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1.
DNA Cell Biol ; 38(10): 1134-1142, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433203

RESUMO

Diabetes mellitus is a complicated metabolic disease characterized by hyperglycemia. Diabetic nephropathy (DN) is a progressive kidney disease, which results in mortality in diabetic patients. The present study was designed to investigate the effect of applying spironolactone (S), captopril (C), and their combination (S+C) on some renal performance indices and microRNAs' (miRNAs) expression. A total of 35 two-month-old male Wistar rats were provided for the study. Intraperitoneal injection of freshly dissolved streptozotocin (60 mg/kg) in cold citrate buffer was used to induce diabetes. Blood samples were examined through calorimetry to assess serum concentrations of glucose, blood urea nitrogen (BUN), and creatinine. To measure the microalbuminuria and transforming growth factor-ß (TGF-ß) levels and to evaluate the miRNAs expression levels of the kidney tissue, the ELISA method and the real-time PCR were used. The obtained results serve as in vivo evidence for the positive relationship between miR-192 and TGF-ß levels in the DN rats. A significant increase and decrease were found for miR-29a/b/c and the miR-192 expression of DN after treatment with S, C, and S+C. TGF-ß levels and microalbuminuria of diabetic rats also increased. The results obtained from this research study suggest that S, C, and S + C can improve DN by targeting miR-192 and miR-29 family and changing their expression. These findings suggest that miR-192 and miRs-29a/b/c can be potential targets for DN remediation.


Assuntos
Captopril/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Espironolactona/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Diuréticos/farmacologia , Combinação de Medicamentos , Reposicionamento de Medicamentos , Hiperglicemia/induzido quimicamente , Hiperglicemia/genética , Hiperglicemia/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento
2.
Chem Biol Interact ; 310: 108742, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31295448

RESUMO

Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women of reproductive age and hyperandrogenism is a prominent feature of PCOS resulting in infertility and increased risk of developing metabolic disorders including insulin resistance (IR), abdominal adiposity, glucose intolerance and cardiovascular diseases. Spironolactone (SPL), a non-selective mineralocorticoid receptor (MR) antagonist, has been in wide clinical use for several decades. In this study, we investigated the effects of SPL on IR and metabolic disturbances in letrozole-induced PCOS rats. Eighteen adults female Wistar rats were randomly divided into 3 groups and treated with vehicle, letrozole (LET; 1 mg/kg) and LET + SPL (SPL; 0.25 mg/kg), p.o. once daily for 21 consecutive days. Results showed that LET treatment induced PCOS characterised by elevated plasma testosterone and luteinizing hormone (LH) accompanied with increased body weight and visceral adiposity, IR, glucose intolerance, dyslipidemia and altered histomorphological ovaries. Treatment with SPL however attenuated the elevated testosterone in LET-induced PCOS model accompanied with a reversal in all the observed alterations. Taken together, analysis of the physical, biochemical and histological evidences shows that the protective effect of this very low dose spironolactone may be through its anti-androgenic mechanism.


Assuntos
Resistência à Insulina , Síndrome do Ovário Policístico/tratamento farmacológico , Espironolactona/farmacologia , Testosterona/sangue , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Animais , Feminino , Letrozol , Hormônio Luteinizante/sangue , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Ratos , Ratos Wistar , Espironolactona/uso terapêutico
3.
Eur J Med Chem ; 178: 446-457, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202992

RESUMO

Motivated by our interest in hydrogen sulfide bio-chemistry and ent-kaurane diterpenoid chemistry, 14 hydrogen sulfide donating derivatives (9, 11a-c, 12a-c, 13, 14, 16a-c and 17a-b) of ent-kaurane and spirolactone-type 6,7-seco-ent-kaurane were designed and synthesized. Four human cancer cell lines (K562, Bel-7402, SGC-7901 and A549) and two normal cell lines (L-02 and PBMC) were selected for antiproliferative assay. Most derivatives showed more potent activities than the lead ent-kaurane oridonin. Among them, compound 12b exhibited the most potent antiproliferative activities, with IC50 values of 1.01, 0.88, 4.36 and 5.21 µM against above human cancer cell lines, respectively. Further apoptosis-related mechanism study indicated that 12b could arrest Bel-7402 cell cycle at G1 phase and induce apoptosis through mitochondria related pathway. Through Western blot assay, 12b was shown to influence the intrinsic pathway by increasing the expression of Bax, cleaved caspase-3, cytochrome c and cleaved PARP, meanwhile suppressing procaspase-3, Bcl-2, Bcl-xL and PARP.


