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1.
Acta Pharmacol Sin ; 42(6): 871-884, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34002042

RESUMEN

Stroke is a common cause of death and disability. Allisartan isoproxil (ALL) is a new angiotensin II receptor blocker and a new antihypertensive drug discovered and developed in China. In the present study we investigated the therapeutic effects of ALL in stroke-prone renovascular hypertensive rats (RHR-SP) and the underlying mechanisms. The model rats were generated via two-kidney two-clip (2K2C) surgery, which led to 100% of hypertension, 100% of cerebrovascular damage as well as 100% of mortality 1 year after the surgery. Administration of ALL (30 mg · kg-1 · d-1 in diet, for 55 weeks) significantly decreased stroke-related death and prolonged lifespan in RHR-SP, but the survival ALL-treated RHR-SP remained of hypertension and cardiovascular hypertrophy compared with sham-operated normal controls. In addition to cardiac, and aortic protection, ALL treatment for 10 or 12 weeks significantly reduced cerebrovascular damage incidence and scoring, along with a steady reduction of blood pressure (BP) in RHR-SP. Meanwhile, it significantly decreased serum aldosterone and malondialdehyde levels and cerebral NAD(P)H oxidase expressions in RHR-SP. We conducted 24 h continuous BP recording in conscious freely moving RHR-SP, and found that a single intragastric administration of ALL produced a long hypotensive effect lasting for at least 12 h on systolic BP. Taken together, our results in RHR-SP demonstrate that ALL can be used for stroke prevention via BP reduction and organ protection, with the molecular mechanisms related to inhibition of angiotensin-aldosterone system and oxidative stress. This study also provides a valuable scoring for evaluation of cerebrovascular damage and drug efficacy.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antihipertensivos/uso terapéutico , Enfermedades de la Aorta/prevención & control , Compuestos de Bifenilo/uso terapéutico , Trastornos Cerebrovasculares/prevención & control , Imidazoles/uso terapéutico , Accidente Cerebrovascular/prevención & control , Aldosterona/metabolismo , Animales , Aorta/efectos de los fármacos , Enfermedades de la Aorta/complicaciones , Enfermedades de la Aorta/mortalidad , Presión Sanguínea/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Trastornos Cerebrovasculares/complicaciones , Trastornos Cerebrovasculares/mortalidad , Trastornos Cerebrovasculares/patología , Corazón/efectos de los fármacos , Hipertensión/complicaciones , Hipertensión/mortalidad , Estimación de Kaplan-Meier , Riñón/efectos de los fármacos , Riñón/patología , Riñón/cirugía , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/mortalidad
2.
Acta Pharmacol Sin ; 41(12): 1568-1575, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32265491

RESUMEN

Dyslipidemia is a risk factor for cardiovascular diseases and type 2 diabetes. Several adipokines play important roles in modulation of blood lipids. Metrnl is a recently identified adipokine, and adipose Metrnl participates in regulation of blood triglyceride (TG). In this study, we generated Metrnl global, intestine-specific and liver-specific knockout mice, and explored the effects of Metrnl on serum lipid parameters. Global knockout of Metrnl had no effects on serum lipid parameters under normal chow diet, but increased blood TG by 14%, and decreased total cholesterol (TC) by 16% and high density lipoprotein cholesterol (HDL-C) by 24% under high fat diet. Nevertheless, intestine-specific knockout of Metrnl did not alter the serum lipids parameters under normal chow diet or high fat diet. Notably, liver-specific knockout of Metrnl decreased HDL-C by 24%, TC by 20% and low density lipoprotein cholesterol (LDL-C) by 16% without alterations of blood TG and nonesterified fatty acids (NEFA) under high fat diet. But deficiency of Metrnl in liver did not change VLDL secretion and expression of lipid synthetic and metabolic genes. We conclude that tissue-specific Metrnl controls different components of blood lipids. In addition to modulation of blood TG by adipose Metrnl, blood HDL-C is regulated by liver Metrnl.


