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1.
Nat Commun ; 12(1): 5492, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535643

RESUMO

Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) in human. It is an important validated drug target for cardiovascular diseases. sGC can be pharmacologically activated by stimulators and activators. However, the detailed structural mechanisms, through which sGC is recognized and positively modulated by these drugs at high spacial resolution, are poorly understood. Here, we present cryo-electron microscopy structures of human sGC in complex with NO and sGC stimulators, YC-1 and riociguat, and also in complex with the activator cinaciguat. These structures uncover the molecular details of how stimulators interact with residues from both ß H-NOX and CC domains, to stabilize sGC in the extended active conformation. In contrast, cinaciguat occupies the haem pocket in the ß H-NOX domain and sGC shows both inactive and active conformations. These structures suggest a converged mechanism of sGC activation by pharmacological compounds.


Assuntos
Ativadores de Enzimas/farmacologia , Guanilil Ciclase Solúvel/metabolismo , Animais , Benzoatos/química , Benzoatos/farmacologia , Sítios de Ligação , Linhagem Celular , Microscopia Crioeletrônica , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/química , Humanos , Indazóis/química , Indazóis/farmacologia , Modelos Moleculares , Óxido Nítrico/farmacologia , Multimerização Proteica , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Guanilil Ciclase Solúvel/química , Guanilil Ciclase Solúvel/ultraestrutura
2.
J Enzyme Inhib Med Chem ; 36(1): 1783-1797, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34340630

RESUMO

Carbonic Anhydrase Activators (CAAs) could represent a novel approach for the treatment of Alzheimer's disease, ageing, and other conditions that require remedial achievement of spatial learning and memory therapy. Within a research project aimed at developing novel CAAs selective for certain isoforms, three series of indole-based derivatives were investigated. Enzyme activation assay on human CA I, II, VA, and VII isoforms revealed several effective micromolar activators, with promising selectivity profiles towards the brain-associated cytosolic isoform hCA VII. Molecular modelling studies suggested a theoretical model of the complex between hCA VII and the new activators and provide a possible explanation for their modulating as well as selectivity properties. Preliminary biological evaluations demonstrated that one of the most potent CAA 7 is not cytotoxic and is able to increase the release of the brain-derived neurotrophic factor (BDNF) from human microglial cells, highlighting its possible application in the treatment of CNS-related disorders.


Assuntos
Anidrases Carbônicas/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Indóis/farmacologia , Isoenzimas/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Anidrases Carbônicas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática , Ativadores de Enzimas/química , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Indóis/química , Isoenzimas/metabolismo , Microglia/citologia , Microglia/efeitos dos fármacos , Modelos Moleculares , Espectroscopia de Prótons por Ressonância Magnética , Especificidade por Substrato
3.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360780

RESUMO

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder, affecting one in 3500 to 5000 boys worldwide. The NO-sGC-cGMP pathway plays an important role in skeletal muscle function, primarily by improving blood flow and oxygen supply to the muscles during exercise. In fact, PDE5 inhibitors have previously been investigated as a potential therapy for DMD, however, a large-scale Phase III clinical trial did not meet its primary endpoint. Since the efficacy of PDE5i is dependent on sufficient endogenous NO production, which might be impaired in DMD, we investigated if NO-independent sGC stimulators, could have therapeutic benefits in a mouse model of DMD. Male mdx/mTRG2 mice aged six weeks were given food supplemented with the sGC stimulator, BAY-747 (150 mg/kg of food) or food alone (untreated) ad libitum for 16 weeks. Untreated C57BL6/J mice were used as wild type (WT) controls. Assessments of the four-limb hang, grip strength, running wheel and serum creatine kinase (CK) levels showed that mdx/mTRG2 mice had significantly reduced skeletal muscle function and severe muscle damage compared to WT mice. Treatment with BAY-747 improved grip strength and running speed, and these mice also had reduced CK levels compared to untreated mdx/mTRG2 mice. We also observed increased inflammation and fibrosis in the skeletal muscle of mdx/mTRG2 mice compared to WT. While gene expression of pro-inflammatory cytokines and some pro-fibrotic markers in the skeletal muscle was reduced following BAY-747 treatment, there was no reduction in infiltration of myeloid immune cells nor collagen deposition. In conclusion, treatment with BAY-747 significantly improves several functional and pathological parameters of the skeletal muscle in mdx/mTRG2 mice. However, the effect size was moderate and therefore, more studies are needed to fully understand the potential treatment benefit of sGC stimulators in DMD.