Assuntos
Antineoplásicos/farmacologia , Diterpenos de Caurano/farmacologia , Desenho de Drogas , Sulfeto de Hidrogênio/farmacologia , Espironolactona/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos de Caurano/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Sulfeto de Hidrogênio/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Espironolactona/química , Relação Estrutura-Atividade
4.
Drug Des Devel Ther ; 13: 1487-1499, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118582

RESUMO

Objective: To evaluate the safety and cardiovascular effect of low-dose spironolactone administration in end-stage renal failure patients undergoing hemodialysis coupled with conventional treatment. Methods: We conducted a systematic search for clinical trials on the safety and cardiovascular effect of additional low-dose spironolactone in hemodialysis patients. The search was performed on PubMed, EMBASE, Cochrane Library, and CBM databases. Relevant references (up to February 2016) were retrieved and subsequent results analyzed with a random-effects model or a fixed-effects model. Results: We identified nine trials with a total sample size of 765 patients. The results did not indicate significant differences regarding safety and serum potassium levels (mean difference [MD]=0.23, P=0.09) between the two treatment options. However, patients receiving low-dose spironolactone exhibited improvements in left venticular mass index (LVMI) (standardized mean difference= -0.58, P<0.00001) and left ventricular ejection fraction (LVEF) (MD=4.91, P<0.0001) with an additional decrease in systolic blood pressure (MD= -6.97, P=0.0001) and diastolic blood pressure (MD= -4.01, P=0.007). Furthermore, the clinical (OR=0.4, P=0.0003) or cardiovascular and cerebrovascular-related (OR=0.4, P=0.002) mortality was significantly lower among those patients. Conclusion: These results indicated that additional use of low-dose spironolactone associated with conventional treatment does not have a significant impact on serum potassium levels in hemodialysis patients. What's more, it might exert a protective effect on the cardiovascular system by optimizing LVMI, improving LVEF, decreasing arterial blood pressure and reducing events-related mortality. Further large sample size studies are needed to support these findings.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Diálise Renal , Espironolactona/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Ensaios Clínicos como Assunto , Humanos , Potássio/sangue , Espironolactona/administração & dosagem , Espironolactona/efeitos adversos
5.
Am J Clin Dermatol ; 20(4): 503-513, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31073704

RESUMO

BACKGROUND: Hidradenitis suppurativa/acne inversa is a disease with deep-seated chronic painful nodules, abscesses, and draining sinus tracts, which manifests on the apocrine gland-rich skin areas of the body. Observational findings demonstrate that the disease usually appears after puberty, exhibits pre-menstrual flares in women, improves in pregnancy, and worsens post-partum, which indicates a role of hormones and particularly of androgens in its pathophysiology. Because increased androgen levels in serum have not been widely reported, an end-organ androgen hypersensitivity has been postulated. OBJECTIVE: The aim of this systematic review was to identify and present evidence for antiandrogen therapeutic options for the treatment of hidradenitis suppurativa/acne inversa. METHODS: A literature search was conducted in different medical electronic databases using the keywords "hidradenitis", "suppurativa", "acne inversa", and "antiandrogen" on 1 December, 2018. The main therapeutic options were subsequently used as separate keywords with the disease terms in a separate search. RESULTS: The main therapeutic options yielded were cyproterone acetate, spironolactone, finasteride, and metformin. One randomized controlled crossover trial and seven case series were identified following use of a standard extraction form for eligibility. CONCLUSION: The existing studies do not allow a robust evidence-based recommendation for the use of antiandrogens in the treatment of hidradenitis suppurativa/acne inversa. Further randomized controlled trials are needed to define the role of hormonal treatment as an alternative or concomitant therapy together with antibiotics or biologics.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Androgênios/metabolismo , Hidradenite Supurativa/tratamento farmacológico , Antagonistas de Androgênios/farmacologia , Acetato de Ciproterona/farmacologia , Acetato de Ciproterona/uso terapêutico , Quimioterapia Combinada/métodos , Finasterida/farmacologia , Finasterida/uso terapêutico , Hidradenite Supurativa/etiologia , Hidradenite Supurativa/patologia , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Espironolactona/farmacologia , Espironolactona/uso terapêutico , Resultado do Tratamento
6.
Fitoterapia ; 134: 290-296, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30831200

