosis and was shown to increase the risk of diabetes. Visfatin, an adipokine, has anti-diabetic, anti-tumor, and regulating inflammatory properties. In this study we investigated the effect of visfatin on IFN-γ-induced apoptosis in rat pancreatic β-cells.

METHODSThe RINm5F (rat insulinoma cell line) cells exposed to IFN-γ were treated with or without visfatin. The viability and apoptosis of the cells were assessed by using MTT and flow cytometry. The expressions of mRNA and protein were detected by using real-time PCR and western blot analysis.

RESULTSThe exposure of RINm5F cells to IFN-γ for 48 h led to increased apoptosis percentage of the cells. Visfatin pretreatment significantly increased the cell viability and reduced the cell apoptosis induced by IFN-γ. IFN-γ-induced increase in expression of p53 mRNA and cytochrome c protein, decrease in mRNA and protein levels of anti-apoptotic protein Bcl-2 were attenuated by visfatin pretreatment. Visfatin also increased AMPK and ERK1/2 phosphorylation and the anti-apoptotic action of visfatin was attenuated by the AMPK and ERK1/2 inhibitor.

CONCLUSIONThese results suggested that visfatin protected pancreatic islet cells against IFN-γ-induced apoptosis via mitochondria-dependent apoptotic pathway. The anti-apoptotic action of visfatin is mediated by activation of AMPK and ERK1/2 signaling molecules.

Adenylate Kinase ; metabolism ; Animals ; Apoptosis ; physiology ; Cell Line ; Cytokines ; physiology ; Flow Cytometry ; Interferon-gamma ; physiology ; Islets of Langerhans ; cytology ; MAP Kinase Signaling System ; Nicotinamide Phosphoribosyltransferase ; physiology ; Rats ; Real-Time Polymerase Chain Reaction ; Signal Transduction

Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme for synthesis of nicotinamide adenine dinucleotide in mammalian cells. Recent studies show that Nampt also works as a cytokine that exerts insulin-mimetic effects by binding to the insulin receptor, induces B-cell differentiation, inhibits neutrophil apoptosis, and affects immune and inflammatory functions. This review is focused on current knowledge regarding the structure and function of Nampt and its roles in carcinogenesis.
Humans ; Neoplasms ; enzymology ; Nicotinamide Phosphoribosyltransferase ; metabolism ; physiology

INTRODUCTIONThe present study aimed to investigate the possible associations between serum levels of visfatin, an adipokine, and atherosclerosis in patients with ischaemic cerebrovascular disease.

METHODSA total of 95 participants were recruited for this study. Group A comprised 35 individuals with no history of cerebrovascular disease (control group) and Group B comprised 60 patients with ischaemic cerebrovascular disease. Group B was further categorised into two subgroups based on the ultrasonographic findings of the common carotid artery intima‑media thickness (CCA‑IMT) - Group B1 consisted of 21 patients with no atherosclerosis (i.e. CCA‑IMT ≤ 0.9 mm) and Group B2 consisted of 39 patients with atherosclerosis (i.e. CCA‑IMT > 0.9 mm). The body mass index, fasting blood total cholesterol, triglycerides, high‑density lipoprotein cholesterol, low‑density lipoprotein cholesterol and glucose levels of each patient were measured. Serum visfatin levels were determined using enzyme‑linked immunosorbent assays. Visfatin levels were compared between groups, and stepwise logistic regression analysis was used to identify risk factors for atherosclerosis, including visfatin levels.

RESULTSThe mean serum visfatin level of the patients in Group B was higher than that in Group A (75.5 ± 77.80 ng/mL vs. 8.6 ± 4.69 ng/mL; p < 0.05) and the level was higher in patients from Group B2 than those from Group B1 (89.0 ± 80.68 ng/mL vs. 50.4 ± 72.44 ng/mL; p < 0.05). Multivariate regression analysis showed that CCA‑IMT values were not significantly associated with visfatin levels. However, logistic regression analysis showed that serum visfatin was an independent risk factor for atherosclerosis (odds ratio 37.80; p = 0.004).

CONCLUSIONSerum visfatin may be an independent risk factor for cerebral infarction, as high serum visfatin levels are positively associated with the underlying pathogenic mechanisms of ischaemic cerebrovascular disease.

Adipokines ; metabolism ; Adipose Tissue ; pathology ; Adult ; Aged ; Atherosclerosis ; blood ; complications ; Body Mass Index ; Brain Ischemia ; blood ; complications ; Carotid Intima-Media Thickness ; Case-Control Studies ; Cerebrovascular Disorders ; blood ; complications ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Inflammation ; Logistic Models ; Male ; Middle Aged ; Nicotinamide Phosphoribosyltransferase ; blood ; Risk Factors