Assuntos
Ativadores de Enzimas/farmacologia , Músculo Esquelético/enzimologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Guanilil Ciclase Solúvel/metabolismo , Animais , Camundongos , Camundongos Endogâmicos mdx , Camundongos Transgênicos , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/enzimologia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia
4.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199160

RESUMO

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Benzofuranos/uso terapêutico , Desenvolvimento de Medicamentos , Ativadores de Enzimas/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Benzofuranos/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Colo/efeitos dos fármacos , Colo/patologia , Dinitrofluorbenzeno/análogos & derivados , Eletroforese em Gel Bidimensional , Ontologia Genética , Doenças Inflamatórias Intestinais/patologia , Interleucina-10/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
5.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065957

RESUMO

The presented research concerns the triple activity of trans-cinnamic (tCA), ferulic (FA) and syringic acids (SA). They act as thyroid peroxidase (TPO) activators, lipoxygenase (LOX) inhibitors and show antiradical activity. All compounds showed a dose-dependent TPO activatory effect, thus the AC50 value (the concentration resulting in 50% activation) was determined. The tested compounds can be ranked as follows: tCA > FA > SA with AC50 = 0.10, 0.39, 0.69 mM, respectively. Strong synergism was found between FA and SA. The activatory effects of all tested compounds may result from interaction with the TPO allosteric site. It was proposed that conformational change resulting from activator binding to TPO allosteric pocket results from the flexibility of a nearby loop formed by residues Val352-Tyr363. All compounds act as uncompetitive LOX inhibitors. The most effective were tCA and SA, whereas the weakest was FA (IC50 = 0.009 mM and IC50 0.027 mM, respectively). In all cases, an interaction between the inhibitors carboxylic groups and side-chain atoms of Arg102 and Arg139 in an allosteric pocket of LOX was suggested. FA/tCA and FA/SA acted synergistically, whereas tCA/SA demonstrated antagonism. The highest antiradical activity was found in the case of SA (IC50 = 0.22 mM). FA/tCA and tCA/SA acted synergistically, whereas antagonism was found for the SA/FA mixture.


Assuntos
Autoantígenos/metabolismo , Ativadores de Enzimas/farmacologia , Iodeto Peroxidase/metabolismo , Proteínas de Ligação ao Ferro/metabolismo , Inibidores de Lipoxigenase/farmacologia , Compostos Fitoquímicos/farmacologia , Proteína-Lisina 6-Oxidase/metabolismo , Autoantígenos/química , Cinamatos/química , Cinamatos/farmacologia , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Relação Dose-Resposta a Droga , Ativadores de Enzimas/química , Ácido Gálico/análogos & derivados , Ácido Gálico/química , Ácido Gálico/farmacologia , Humanos , Concentração Inibidora 50 , Iodeto Peroxidase/química , Proteínas de Ligação ao Ferro/química , Inibidores de Lipoxigenase/química , Modelos Moleculares , Compostos Fitoquímicos/química , Proteína-Lisina 6-Oxidase/química , Relação Estrutura-Atividade
6.
ACS Chem Biol ; 16(7): 1159-1163, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34165961

RESUMO

The nuclear receptor-related 1 protein, Nurr1, is a transcription factor critical for the development and maintenance of dopamine-producing neurons in the substantia nigra pars compacta, a cell population that progressively loses the ability to make dopamine and degenerates in Parkinson's disease. Recently, we demonstrated that Nurr1 binds directly to and is regulated by the endogenous dopamine metabolite 5,6-dihydroxyindole (DHI). Unfortunately, DHI is an unstable compound, and thus a poor tool for studying Nurr1 function. Here, we report that 5-chloroindole, an unreactive analog of DHI, binds directly to the Nurr1 ligand binding domain with micromolar affinity and stimulates the activity of Nurr1, including the transcription of genes governing the synthesis and packaging of dopamine.