RESUMO

A different type of biologically active compound from Kuji amber (Late Cretaceous, Japan) before the K-Pg boundary [65 million years ago (Ma)] was isolated based on the growth-restoring activity of a mutant yeast involving Ca2+ signal transduction. It was identified as a spirolactone norditerpenoid, (4R*, 5S*, 8R*, 9R*, 10S*)-14,15,16,19-tetranor-labdan-13,9-olide (1) from spectral analyses with high-resolution electron ionization mass spectrometry (HREIMS), 1D and 2D nuclear magnetic resonance (NMR). Although the planar structure of 1 is known as an artificial derivative from marrubiin, it was isolated as a natural product from Kuji amber and its structure was elucidated for the first time. It had a growth-restoring activity against the mutant yeast through the direct or indirect inhibition of calcineurin activity [protein phosphatase, Mg2+/Mn2+-dependent 1A (PPM1A) activation]. Furthermore, the compound had potent inhibitory effect against the degranulation of rat basophilic leukemia 2H3 (RBL-2H3) cells.


Assuntos
Âmbar/química , Diterpenos/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Espironolactona/farmacologia , Animais , Degranulação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Diterpenos/isolamento & purificação , Japão , Mastócitos/efeitos dos fármacos , Estrutura Molecular , Ratos , Espironolactona/isolamento & purificação
7.
Mol Med Rep ; 19(5): 3622-3632, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896801

RESUMO

Vascular calcification (VC) is highly prevalent in chronic kidney disease (CKD), especially in patients with end stage renal disease and is strongly associated with cardiovascular morbidity and mortality. Clinical observations have demonstrated that hyperphosphatemia and hyperglycemia can accelerate VC. Spironolactone (SPL) has been proven to improve cardiovascular outcomes in clinical trials and its protective effect on VC has been reported recently; however, the underlying mechanisms are not completely understood and require further investigation. Furthermore, the current CKD rat models that are used to research VC do not match well with the clinical characteristics of CKD patients. Aortic rings were obtained from male Sprague­Dawley rats, then cultured in different media with varying phosphorus and glucose concentrations to investigate the effects and the possible mechanisms, as well as the effective serum concentrations of SPL, on VC and type III sodium­dependent phosphate cotransporter­1 (Pit­1) expression. SPL dose­dependently alleviated VC by suppressing the phenotypic transition of vascular smooth muscle cell (VSMCs) through downregulation of Pit­1 in a high phosphorus medium and even in a high phosphorus combined with high glucose medium. The combined effects of hyperglycemia and hyperphosphatemia on the calcification of aortic rings ex vivo were demonstrated. In conclusion to the best of our knowledge, this article is the first report on the effective serum concentrations of SPL capable of protecting VSMCs from calcification and provides the first experimental evidence for the combined effects of hyperglycemia and hyperphosphatemia on VC of aortic rings. Additionally, the Pit­1 protein level may be a novel index for evaluating the magnitude of VC in CKD patients.


Assuntos
Hiperfosfatemia/metabolismo , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Espironolactona/farmacologia , Fator de Transcrição Pit-1/genética , Calcificação Vascular/metabolismo , Animais , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Imunofenotipagem , Masculino , Fenótipo , Ratos , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/etiologia
8.
Genes Cells ; 24(4): 284-296, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30762924

RESUMO

The multisubunit complex transcription factor IIH (TFIIH) has dual functions in transcriptional initiation and nucleotide excision repair (NER). TFIIH is comprised of two subcomplexes, the core subcomplex (seven subunits) including XPB and XPD helicases and the cyclin-dependent kinase (CDK)-activating kinase (CAK) subcomplex (three subunits) containing CDK7 kinase. Recently, it has been reported that spironolactone, an anti-aldosterone drug, inhibits cellular NER by inducing proteasomal degradation of XPB and potentiates the cytotoxicity of platinum-based drugs in cancer cells, suggesting possible drug repositioning. In this study, we have tried to uncover the mechanism underlying the chemical-induced XPB destabilization. Based on siRNA library screening and subsequent analyses, we identified SCFFBXL18 E3 ligase consisting of Skp1, Cul1, F-box protein FBXL18 and Rbx1 responsible for spironolactone-induced XPB polyubiquitination and degradation. In addition, we showed that CDK7 kinase activity is required for this process. Finally, we found that the Ser90 residue of XPB is essential for the chemical-induced destabilization. These results led us to propose a model that spironolactone may trigger the phosphorylation of XPB at Ser90 by CDK7, which promotes the recognition and polyubiquitination of XPB by SCFFBXL18 for proteasomal degradation.