The aim of the current study is to investigate the effect of visfatin on cardiomyocyte hypertrophy. Cultured H9c2 cardiomyocytes were exposed to visfatin at different concentrations for different periods of time, and the markers of cardiomyocyte hypertrophy were detected. Moreover, pravastatin, the inhibitor of endoplasmic reticulum stress (ERS) or thapsigargin, an ERS agonist was used respectively to pre-treat the cells before visfatin stimulation. F-actin staining was performed to measure the cell surface change. The mRNA expressions of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and ERS markers including glucose-regulated protein 78(GRP78), C/EPB homologous protein (CHOP) and activating transcription factor 6 (ATF6) were assessed by real time RT-PCR. The change of protein level of GRP78 and CHOP was detected by Western blot. The experimental data demonstrated that exposure to 100 or 150 ng/mL concentrations of visfatin for 24 h, or 100 ng/mL of visfatin for 24 or 48 h, significantly increased the expression of markers for cardiomyocyte hypertrophy. Visfatin stimulation provoked ERS in H9c2 cells. Furthermore, pre-treatment with pravastatin partially inhibited the visfatin-induced mRNA expression of ANP and BNP in H9c2 cells, whereas thapsigargin promoted the visfatin-induced expression of cardiomyocyte hypertrophy markers. The results suggest that visfatin might induce cardiomyocyte hypertrophy via ERS -dependent pathways.
Actins ; Activating Transcription Factor 6 ; metabolism ; Animals ; Cell Line ; Heat-Shock Proteins ; metabolism ; Hypertrophy ; Myocytes, Cardiac ; cytology ; drug effects ; Natriuretic Peptide, Brain ; metabolism ; Nicotinamide Phosphoribosyltransferase ; pharmacology ; Rats ; Transcription Factor CHOP ; metabolism

Nicotinamide phosphoribosyltransferase (Nampt) is also called visfatin or pre-B-cell colony-enhancing factor. The functions of Nampt have been reported as a cytokine, an adipokine and the rate-limiting enzyme in nicotinamide adenine dinucleotide biosynthesis. As a pleiotropic multifunctional protein, Nampt is involved in a variety of physiological and pathological conditions including innate immunity, metabolic disorders, and stress; and Nampt also participates in inflammatory disorders such as acute lung injury, atherosclerosis, myocardial infarct, obesity, type 2 diabetes, and rheumatoid arthritis. The studies indicate that Nampt might be a potential target for pharmacological intervention against inflammatory diseases. We review research advances on the roles of Nampt in inflammation.
Animals ; Humans ; Inflammation ; enzymology ; Nicotinamide Phosphoribosyltransferase ; metabolism

OBJECTIVETo observe the effect of recombinant human nicotinamide phosphoribosyl-transferase (NAMPT) on physiological/biochemical indexes and brain structure in mice.

METHODSWild type human recombinant NAMPT (10, 30 and 100 μg/kg) or H247A mutant NAMPT (with very weak enzymatic activity) were administrated by intravenous injection in mice once every 3 d for 32 d. The changes of body weight, blood pressure, heart rate, serum glucose, serum total cholesterol and triglyceride were determined, and the morphology of neuron, astrocyte and microglia in hippocampus were observed.

RESULTSThe injection of wild and mutated type NAMPT had no significant effect on body weight, blood pressure,heart rate, blood glucose, total cholesterol and triglyceride, and did not affect the morphology of neuron, astrocyte and microglia in hippocampus of mice.

CONCLUSIONElevation of plasma NAMPT may not induce metabolic and neuronal dysfunction in normal individual.

Animals ; Blood Glucose ; metabolism ; Brain ; anatomy & histology ; drug effects ; Cholesterol ; blood ; Cytokines ; pharmacology ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Nicotinamide Phosphoribosyltransferase ; pharmacology ; Recombinant Proteins ; pharmacology ; Triglycerides ; blood

OBJECTIVE: To determine the levels of visfatin in patients with chronic kidney disease (CKD) and to explore the relationship between visfatin levels and caroid atherosclerosis in CKD patients. METHODS: A total of 180 CKD patients (102 non-dialyzed patients and 78 dialysis patients) and 42 healthy subjects enrolled in this study. The serum levels of visfatin, IL-6, and high sensitive C-reactive protein (hsCRP) were measured by ELISA. Common carotid arteries intima-media thickness (CCA-IMT), cross-sectional calculated intima-media thickness (c IMT) area and atherosclerotic plaque were detected by non-invasive high-resolution B-mode ultrasonography. RESULTS: The serum levels of visfatin, IL-6 and hsCRP were significantly increased in CKD patients compared with age matched healthy subjects (P<0.01). The serum levels of visfatin, IL-6 and hsCRP in the dialyzed patients were significantly higher than those in non-dialyzed patients (P<0.05). Visfatin levels increased with the progression of renal dysfunction and inversely related to creatinine clearance (Ccr) in non-dialyzed patients (r=-0.415, P<0.05). Patients with carotid artery plaques showed significantly higher levels of visfatin[(34.22±7.96) ng/mL)] compared with those without plaques [(28.24±6.18) ng/mL, P<0.05]. The serum levels of visfatin were closely correlated with IL-6 (r=0.548, P<0.001), hsCRP (r=0.430, P<0.001), CCA-IMT (r=0.462, P<0.05), and c IMT area (r=0.411, P<0.05). After adjusting for GFR, age, gender, and other risk factors associated with atherosclerosis, multiple stepwise regression analysis showed that serum visfatin is a independent risk factor for CCA-IMT (β=0.433, P<0.01) and c IMT area (β=0.412, P<0.01). CONCLUSION The serum level of visfatin increase with the progression of CKD and should be considered to be a new risk factor for atherosclerosis in CKD.
Adult ; Aged ; C-Reactive Protein ; metabolism ; Carotid Artery Diseases ; blood ; complications ; Case-Control Studies ; Female ; Humans ; Interleukin-6 ; blood ; Male ; Middle Aged ; Nicotinamide Phosphoribosyltransferase ; blood ; Renal Insufficiency, Chronic ; blood ; complications ; Risk Factors