Assuntos
Ativadores de Enzimas/farmacologia , Indóis/farmacologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/agonistas , Animais , Linhagem Celular , Ativadores de Enzimas/metabolismo , Ativadores de Enzimas/toxicidade , Indóis/metabolismo , Indóis/toxicidade , Camundongos , Mutação , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/química , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Ligação Proteica , Domínios Proteicos/genética
7.
Life Sci ; 280: 119694, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102192

RESUMO

Cancer is a leading cause of death globally. Cancer cell transformation is the result of intricate crosstalk between intracellular components and proteins. A characteristic feature of cancer cells is the ability to reprogram their metabolic pathways to ensure their infinite proliferative potential. Pyruvate kinase muscle isoform 2 (PKM2) is a glycolytic enzyme that plays crucial roles in cancer, apart from carrying out its metabolic roles. PKM2 is involved in all the major events associated with cancer growth. Modulation of PKM2 activity (dimer inhibition or tetramer activation) has been successful in controlling cancer. However, recent studies provide contrary evidences regarding the oncogenic functions of PKM2. Moreover, several studies have highlighted the cancerous roles of PKM1 isoform in certain contexts. The present review aims at providing the current updates regarding PKM2 targeting in cancer. Further, the review discusses the contradictory results that suggest that both the isoforms of PKM can lead to cancer growth. In conclusion, the review emphasizes revisiting the approaches to target cancer metabolism through PKM to find novel and effective targets for anticancer therapy.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Proteínas de Transporte/agonistas , Proteínas de Transporte/análise , Proteínas de Transporte/antagonistas & inibidores , Descoberta de Drogas , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Proteínas de Membrana/agonistas , Proteínas de Membrana/análise , Proteínas de Membrana/antagonistas & inibidores , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Hormônios Tireóideos/agonistas , Hormônios Tireóideos/análise
8.
J Med Chem ; 64(9): 5323-5344, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33872507

RESUMO

Herein we describe the discovery, mode of action, and preclinical characterization of the soluble guanylate cyclase (sGC) activator runcaciguat. The sGC enzyme, via the formation of cyclic guanosine monophoshphate, is a key regulator of body and tissue homeostasis. sGC activators with their unique mode of action are activating the oxidized and heme-free and therefore NO-unresponsive form of sGC, which is formed under oxidative stress. The first generation of sGC activators like cinaciguat or ataciguat exhibited limitations and were discontinued. We overcame limitations of first-generation sGC activators and identified a new chemical class via high-throughput screening. The investigation of the structure-activity relationship allowed to improve potency and multiple solubility, permeability, metabolism, and drug-drug interactions parameters. This program resulted in the discovery of the oral sGC activator runcaciguat (compound 45, BAY 1101042). Runcaciguat is currently investigated in clinical phase 2 studies for the treatment of patients with chronic kidney disease and nonproliferative diabetic retinopathy.


Assuntos
Desenho de Fármacos , Ativadores de Enzimas/química , Guanilil Ciclase Solúvel/química , Animais , Sítios de Ligação , Cristalografia por Raios X , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Cães , Ativadores de Enzimas/metabolismo , Ativadores de Enzimas/farmacologia , Ativadores de Enzimas/uso terapêutico , Meia-Vida , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Simulação de Dinâmica Molecular , Ratos , Ratos Endogâmicos SHR , Solubilidade , Guanilil Ciclase Solúvel/metabolismo , Relação Estrutura-Atividade
9.
J Clin Invest ; 131(10)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33822774

RESUMO

Anemia in ß-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired α-globin chains impose substantial oxidative stress on ß-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbbth3/+ mouse model for ß-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism. Oral mitapivat administration ameliorated ineffective erythropoiesis and anemia in Hbbth3/+ mice. Increased ATP, reduced reactive oxygen species production, and reduced markers of mitochondrial dysfunction associated with improved mitochondrial clearance suggested enhanced metabolism following mitapivat administration in ß-thalassemia. The amelioration of responsiveness to erythropoietin resulted in reduced soluble erythroferrone, increased liver Hamp expression, and diminished liver iron overload. Mitapivat reduced duodenal Dmt1 expression potentially by activating the pyruvate kinase M2-HIF2α axis, representing a mechanism additional to Hamp in controlling iron absorption and preventing ß-thalassemia-related liver iron overload. In ex vivo studies on erythroid precursors from patients with ß-thalassemia, mitapivat enhanced erythropoiesis, promoted erythroid maturation, and decreased apoptosis. Overall, pyruvate kinase activation as a treatment modality for ß-thalassemia in preclinical model systems had multiple beneficial effects in the erythropoietic compartment and beyond, providing a strong scientific basis for further clinical trials.