Assuntos
Quinases Ciclina-Dependentes/metabolismo , Proteínas F-Box/metabolismo , Espironolactona/farmacologia , Fator de Transcrição TFIIH/metabolismo , Células HEK293 , Células HeLa , Humanos , Proteólise/efeitos dos fármacos
9.
Med Sci Monit ; 25: 1102-1104, 2019 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-30739121

RESUMO

Widespread usage of the calcineurin inhibitors tacrolimus and cyclosporine A as post-transplantation immunosuppressive agents is fraught with severe nephrotoxic and diabetogenic side effects. More recently, tapering of calcineurin inhibitor-based immunotherapies with concurrent administration of the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus has been employed within pharmacological regimens designed to achieve better safety and efficacy for preservation of allograft kidney function. Collected preclinical data and recent clinical study, however, indicate that usage of calcineurin inhibitors and/or mTOR blockers as immunosuppressive agents promotes equivalent diabetogenic side effects. Based on a wealth of validating preclinical studies, we contend that the favorable metabolic effects of mineralocorticoid receptor antagonists, such as spironolactone, support their inclusion in novel immunosuppressive strategies to inhibit new onset type II diabetic symptoms in post-transplantation patient populations.


Assuntos
Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Espironolactona/uso terapêutico , Calcineurina/metabolismo , Inibidores de Calcineurina , Ciclosporina , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus/induzido quimicamente , Everolimo , Rejeição de Enxerto/tratamento farmacológico , Humanos , Imunossupressores/metabolismo , Imunossupressores/farmacologia , Transplante de Rim , Sirolimo , Espironolactona/farmacologia , Tacrolimo , Tolerância ao Transplante/fisiologia
10.
Int Urol Nephrol ; 51(4): 755-764, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30734886

RESUMO

PURPOSE: Podocytes are terminally differentiated cells lining the Bowman's capsule. Podocytes are critical for the proper glomerular filtration barrier function. At the same time, autophagy is crucial for maintaining podocyte homeostasis and insufficient autophagy could cause podocyte loss and proteinuria that is commonly observed in diabetic nephropathy (DN). METHODS: In this study, we investigated the role of spironolactone in podocyte loss and autophagy. DN model was established in male Sprague-Dawley rats using high-fat diet and low-dose streptozotocin. The impact of spironolactone on metabolic and biochemical parameters were tested by automatic biochemical analyzer. The angiotensin converting enzyme 1 and 2 (ACE1 and ACE2) and aldosterone were examined by ELISA. We examined the kidney histology and autophagy in podocytes by histochemical staining and electron microscopy. Podocyte loss and autophagy were analyzed by anti-NPHS2 and anti-WT1 as well as anti-Beclin1 and anti-LC3B, respectively. RESULTS: Spironolacton decreased the urinary albumin excretion, lipids and fasting glucose levels, and alleviated kidney damage. Further, spironolactone increased the expression of the podocyte-specific markers WT1 and NPHS2, as well as the autophagic markers Beclin1 and LC3B (P < 0.05). Additionally, spironolactone partially blocked the rennin angiotensin aldosterone system (RAAS) by regulating the ACE1, ACE2 and aldosterone levels. CONCLUSIONS: In conclusion, spironolactone promoted autophagy in podocytes and further alleviated DN through partially blocking the RAAS.


Assuntos
Autofagia/efeitos dos fármacos , Nefropatias Diabéticas/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Podócitos , Espironolactona/uso terapêutico , Albuminúria/tratamento farmacológico , Aldosterona/metabolismo , Animais , Proteína Beclina-1/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Peptidil Dipeptidase A/sangue , Sistema Renina-Angiotensina/efeitos dos fármacos , Espironolactona/farmacologia , Proteínas WT1/metabolismo
11.
Life Sci ; 224: 177-186, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30658104