Asunto(s)
HDL-Colesterol/metabolismo , Factores de Crecimiento Nervioso/deficiencia , Triglicéridos/metabolismo , Animales , HDL-Colesterol/sangre , Dieta Alta en Grasa , Técnicas de Inactivación de Genes , Ratones Endogámicos C57BL , Ratones Transgénicos , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Triglicéridos/sangre
3.
Acta Pharmacol Sin ; 41(6): 763-770, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31949292

RESUMEN

Metrnl is a newly identified secreted protein highly expressed in the intestinal epithelium. This study aimed to explore the role and mechanism of intestinal epithelial Metrnl in ulcerative colitis. Metrnl-/- (intestinal epithelial cell-specific Metrnl knockout) mice did not display any phenotypes of colitis under basal conditions. However, under administration of 3% dextran sodium sulfate (DSS) drinking water, colitis was more severe in Metrnl-/- mice than in WT mice, as indicated by comparisons of body weight loss, the presence of occult or gross blood per rectum, stool consistency, shrinkage in the colon, intestinal damage, and serum levels of inflammatory factors. DSS-induced colitis activated autophagy in the colon. This activation was partially inhibited by intestinal epithelial Metrnl deficiency, as indicated by a decrease in Beclin-1 and LC3-II/I and an increase in p62 in DSS-treated Metrnl-/- mice compared with WT mice. These phenomena were further confirmed by observation of autophagosomes and immunofluorescence staining for LC3 in epithelial cells. The autophagy-related AMPK-mTOR-p70S6K pathway was also activated in DSS-induced colitis, and this pathway was partially blocked by intestinal epithelial Metrnl deficiency, as indicated by a decrease in AMPK phosphorylation and an increase in mTOR and p70S6K phosphorylation in DSS-treated Metrnl-/- mice compared with WT mice. Therefore, Metrnl deficiency deteriorated ulcerative colitis at least partially through inhibition of autophagy via the AMPK-mTOR-p70S6K pathway, suggesting that Metrnl is a therapeutic target for ulcerative colitis.


Asunto(s)
Autofagia , Colitis Ulcerosa/metabolismo , Células Epiteliales/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Administración Oral , Animales , Células CACO-2 , Células Cultivadas , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/patología , Sulfato de Dextran/administración & dosificación , Células Epiteliales/patología , Humanos , Ratones , Ratones Noqueados , Ratones Transgénicos , Factores de Crecimiento Nervioso/deficiencia , Factores de Crecimiento Nervioso/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo
4.
Acta Pharmacol Sin ; 39(2): 294-301, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28858298

RESUMEN

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is a novel strategy for cancer therapy, but only two inhibitors of NAMPT (FK866 and CHS828) have progressed into clinical trials. This study seeks to compare a novel potent NAMPT inhibitor, MS0, with a classical inhibitor FK866 in their biological activity and molecular binding mode, thereby contributing to future chemical optimization and a further understanding of the action mode of NAMPT inhibitors. The IC50 values of MS0 and FK866 in inhibition of recombinant human NAMPT activity were 9.08±0.90 and 1.60±0.32 nmol/L, respectively. Consistently, FK866 exerted better antiproliferation in 6 human cancer cell lines (HepG2, A2780, 95-D, A549, U2OS and U266) than MS0 with IC50 values nearly 12-fold to 225-fold lower than those of MS0. Co-crystal structures of wild-type human NAMPT complexed with MS0 or FK866 were elucidated, which revealed that MS0 did not interact with Ser241. The hydrogen bond mediated by crystallographic water between MS0 and His191 or Val350 of NAMPT did not exist in FK866. Instead, FK866 exhibited hydrophobic interactions with Arg349. Based on the activity assays and crystal structure analyses, we elaborate the reason why the antiproliferation activity of MS0 was not as good as that of FK866, which would contributes to the current understanding of the mode of action of NAMPT inhibitors and will also contribute to further development of anticancer drugs in the future.


Asunto(s)
Acrilamidas/química , Antineoplásicos/química , Inhibidores Enzimáticos/química , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Piperidinas/química , Acrilamidas/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Inhibidores Enzimáticos/farmacología , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Piperidinas/farmacología
5.
Acta Pharmacol Sin ; 37(11): 1458-1466, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27546006