Assuntos
Ativadores de Enzimas/farmacologia , Hemólise/efeitos dos fármacos , Piperazinas/farmacologia , Piruvato Quinase/metabolismo , Quinolinas/farmacologia , Talassemia beta/tratamento farmacológico , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Transgênicos , Talassemia beta/enzimologia , Talassemia beta/genética
10.
Life Sci ; 276: 119470, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33831423

RESUMO

AIMS: AMPK plays a critical role regulating cell metabolism, growth and survival. Interfering with this enzyme activity has been extensively studied as putative mechanism for cancer therapy. The present work aims to identify a specific AMPK activator for cancer cells among a series of novel heterocyclic compounds. MATERIALS AND METHODS: A series of novel hybrid heterocyclic compounds, namely naphtoquinone-4-oxoquinoline and isoquinoline-5,8-quinone-4-oxoquinoline derivatives, were synthesized via Michael reaction and their structures confirmed by spectral data: infrared; 1H and 13C NMR spectroscopy (COSY, HSQC, HMBC); and high-resolution mass spectrometry (HRMS). The novel compounds were screened and tested for antitumoral activity and have part of their mechanism of action scrutinized. KEY FINDINGS: Here, we identified a selective AMPK activator among the new hybrid heterocyclic compounds. This new compound presents selective cytotoxicity on breast cancer cells but not on non-cancer counterparts. We identified that by specifically activating AMPK in cancer cells, the drug downregulates unfolded protein response pathway, as well as inhibits mTOR signaling. SIGNIFICANCE: These effects, that are selective for cancer cells, lead to activation of autophagy and, ultimately, to cancer cells death. Taken together, our data support the promising anticancer activity of this novel compound which is a strong modulator of metabolism.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Apoptose , Autofagia , Neoplasias da Mama/tratamento farmacológico , Ativadores de Enzimas/farmacologia , Resposta a Proteínas não Dobradas , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Transdução de Sinais , Células Tumorais Cultivadas
11.
Nat Commun ; 12(1): 2263, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859183

RESUMO

Argininosuccinate synthase (ASS1) is a ubiquitous enzyme in mammals that catalyzes the formation of argininosuccinate from citrulline and aspartate. ASS1 genetic deficiency in patients leads to an autosomal recessive urea cycle disorder citrullinemia, while its somatic silence or down-regulation is very common in various human cancers. Here, we show that ASS1 functions as a tumor suppressor in breast cancer, and the pesticide spinosyn A (SPA) and its derivative LM-2I suppress breast tumor cell proliferation and growth by binding to and activating ASS1. The C13-C14 double bond in SPA and LM-2I while the Cys97 (C97) site in ASS1 are critical for the interaction between ASS1 and SPA or LM-2I. SPA and LM-2I treatment results in significant enhancement of ASS1 enzymatic activity in breast cancer cells, particularly in those cancer cells with low ASS1 expression, leading to reduced pyrimidine synthesis and consequently the inhibition of cancer cell proliferation. Thus, our results establish spinosyn A and its derivative LM-2I as potent ASS1 enzymatic activator and tumor inhibitor, which provides a therapeutic avenue for tumors with low ASS1 expression and for those non-tumor diseases caused by down-regulation of ASS1.


Assuntos
Argininossuccinato Sintase/metabolismo , Neoplasias da Mama/tratamento farmacológico , Citrulinemia/tratamento farmacológico , Ativadores de Enzimas/farmacologia , Macrolídeos/farmacologia , Proteínas Supressoras de Tumor/agonistas , Adulto , Idoso , Animais , Argininossuccinato Sintase/genética , Argininossuccinato Sintase/isolamento & purificação , Ácido Aspártico/metabolismo , Mama/patologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citrulina/metabolismo , Citrulinemia/genética , Ativadores de Enzimas/uso terapêutico , Feminino , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Macrolídeos/uso terapêutico , Metabolômica , Camundongos , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica , Pirimidinas/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Am J Physiol Heart Circ Physiol ; 320(5): H1923-H1934, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33739156