RESUMO

AIMS: The mechanisms underlying cardiorenal syndromes are complex and not fully understood; Fibrosis seems to be a primary driver of the diseases' pathophysiology. Spironolactone can reduce cardiac or renal fibrosis by inhibiting endothelial-mesenchymal transition (EndMT). Spironolactone protection may rely on activation of adenosine receptors, but the role of the adenosine A2A receptor (A2AR) is unclear. We hypothesize that spironolactone may modulate A2AR to suppress EndMT and reduce cardiorenal remodeling. MAIN METHODS: A model of renal injury followed by heart failure was established by subcutaneous administration of isoprenaline (Iso) to rats. Assessment of cardiac and renal function, fibrosis, EndMT markers, adenosine and A2AR expression was performed. TGF-ß was used to induce EndMT in primary human umbilical vein endothelial cells (HUVECs). Rats or cells were divided into four groups: those that treated with spironolactone alone or in combination with A2AR antagonist ZM241385 or neither, and compared to normal controls. KEY FINDINGS: Isoprenaline-treated rats exhibited cardiac and renal fibrosis, impaired cardiac and renal function, enhanced EndMT, and lower A2AR expression. Spironolactone significantly up-regulated A2AR expression and inhibited EndMT in vivo and in vitro. Moreover, spironolactone improved cardiorenal remodeling and reduced dysfunction. These changes were exacerbated by administration of ZM241385. Together, these findings show that spironolactone up-regulated A2AR to reduce EndMT and ameliorate cardiorenal fibrosis. SIGNIFICANCE: The anti-fibrotic effects of spironolactone may partly depend on the up-regulation of A2AR, and that A2AR might be a potential therapeutic target for the treatment of cardiorenal syndrome.


Assuntos
Síndrome Cardiorrenal/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Receptor A2A de Adenosina/metabolismo , Espironolactona/farmacologia , Animais , Síndrome Cardiorrenal/metabolismo , Síndrome Cardiorrenal/patologia , Células Cultivadas , Fibrose/metabolismo , Fibrose/patologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Receptor A2A de Adenosina/química , Receptor A2A de Adenosina/genética
12.
Oncogene ; 38(17): 3103-3118, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30622338

RESUMO

The cancer stem cell (CSC) model suggests that a subpopulation of cells within the tumor, the CSCs, is responsible for cancer relapse and metastasis formation. CSCs hold unique characteristics, such as self-renewal, differentiation abilities, and resistance to chemotherapy, raising the need for discovering drugs that target CSCs. Previously we have found that the antihypertensive drug spironolactone impairs DNA damage response in cancer cells. Here we show that spironolactone, apart from inhibiting cancerous cell growth, is also highly toxic to CSCs. Notably, we demonstrate that CSCs have high basal levels of DNA double-strand breaks (DSBs). Mechanistically, we reveal that spironolactone does not damage the DNA but impairs DSB repair and induces apoptosis in cancer cells and CSCs while sparing healthy cells. In vivo, spironolactone treatment reduced the size and CSC content of tumors. Overall, we suggest spironolactone as an anticancer reagent, toxic to both cancer cells and, particularly to, CSCs.


Assuntos
Antineoplásicos/administração & dosagem , Reparo do DNA/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Espironolactona/administração & dosagem , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Reposicionamento de Medicamentos , Células HeLa , Humanos , Camundongos , Neoplasias/genética , Espironolactona/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Pest Manag Sci ; 75(1): 292-301, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29885056

RESUMO

BACKGROUND: Plant viral diseases cause tremendous decreases in yield and quality. Natural polycyclic compounds such as those containing carbocycles are often very important lead compounds for drug and pesticide development. Tricyclic spiranoid lactones with 5A 5B 6C -ring fusion topologies possess various bioactivities. In this study, 33 new 5A 5B 6C tricyclic spirolactones were rationally designed, synthesized, characterized and evaluated for antiviral activities. RESULT: These compounds showed no apparent toxicity against Italian honeybees up to 2.73 µg bee-1 . Spirolactones 14, 16, 19, 23 and 28 at a concentration of 100 µg mL-1 inactivated 90% of tobacco mosaic virus (TMV) infection, making these compounds much more potent than the positive controls. Significantly, compound 19 displayed the best inactivation activity causing inhibition of up to 98%. CONCLUSION: The results of the bioassays and QSAR studies indicated that the carbon-containing cyclic moiety was the antiviral pharmacophore, and derivative 19, which showed the best inactivation activity, could emerge as a potential antiviral agent against TMV. In vitro capsid protein (CP) assembly and TMV assembly inhibition determinations indicated that these compounds induced crosslinking in the TMV and prevented its uncoating, which was a putative new mode of action for TMV inactivation. © 2018 Society of Chemical Industry.


Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Espironolactona/síntese química , Espironolactona/farmacologia , Animais , Antivirais/química , Antivirais/toxicidade , Abelhas/efeitos dos fármacos , Proteínas do Capsídeo/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Relação Quantitativa Estrutura-Atividade , Espironolactona/química , Espironolactona/toxicidade , Vírus do Mosaico do Tabaco/efeitos dos fármacos , Montagem de Vírus/efeitos dos fármacos
14.
Virology ; 526: 105-116, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30388626

RESUMO

Equid alpha-herpesviruses (EHV) are responsible for different diseases in equine population. EHV-1 causes respiratory diseases, abortions and nervous disorders, EHV-4 causes respiratory diseases and sporadic abortion, while EHV-3 is responsible of equine coital exanthema. In view of the lack of efficacy of vaccines against EHV-1 and EHV-4 and in the absence of vaccines against EHV-3, the use of antiviral treatment is of great interest. In this study, we documented the interest of the Real-Time Cell Analysis (RTCA) technology to monitor the cytopathic effects induced by these viruses on equine dermal cells, and established the efficacy of this method to evaluate the antiviral effect of aciclovir (ACV) and ganciclovir (GCV). In addition, the RTCA technology has also been found appropriate for the high-throughput screening of small molecules against EHV, allowing the identification of spironolactone as a novel antiviral against EHV.


Assuntos
Antivirais/farmacologia , Impedância Elétrica , Infecções por Herpesviridae/veterinária , Herpesvirus Equídeo 1/efeitos dos fármacos , Ensaios de Triagem em Larga Escala/métodos , Animais , Linhagem Celular , Efeito Citopatogênico Viral/efeitos dos fármacos , Infecções por Herpesviridae/patologia , Infecções por Herpesviridae/virologia , Herpesvirus Equídeo 1/classificação , Herpesvirus Equídeo 3/efeitos dos fármacos , Herpesvirus Equídeo 4/efeitos dos fármacos , Cavalos , Espironolactona/farmacologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-30559137

RESUMO

Schistosomiasis is a parasitic flatworm disease that infects over 200 million people worldwide, especially in poor communities. Treatment and control of the disease rely on just one drug, praziquantel. Since funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, from a screening of 13 marketed diuretics, we identified that spironolactone, a potassium-sparing diuretic, had potent antischistosomal effects on Schistosoma mansoni in vitro and in vivo in a murine model of schistosomiasis. In vitro, spironolactone at low concentrations (<10 µM) is able to alter worm motor activity and the morphology of adult schistosomes, leading to parasitic death. In vivo, oral treatment with spironolactone at a single dose (400 mg/kg) or daily for five consecutive days (100 mg/kg/day) in mice harboring either patent or prepatent infections significantly reduced worm burden, egg production, and hepato- and splenomegaly (P < 0.05 to P < 0.001). Taken together, with the safety profile of spironolactone, supported by its potential to affect schistosomes, these results indicate that spironolactone could be a potential treatment for schistosomiasis and make it promising for repurposing.


Assuntos
Reposicionamento de Medicamentos/métodos , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose/tratamento farmacológico , Esquistossomicidas/farmacologia , Espironolactona/farmacologia , Animais , Modelos Animais de Doenças , Diuréticos/farmacologia , Feminino , Masculino , Camundongos , Praziquantel/farmacologia
16.
Circ Heart Fail ; 11(11): e005288, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30571191