RESUMEN

AIM: Metrnl is a novel secreted protein, but its physiological roles remain elusive. In this study, we investigated the tissue expression pattern of Metrnl in humans and explored its possible physiological role in the tissues with most highly expressed levels. METHODS: A human tissue microarray containing 19 types of tissues from 69 donors was used to examine the tissue expression pattern of Metrnl, and the expression pattern was further verified in fresh human and mouse tissues. Intestinal epithelial cell-specific Metrnl knockout mice were generated, which were used to analyze the physiological roles of Metrnl. RESULTS: Metrnl was the most highly expressed in the human gastrointestinal tract, and was specifically expressed in the intestinal epithelium. Consistent with this, Metrnl mRNA was also most highly expressed in the mouse gastrointestinal tract among the 14 types of tissues tested. In the intestinal epithelial cell-specific Metrnl knockout mice, the Metrnl levels in the gut fluid were significantly reduced, whereas the Metrnl serum levels showed a trend towards a reduction, but this change was not statistically significant. This cell-specific deletion of Metrnl did not affect body weight, food intake, blood glucose, colon length and histology, intestinal permeability, mucus content or mucin 2 expression under physiological conditions, but statistically decreased the expression of antimicrobial peptides, such as regenerating islet-derived 3 gamma (Reg3g) and lactotransferrin. CONCLUSION: Metrnl is highly expressed in the intestinal epithelial cells of humans and mice, which mainly contributes to the local gut Metrnl levels and affects the serum Metrnl level to a lesser extent. Metrnl plays a role in maintaining gut antimicrobial peptides.


Asunto(s)
Adipoquinas/metabolismo , Péptidos Catiónicos Antimicrobianos/metabolismo , Mucosa Intestinal/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Adulto , Anciano , Animales , Colon/metabolismo , Células Epiteliales/metabolismo , Femenino , Humanos , Lactoferrina/metabolismo , Masculino , Ratones Noqueados , Persona de Mediana Edad , Factores de Crecimiento Nervioso/genética , Especificidad de Órganos , Proteínas Asociadas a Pancreatitis , Proteínas/metabolismo , Proteína Amiloide A Sérica/metabolismo , Análisis de Matrices Tisulares
6.
Acta Pharmacol Sin ; 36(4): 429-39, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25832423

RESUMEN

AIM: To investigate the effect of chronic nicotine treatment on vascular function and to identify the underlying mechanisms. METHODS: Adult rats were treated with nicotine (3 mg·kg(-1)·d(-1), sc) for 6 weeks. After the rats were sacrificed, aortic rings were prepared for detecting vascular reactivity, and thoracic aorta and periaortic fat samples were collected for histological and molecular biology studies. RESULTS: Chronic nicotine treatment significantly reduced periaortic fat, and specifically enhanced smooth muscle relaxation without altering the aortic adventitial fat and endothelium function. Pretreatment with the soluble guanylyl cyclase inhibitor ODQ (3 µmol/L) or PKG inhibitor Rp-8-Br-PET-cGMP (30 µmol/L) abolished the nicotine-induced enhancement of smooth muscle relaxation, whereas the cGMP analogue 8-Br-cGMP could mimic the nicotine-induced enhancement of smooth muscle relaxation. However, the chronic nicotine treatment did not alter PKG protein expression and activity in aortic media. CONCLUSION: Chronic nicotine treatment enhances vascular smooth muscle relaxation of rats via activation of PKG pathway.


Asunto(s)
Aorta/efectos de los fármacos , Estimulantes Ganglionares/farmacología , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Vasodilatación/efectos de los fármacos , Animales , Aorta/fisiología , Proteína Quinasa Dependiente de GMP Cíclico Tipo I/metabolismo , Grasas/metabolismo , Estimulantes Ganglionares/administración & dosificación , Masculino , Músculo Liso Vascular/fisiología , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos
7.
Front Immunol ; 8: 1674, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29234327

RESUMEN

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) with chronic and recurrent characteristics caused by multiple reasons. Although the pathogenic factors have not been clarified yet, recent studies have demonstrated that intestinal microbiota plays a major role in UC, especially in the immune system. This review focuses on the description of several major microbiota communities that affect UC and their interactions with the host. In this review, eight kinds of microbiota that are highly related to IBD, including Faecalibacterium prausnitzii, Clostridium clusters IV and XIVa, Bacteroides, Roseburia species, Eubacterium rectale, Escherichia coli, Fusobacterium, and Candida albicans are demonstrated on the changes in amount and roles in the onset and progression of IBD. In addition, potential therapeutic targets for UC involved in the regulation of microbiota, including NLRPs, vitamin D receptor as well as secreted proteins, are discussed in this review.