RESUMO

Stimulation of soluble guanylate cyclase (sGC) improves fetal growth at gestational day 20 in the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia suggesting a role for sGC in the etiology of intrauterine growth restriction (IUGR). This study tested the hypothesis that stimulation of sGC until birth attenuates asymmetric IUGR mitigating increased cardiovascular risk in offspring. Sham or RUPP surgery was performed at gestational day 14 (G14); vehicle or the sGC stimulator Riociguat (10 mg/kg/day sc) was administered G14 until birth. Birth weight was reduced in offspring from RUPP [intrauterine growth restricted (IUGR)], sGC RUPP (sGC IUGR), and sGC Sham (sGC Control) compared with Sham (Control). Crown circumference was maintained, but abdominal circumference was reduced in IUGR and sGC IUGR compared with Control indicative of asymmetrical growth. Gestational length was prolonged in sGC RUPP, and survival at birth was reduced in sGC IUGR. Probability of survival to postnatal day 2 was also significantly reduced in IUGR and sGC IUGR versus Control and in sGC IUGR versus IUGR. At 4 mo of age, blood pressure was increased in male IUGR and sGC IUGR but not male sGC Control born with symmetrical IUGR. Global longitudinal strain was increased and stroke volume was decreased in male IUGR and sGC IUGR compared with Control. Thus late gestational stimulation of sGC does not mitigate asymmetric IUGR or increased cardiovascular risk in male sGC IUGR. Furthermore, late gestational stimulation of sGC is associated with symmetrical growth restriction in sGC Control implicating contraindications in normal pregnancy.NEW & NOTEWORTHY The importance of the soluble guanylate cyclase-cGMP pathway in a rat model of placental ischemia differs during critical windows of development, implicating other factors may be critical mediators of impaired fetal growth in the final stages of gestation. Moreover, increased blood pressure at 4 mo of age in male intrauterine growth restriction offspring is associated with impaired cardiac function including an increase in global longitudinal strain in conjunction with a decrease in stroke volume, ejection fraction, and cardiac output.


Assuntos
Retardo do Crescimento Fetal/metabolismo , Placenta/irrigação sanguínea , Insuficiência Placentária/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Animais , Pressão Sanguínea/fisiologia , Ativadores de Enzimas/farmacologia , Feminino , Retardo do Crescimento Fetal/etiologia , Gravidez , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Resistência Vascular/fisiologia
13.
Eur J Pharmacol ; 899: 173978, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33691164

RESUMO

Metabolic syndrome is linked to an increased risk of cardiovascular complications by a mechanism involving mainly decreased nitric oxide (NO) bioavailability and impaired NO-soluble guanylate cyclase (sGC)- cyclic guanosine monophosphate (cGMP) signalling (NO-sGC-cGMP). To further develop this scientific point, this study aimed to investigate the effects of long-term treatment with BAY 41-2272 (a sGC stimulator) on cardiovascular reactivity of spontaneously hypertensive rats (SHR) as a model of metabolic syndrome. SHR were randomly divided into 3 groups: control group, cafeteria diet (CD)-fed group and CD-fed group treated daily with BAY 41-2272 (5 mg/kg) by gastric gavage for 12 weeks. In vivo measurements of body weight, abdominal circumference, blood pressure and glucose tolerance test were performed. At the end of the feeding period, ex vivo cumulative concentration-response curves were performed on isolated perfused heart (isoproterenol (0.1 nM - 1 µM)) and thoracic aorta (phenylephrine (1 nM-10 µM), acetylcholine (1 nM-10 µM), and sodium nitroprusside (SNP) (0.1 nM-0.1 µM)). We showed that chronic CD feeding induced abdominal obesity, hypertriglyceridemia, glucose intolerance and exacerbated arterial hypertension in SHR. Compared to control group, CD-fed group showed a decrease in ß-adrenoceptor-induced cardiac inotropy, in coronary perfusion pressure and in aortic contraction to phenylephrine. While relaxing effects of acetylcholine and SNP were unchanged. BAY 41-2272 long-term treatment markedly prevented arterial hypertension development and glucose intolerance, enhanced the α1-adrenoceptor-induced vasoconstriction, and restored cardiac inotropy and coronary vasodilation. These findings suggest that BAY 41-2272 may be a potential novel drug for preventing metabolic and cardiovascular complications of metabolic syndrome.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Ativadores de Enzimas/farmacologia , Síndrome Metabólica/prevenção & controle , Pirazóis/farmacologia , Piridinas/farmacologia , Guanilil Ciclase Solúvel/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/enzimologia , Aorta Torácica/fisiopatologia , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Circulação Coronária/efeitos dos fármacos , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Ativação Enzimática , Intolerância à Glucose/enzimologia , Intolerância à Glucose/etiologia , Intolerância à Glucose/fisiopatologia , Intolerância à Glucose/prevenção & controle , Hipertensão/enzimologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Hipertrigliceridemia/enzimologia , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/fisiopatologia , Hipertrigliceridemia/prevenção & controle , Preparação de Coração Isolado , Masculino , Síndrome Metabólica/enzimologia , Síndrome Metabólica/etiologia , Síndrome Metabólica/fisiopatologia , Óxido Nítrico Sintase Tipo II/metabolismo , Obesidade Abdominal/enzimologia , Obesidade Abdominal/etiologia , Obesidade Abdominal/fisiopatologia , Obesidade Abdominal/prevenção & controle , Ratos Endogâmicos SHR , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacos
14.
Biomed Pharmacother ; 138: 111403, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33714782