RESUMO

BACKGROUND: Albuminuria predicts adverse events in heart failure with preserved ejection fraction. No therapies to date have reduced albuminuria in heart failure with preserved ejection fraction. METHODS AND RESULTS: We analyzed 1175 participants from the Americas from the TOPCAT study (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) with urinary albumin:creatinine ratio (UACR) measurements at baseline. We examined the association of UACR with the primary outcome (cardiovascular death, aborted cardiac arrest, or heart failure hospitalization) and its individual components, all-cause mortality, and several safety end points using multivariable-adjusted Cox regression. We evaluated whether spironolactone reduced albuminuria at the 1-year visit in a subpopulation (N=744). Thirty-five percent had microalbuminuria, 13% had macroalbuminuria, and 80% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Increasing UACR was associated with male sex, higher systolic blood pressure, diabetes mellitus, and renal dysfunction. Macroalbuminuria (hazard ratio, 1.67; 95% CI, 1.22-2.28) and microalbuminuria (hazard ratio, 1.47; 95% CI, 1.15-1.86) were independently associated with the TOPCAT primary end point (compared with normoalbuminuria). Adjusting for placebo response, spironolactone reduced albuminuria by 39% in all participants at the 1-year visit compared with baseline (geometric mean ratio, 0.61; 95% CI, 0.49-0.77) and by 76% (geometric mean ratio, 0.24; 95% CI, 0.10-0.56) among those with macroalbuminuria. Reducing UACR by 50% was independently associated with a reduction in heart failure hospitalization (hazard ratio, 0.90; P=0.017) and all-cause mortality (hazard ratio, 0.91; P=0.019). The change in UACR was significantly associated with change in systolic blood pressure ( P=0.001). CONCLUSIONS: In TOPCAT, albuminuria was independently associated with worse cardiovascular outcomes. Spironolactone significantly reduced albuminuria compared with placebo. Reducing albuminuria was independently associated with improved outcomes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00094302.


Assuntos
Albuminúria/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Espironolactona/farmacologia , Idoso , Idoso de 80 Anos ou mais , Albuminúria/tratamento farmacológico , Creatinina/metabolismo , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Espironolactona/efeitos adversos , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologia , Resultado do Tratamento
17.
Hormones (Athens) ; 17(4): 573-579, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30467685

RESUMO

AIM: The evaluation of (a) noggin levels in patients with simple steatosis (SS) vs. nonalcoholic steatohepatitis (NASH) vs. controls, and (b) the effect of combined spironolactone plus vitamin E vs. vitamin E monotherapy on noggin levels in biopsy-proven patients with nonalcoholic fatty liver disease (NAFLD). METHODS: In the case-control study, 15 patients with SS, 16 with NASH, and 24 controls were included. In the randomized controlled trial, NAFLD patients were assigned to vitamin E (400 IU/d) or spironolactone (25 mg/d) plus vitamin E for 52 weeks. RESULTS: Noggin levels were lower in SS (5.8 ± 1.5 pmol/l) and NASH (8.7 ± 2.4 pmol/l) patients than in controls (13.7 ± 2.7 pmol/l; p for trend = 0.040), but were similar in SS and NASH patients. After adjustment for potential cofounders, log(noggin) remained different between groups. Log(noggin) levels similarly increased post-treatment in both groups: log(noggin) was not different between groups (p = 0.20), but increased within groups over time (p < 0.001), without a significant group × time interaction (p = 0.62). Log(noggin) significantly increased at month 2 post-treatment (p = 0.008 vs. baseline) and remained stable thereafter. CONCLUSIONS: Lower noggin levels were observed in NAFLD patients than in controls. Noggin levels increased similarly by either combined low-dose spironolactone plus vitamin E or vitamin E monotherapy. TRIAL REGISTRATION: NCT01147523.


Assuntos
Proteínas de Transporte/sangue , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Espironolactona/farmacologia , Vitamina E/farmacologia , Proteínas de Transporte/efeitos dos fármacos , Estudos de Casos e Controles , Quimioterapia Combinada , Humanos , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Espironolactona/administração & dosagem , Vitamina E/administração & dosagem
18.
J Diabetes Res ; 2018: 9232065, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30406151

RESUMO

Spironolactone (SPR) has been shown to protect diabetic cardiomyopathy (DCM), but the specific mechanisms are not fully understood. Here, we determined the cardioprotective role of SPR in diabetic mice and further explored the potential mechanisms in both in vivo and in vitro models. Streptozotocin- (STZ-) induced diabetic rats were used as the in vivo model. After the onset of diabetes, rats were treated with either SPR (STZ + SPR) or saline (STZ + NS) for 12 weeks; nondiabetic rats were used as controls (NDCs). In vitro, H9C2 cells were exposed to aldosterone, with or without SPR. Cardiac structure was investigated with transmission electron microscopy and pathological examination; immunohistochemistry was performed to detect nitrotyrosine, collagen-1, TGF-ß1, TNF-α, and F4/80 expression; and gene expression of markers for oxidative stress, inflammation, fibrosis, and energy metabolism was detected. Our results suggested that SPR attenuated mitochondrial morphological abnormalities and sarcoplasmic reticulum enlargement in diabetic rats. Compared to the STZ + NS group, cardiac oxidative stress, fibrosis, inflammation, and mitochondrial dysfunction were improved by SPR treatment. Our study showed that SPR had cardioprotective effects in diabetic rats by ameliorating mitochondrial dysfunction and reducing fibrosis, oxidative stress, and inflammation. This study, for the first time, indicates that SPR might be a potential treatment for DCM.