8.
CNS Neurosci Ther ; 22(9): 782-8, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27333812

RESUMEN

AIM: NAMPT is a novel therapeutic target of ischemic stroke. The aim of this study was to investigate the effect of a potential NAMPT activator, P7C3-A20, an aminopropyl carbazole derivative, on ischemic stroke. METHODS: In vitro study, neuron protection effect of P7C3-A20 was investigated by co-incubation with primary neurons subjected to oxygen-glucose deprivation (OGD) or oxygen-glucose deprivation/reperfusion (OGD/R) injury. In vivo experiment, P7C3-A20 was administrated in middle cerebral artery occlusion (MCAO) rats and infarct volume was examined. Lastly, the brain tissue nicotinamide adenine dinucleotide (NAD) levels were detected in P7C3-A20 treated normal or MCAO mice. RESULTS: Cell viability, morphology, and Tuj-1 staining confirmed the neuroprotective effect of P7C3-A20 in OGD or OGD/R model. P7C3-A20 administration significantly reduced cerebral infarction in MCAO rats. Moreover, brain NAD levels were elevated both in normal and MCAO mice after P7C3-A20 treatment. CONCLUSIONS: P7C3-A20 has neuroprotective effect in cerebral ischemia. The study contributes to the development of NAMPT activators against ischemic stroke and expands the horizon of the neuroprotective effect of aminopropyl carbazole chemicals.


Asunto(s)
Infarto Encefálico/prevención & control , Carbazoles/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Animales , Infarto Encefálico/etiología , Hipoxia de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/citología , Modelos Animales de Enfermedad , Proteína Ácida Fibrilar de la Glía/metabolismo , Glucosa/deficiencia , Infarto de la Arteria Cerebral Media/complicaciones , Masculino , Ratones , Ratones Endogámicos C57BL , NAD/metabolismo , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Tubulina (Proteína)/metabolismo
9.
Sci Rep ; 5: 10043, 2015 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-26040985

RESUMEN

Nicotinamide phosphoribosyltransferase (NAMPT) is a promising anticancer target. Using high throughput screening system targeting NAMPT, we obtained a potent NAMPT inhibitor MS0 (China Patent ZL201110447488.9) with excellent in vitro activity (IC50 = 9.87 ± 1.15 nM) and anti-proliferative activity against multiple human cancer cell lines including stem-like cancer cells. Structure-activity relationship studies yielded several highly effective analogues. These inhibitors specifically bound NAMPT, rather than downstream NMNAT. We provided the first chemical case using cellular thermal shift assay to explain the difference between in vitro and cellular activity; MS7 showed best in vitro activity (IC50 = 0.93 ± 0.29 nM) but worst cellular activity due to poor target engagement in living cells. Site-directed mutagenesis studies identified important residues for NAMPT catalytic activity and inhibitor binding. The present findings contribute to deep understanding the action mode of NAMPT inhibitors and future development of NAMPT inhibitors as anticancer agents.


Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Ensayos Analíticos de Alto Rendimiento , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Conformación Molecular , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Nicotinamida Fosforribosiltransferasa/química , Unión Proteica , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad
10.
Sci Rep ; 5: 12657, 2015 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-26227784

RESUMEN

Nicotinamide phosphoribosyltransferase (NAMPT) is a promising antitumor target. Novel NAMPT inhibitors with diverse chemotypes are highly desirable for development of antitumor agents. Using high throughput screening system targeting NAMPT on a chemical library of 30000 small-molecules, we found a non-fluorescent compound F671-0003 and a fluorescent compound M049-0244 with excellent in vitro activity (IC50: 85 nM and 170 nM respectively) and anti-proliferative activity against HepG2 cells. These two compounds significantly depleted cellular NAD levels. Exogenous NMN rescued their anti-proliferative activity against HepG2 cells. Structure-activity relationship study proposed a binding mode for NAMPT inhibitor F671-0003 and highlighted the importance of hydrogen bonding, hydrophobic and π-π interactions in inhibitor binding. Imaging study provided the evidence that fluorescent compound M049-0244 (3 µM) significantly stained living HepG2 cells. Cellular fluorescence was further verified to be NAMPT dependent by using RNA interference and NAMPT over expression transgenic mice. Our findings provide novel antitumor lead compounds and a "first-in-class" fluorescent probe for imaging NAMPT.