RESUMO

Gu-Ben-Fang-Xiao decoction (GBFXD), derived from the traditional Chinese medicine Yu-Ping-Feng-San, is widely used in clinical settings and has obvious curative effects in respiratory diseases. GBFXD regulates cholesterol transport and lipid metabolism in chronic persistent asthma. There is evidence for its beneficial effects in the remission stage of asthma; however, its metabolic regulatory effects and underlying mechanisms during asthma remission are unclear. In the present study, we used liquid chromatography-mass spectrometry (LC-MS) to analyse the metabolic profile of mouse serum during asthma remission. The acquired LC-MS data were subjected to a multivariate analysis for identification of significantly altered metabolites. In total, 42 metabolites were significantly differentially expressed among the control, model, and GBFXD groups. In particular, levels of fatty acids, acylcarnitines, phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, triglycerides, and diacylglycerols were altered during asthma remission. GBFXD may maintain lipid homeostasis on the lung surface by modulating lipid metabolism and may thereby alleviate asthma. We further quantified hypogeic acid (FA 16:1) based on targeted metabolomics and found that GBFXD may regulate fatty acid metabolism by activating the AMP-activated protein kinase (AMPK) pathway. These results support the use of GBFXD in patients with asthma remission.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Asma/tratamento farmacológico , Asma/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Ativadores de Enzimas/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Animais , Medicamentos de Ervas Chinesas/farmacologia , Ativadores de Enzimas/farmacologia , Feminino , Metabolismo dos Lipídeos/fisiologia , Metabolômica/métodos , Camundongos , Indução de Remissão/métodos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
15.
Cell Death Dis ; 12(2): 217, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637691

RESUMO

Our previous studies showed that silent mating-type information regulation 2 homologue-1 (SIRT1, a deacetylase) upregulation could attenuate sepsis-induced acute kidney injury (SAKI). Upregulated SIRT1 can deacetylate certain autophagy-related proteins (Beclin1, Atg5, Atg7 and LC3) in vitro. However, it remains unclear whether the beneficial effect of SIRT1 is related to autophagy induction and the underlying mechanism of this effect is also unknown. In the present study, caecal ligation and puncture (CLP)-induced mice, and an LPS-challenged HK-2 cell line were established to mimic a SAKI animal model and a SAKI cell model, respectively. Our results demonstrated that SIRT1 activation promoted autophagy and attenuated SAKI. SIRT1 deacetylated only Beclin1 but not the other autophagy-related proteins in SAKI. SIRT1-induced autophagy and its protective effect against SAKI were mediated by the deacetylation of Beclin1 at K430 and K437. Moreover, two SIRT1 activators, resveratrol and polydatin, attenuated SAKI in CLP-induced septic mice. Our study was the first to demonstrate the important role of SIRT1-induced Beclin1 deacetylation in autophagy and its protective effect against SAKI. These findings suggest that pharmacologic induction of autophagy via SIRT1-mediated Beclin1 deacetylation may be a promising therapeutic approach for future SAKI treatment.