Assuntos
Diabetes Mellitus Experimental/complicações , Cardiomiopatias Diabéticas/prevenção & controle , Substâncias Protetoras/uso terapêutico , Espironolactona/uso terapêutico , Animais , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Inflamação/metabolismo , Masculino , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Espironolactona/farmacologia
19.
Molecules ; 23(11)2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30413071

RESUMO

Diterpenoids are widely distributed natural products and have caused considerable interest because of their unique skeletons and antibacterial and antitumor activities and so on. In light of recent discoveries, ent-kaurane diterpenoids, which exhibit a wide variety of biological activities, such as anticancer and anti-inflammatory activities, pose enormous potential to serve as a promising candidate for drug development. Among them, spirolactone-type 6,7-seco-ent-kaurane diterpenoids, with interesting molecular skeleton, complex oxidation patterns, and bond formation, exhibit attractive activities. Furthermore, spirolactone-type diterpenoids have many modifiable sites, which allows for linking to various substituents, suitable for further medicinal study. Hence, some structurally modified derivatives with improved cytotoxicity activities are also achieved. In this review, natural bioactive spirolactone-type diterpenoids and their synthetic derivatives were summarized.


Assuntos
Fatores Biológicos/síntese química , Diterpenos de Caurano/síntese química , Espironolactona/síntese química , Animais , Fatores Biológicos/química , Fatores Biológicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Diterpenos de Caurano/química , Diterpenos de Caurano/farmacologia , Humanos , Estrutura Molecular , Espironolactona/química , Espironolactona/farmacologia , Relação Estrutura-Atividade
20.
J Mol Cell Cardiol ; 125: 106-116, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30291912

RESUMO

BACKGROUND: High-fat diet (HFD) induces cardiac hypertrophy; however, the underlying cellular and molecular mechanisms are yet unclear. In the present study, we investigated the roles of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an amplifier of local glucocorticoid activity, in the pathogenesis of cardiac dysfunction. METHODS: Male Wistar rats were fed normal chow diet (NC) or HFD and examined the cardiac remolding and functional alteration by echocardiography and histology. Primary neonatal rat ventricular cardiomyocytes (NRCMs) treated with palmitic acid (PA) or infected by lentivirus were used for identifying the role by 11ß-HSD1 in cardiac hypertrophy. Genome microarray of NRCMs was performed to further reveal the mechanism underlying cardiac dysfunction. RESULTS: Palmitic acid induced hypertrophy in NRCMs that upregulated 11ß-HSD1 expression in cardiomyocytes, which led to a significant enlargement in the cell size and expression of cardiac hypertrophy-specific genes. Conversely, a remarkable decrease in cardiomyocytes size was detected in either BVT.2733 (a selective inhibitor of 11ß-HSD1)-treated or 11ß-HSD1-deficient NRCMs. Furthermore, both glucocorticoid receptor (GR) antagonist RU486 and mineralocorticoid receptor (MR) antagonist spironolactone markedly attenuated the 11ß-HSD1-induced cardiomyocytes hypertrophy. Genome microarray revealed that cAMP and calcium signaling pathways are potential downstream signaling pathways regulated by 11ß-HSD1 in cardiomyocytes hypertrophy. Similar to in vitro results, BVT.2733 strikingly attenuated cardiac hypertrophy and improved cardiac function in HFD-fed rats. CONCLUSION: 11ß-HSD1 acts as an important regulator that controls the cardiac remolding via both GR and MR and the pharmacological inhibition of 11ß-HSD1 could be a new therapeutic approach in preventing HFD-induced cardiac hypertrophy.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/metabolismo , Dieta Hiperlipídica/efeitos adversos , Animais , Animais Recém-Nascidos , Sinalização do Cálcio/efeitos dos fármacos , Cardiomiopatias/etiologia , Teste de Tolerância a Glucose , Masculino , Mifepristona/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ácido Palmítico/farmacologia , Ratos , Ratos Wistar , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Espironolactona/farmacologia
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