Asunto(s)
Antineoplásicos/farmacología , Benzamidas/química , Benzamidas/farmacología , Citocinas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Colorantes Fluorescentes/química , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Quinoxalinas/química , Quinoxalinas/farmacología , Animales , Citocinas/química , Descubrimiento de Drogas , Células Hep G2 , Humanos , Ratones , Ratones Transgénicos , Nicotinamida Fosforribosiltransferasa/química , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad
11.
J Gerontol A Biol Sci Med Sci ; 69(1): 44-57, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23946338

RESUMEN

Calorie restriction (CR) is one of the most reproducible treatments for weight loss and slowing aging. However, how CR induces these metabolic alterations is not fully understood. In this work, we studied whether nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for nicotinamide adenine dinucleotide biosynthesis, plays a role in CR-induced beneficial metabolic effects using a specific inhibitor of NAMPT (FK866). CR upregulated NAMPT mRNA and protein levels in rat skeletal muscle and white adipose tissue. Inhibition of NAMPT activity by FK866 in rats did not affect the SIRT1 upregulation by CR but suppressed the CR-induced SIRT1 activity and deacetylation of Forkhead box protein O1/peroxisome proliferator-activated receptor γ coactivator-1α. Inhibition of NAMPT activity by FK866 also attenuated the CR-induced SIRT3 activity, evidenced by deacetylation of superoxide dismutase-2. Furthermore, FK866 not only weakened the CR-induced decrease of oxidative stress (dichlorofluorescin signal, superoxide , and malondialdehyde levels), but also greatly attenuated the CR-induced improvements of antioxidative activity (total superoxide dismutase, glutathione, and glutathione/oxidized glutathione ratio) and mitochondrial biogenesis (mRNA levels of nuclear respiratory factor 1, cytochrome c oxidase IV, peroxisome proliferator-activated receptor-γ coactivator-1α, and transcription factor A, mitochondrial and citrate synthase activity). At last, FK866 blocked the CR-induced insulin sensitizing, Akt signaling activation, and endothelial nitric oxide synthase phosphorylation. Collectively, our data provide the first evidence that the CR-induced beneficial effects in oxidative stress, mitochondrial biogenesis, and metabolic adaptation require NAMPT.


Asunto(s)
Restricción Calórica , Regulación del Desarrollo de la Expresión Génica , Recambio Mitocondrial/genética , Nicotinamida Fosforribosiltransferasa/genética , Estrés Oxidativo/genética , ARN Mensajero/genética , Pérdida de Peso/fisiología , Envejecimiento/genética , Animales , Western Blotting , Modelos Animales de Enfermedad , Masculino , Nicotinamida Fosforribosiltransferasa/biosíntesis , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal
12.
CNS Neurosci Ther ; 19(9): 667-74, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23702193

RESUMEN

BACKGROUND: Ambulatory arterial stiffness index (AASI) has been proposed as a new measure of arterial stiffness for predicting cardio-cerebro-vascular morbidity and mortality. However, there has been no research on the direct relationships between AASI and arterial stiffness-determining factors. METHODS: We utilized beat-to-beat intra-aortic blood pressure (BP) telemetry to characterize AASI in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). By determination of aortic structural components and analysis of their correlations with AASI, we provided the first direct evidence for the associations between AASI and arterial stiffness-determining factors including the collagen content and collagen/elastin. RESULTS: Ambulatory arterial stiffness index was positively correlated with pulse pressure in both WKY and SHR, less dependent on BP and BP variability than pulse pressure, and relatively stable, especially the number of BP readings not less than ~36. The correlations between AASI and aortic components were comparable for various AASI values derived from BP readings not less than ~36. Not only AASI but also BP variability and pulse pressure demonstrated a direct relationship with arterial stiffness. CONCLUSIONS: These findings indicate AASI may become a routine measure in human arterial stiffness assessment. It is recommended to use a cluster of parameters such as AASI, BP variability, and pulse pressure for evaluating arterial stiffness.


Asunto(s)
Aorta/fisiopatología , Telemetría , Rigidez Vascular , Animales , Presión Sanguínea , Hipertensión/fisiopatología , Morbilidad , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY
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