Assuntos
Injúria Renal Aguda/enzimologia , Autofagia , Proteína Beclina-1/metabolismo , Túbulos Renais Proximais/enzimologia , Sepse/complicações , Sirtuína 1/metabolismo , Acetilação , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Injúria Renal Aguda/prevenção & controle , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Ativação Enzimática , Ativadores de Enzimas/farmacologia , Glucosídeos/farmacologia , Humanos , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/ultraestrutura , Masculino , Camundongos Endogâmicos C57BL , Resveratrol/farmacologia , Sepse/microbiologia , Transdução de Sinais , Sirtuína 1/genética , Estilbenos/farmacologia , Fatores de Tempo
16.
Eur J Pharmacol ; 897: 173948, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33609564

RESUMO

The soluble guanylate cyclase (sGC)/GMPc pathway plays an important role in controlling pulmonary arterial hypertension (PAH). We investigated whether the novel sGC stimulator trans-4-methoxy-ß-nitrostyrene (T4MN), ameliorates monocrotaline (MCT)-induced PAH. At Day 0, rats were injected with MCT (60 mg/kg, s. c.). Control (CNT) rats received an equal volume of monocrotaline vehicle only (s.c.). Four weeks later, MCT-treated rats were orally treated for 14 days with T4MN (75 mg/kg/day) (MCT-T4MN group) or its vehicle (MCT-V group), and with sildenafil (SIL; 50 mg/kg) (MCT-SIL group). Compared to the CNT group, MCT treatment induced a significant increase in both the Fulton index and RV systolic pressure but significantly reduced the maximum relaxation induced by acetylcholine. Indeed, MCT treatment increased the wall thickness of small and larger pulmonary arterioles. Oral treatment with T4MN and SIL reduced the Fulton index and RV systolic pressure compared to the MCT-V group. Maximum relaxation induced by acetylcholine was significantly enhanced in MCT-SIL group. Both T4MN and SIL significantly reduced the enhanced wall thickness of small and larger pulmonary arterioles. Treatment with T4MN has a beneficial effect on PAH by reducing RV systolic pressure and consequently right ventricular hypertrophy, and by reducing pulmonary artery remodeling. T4MN may represent a new therapeutic or complementary approach for the treatment of PAH.


Assuntos
Arteríolas/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Pulmão/irrigação sanguínea , Guanilil Ciclase Solúvel/metabolismo , Estirenos/farmacologia , Remodelação Vascular/efeitos dos fármacos , Animais , Arteríolas/enzimologia , Arteríolas/fisiopatologia , Modelos Animais de Doenças , Ativação Enzimática , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/enzimologia , Hipertrofia Ventricular Direita/fisiopatologia , Hipertrofia Ventricular Direita/prevenção & controle , Monocrotalina , Transdução de Sinais , Vasodilatação/efeitos dos fármacos , Disfunção Ventricular Direita/enzimologia , Disfunção Ventricular Direita/fisiopatologia , Disfunção Ventricular Direita/prevenção & controle , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
18.
Medicine (Baltimore) ; 100(7): e24873, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607862

RESUMO

BACKGROUND: Glucokinase activators are a novel family of glucose-lowering agents used for the treatment of type-2 diabetes mellitus (T2DM). Glucokinase activators blind to GK activate the enzyme allosterically. Treatment with different GKAs has been shown to reduce fasting and postprandial glucose in patients with type 2 diabetes. We compared the efficacy/safety of glucokinase activators in T2DM patients through a meta-analysis. METHODS: We searched PubMed, Excerpt Medica Database, and Cochrane Central Register of Controlled Trials databases for articles published before December 30, 2020. Two independent reviewers extracted the information from article. The quality of articles were assessed by 2 independent reviewers using the 5 items of scale proposed by Jadad. We computed the weighted mean difference and 95% confidence interval (CI) for a change from baseline to the study endpoint for glucokinase activators vs placebo. Egger test and Begg test were used to assess the possible publication bias caused by the tendency of published studies to be positive. RESULTS: The present meta-analysis will compare the efficacy and safety of glucokinase activators and placebo for the treatment of T2DM. CONCLUSIONS: This meta-analysis will provide advanced evidence on the efficacy and safety of glucokinase activators for the treatment of T2DM. ETHICS AND DISSEMINATION: Ethical approval and patient consent are not required because this study is a literature-based study. This systematic review and meta-analysis will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021220364.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/farmacologia , Glucoquinase/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Glicemia/análise , Glicemia/efeitos dos fármacos , Estudos de Casos e Controles , Gerenciamento de Dados , Ativadores de Enzimas/uso terapêutico , Jejum/sangue , Glucoquinase/metabolismo , Humanos , Placebos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Resultado do Tratamento
19.
Commun Biol ; 4(1): 209, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608631

RESUMO

Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, is a crucial regulator that produces multiple physiological benefits, such as the prevention of cancer and age-related diseases. SIRT1 is activated by sirtuin-activating compounds (STACs). Here, we report that quercetin 3,5,7,3',4'-pentamethyl ether (KPMF-8), a natural STAC from Thai black ginger Kaempferia parviflora, interacts with SIRT1 directly and stimulates SIRT1 activity by enhancing the binding affinity of SIRT1 with Ac-p53 peptide, a native substrate peptide without a fluorogenic moiety. The binding affinity between SIRT1 and Ac-p53 peptide was enhanced 8.2-fold by KPMF-8 but only 1.4-fold by resveratrol. The specific binding sites of KPMF-8 to SIRT1 were mainly localized to the helix2-turn-helix3 motif in the N-terminal domain of SIRT1. Intracellular deacetylase activity in MCF-7 cells was promoted 1.7-fold by KPMF-8 supplemented in the cell medium but only 1.2-fold by resveratrol. This work reveals that KPMF-8 activates SIRT1 more effectively than resveratrol does.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Ativadores de Enzimas/farmacologia , Quercetina/farmacologia , Sirtuína 1/metabolismo , Zingiberaceae , Regulação Alostérica , Antineoplásicos Fitogênicos/isolamento & purificação , Sítios de Ligação , Neoplasias da Mama/enzimologia , Ativação Enzimática , Ativadores de Enzimas/isolamento & purificação , Feminino , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica em alfa-Hélice , Quercetina/análogos & derivados , Quercetina/isolamento & purificação , Resveratrol/farmacologia , Zingiberaceae/química
20.
Int J Mol Sci ; 22(2)2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33435517

RESUMO

GPR55 is a GPCR of the non-CB1/CB2 cannabinoid receptor family, which is activated by lysophosphatidylinositol (LPI) and stimulates the proliferation of cancer cells. Anandamide, a bioactive lipid endocannabinoid, acts as a biased agonist of GPR55 and induces cancer cell death, but is unstable and psychoactive. We hypothesized that other endocannabinoids and structurally similar compounds, which are more hydrolytically stable, could also induce cancer cell death via GPR55 activation. We chemically synthesized and tested a set of fatty acid amides and esters for cell death induction via GPR55 activation. The most active compounds appeared to be N-acyl dopamines, especially N-docosahexaenoyl dopamine (DHA-DA). Using a panel of cancer cell lines and a set of receptor and intracellular signal transduction machinery inhibitors together with cell viability, Ca2+, NO, ROS (reactive oxygen species) and gene expression measurement, we showed for the first time that for these compounds, the mechanism of cell death induction differed from that published for anandamide and included neuronal nitric oxide synthase (nNOS) overstimulation with concomitant oxidative stress induction. The combination of DHA-DA with LPI, which normally stimulates cancer proliferation and is increased in cancer setting, had an increased cytotoxicity for the cancer cells indicating a therapeutic potential.


Assuntos
Antineoplásicos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Dopamina/análogos & derivados , Ativadores de Enzimas/farmacologia , Óxido Nítrico Sintase Tipo I/metabolismo , Receptores de Canabinoides/metabolismo , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/química , Linhagem Celular Tumoral , Dopamina/química , Dopamina/farmacologia , Ativadores de Enzimas/química , Ácidos Graxos/química , Ácidos Graxos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Células PC12 , Ratos
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