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1.
J Cell Mol Med ; 25(3): 1342-1349, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33443816

RESUMO

SARS-CoV-2, the virus responsible for the global coronavirus disease (COVID-19) pandemic, attacks multiple organs of the human body by binding to angiotensin-converting enzyme 2 (ACE2) to enter cells. More than 20 million people have already been infected by the virus. ACE2 is not only a functional receptor of COVID-19 but also an important endogenous antagonist of the renin-angiotensin system (RAS). A large number of studies have shown that ACE2 can reverse myocardial injury in various cardiovascular diseases (CVDs) as well as is exert anti-inflammatory, antioxidant, anti-apoptotic and anticardiomyocyte fibrosis effects by regulating transforming growth factor beta, mitogen-activated protein kinases, calcium ions in cells and other major pathways. The ACE2/angiotensin-(1-7)/Mas receptor axis plays a decisive role in the cardiovascular system to combat the negative effects of the ACE/angiotensin II/angiotensin II type 1 receptor axis. However, the underlying mechanism of ACE2 in cardiac protection remains unclear. Some approaches for enhancing ACE2 expression in CVDs have been suggested, which may provide targets for the development of novel clinical therapies. In this review, we aimed to identify and summarize the role of ACE2 in CVDs.


Assuntos
/metabolismo , Doenças Cardiovasculares/metabolismo , /farmacologia , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , /metabolismo , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/fisiopatologia , Diminazena/farmacologia , Insuficiência Cardíaca/etiologia , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Proteínas Recombinantes/farmacologia
2.
Life Sci ; 257: 118067, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32652140

RESUMO

Although renin-angiotensin system (RAS) imbalance is manifested in cardiomyopathies with different etiologies, the impact of RAS effectors on Chagas cardiomyopathy and skeletal myositis is poorly understood. Given that diminazene aceturate (DMZ) shares trypanocidal, angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) stimulatory effects, we investigated the impact of DMZ on cardiomyocytes infection in vitro, renin-angiotensin system, Chagas cardiomyopathy and skeletal myositis in vivo. Cardiomyocytes and T. cruzi were used to evaluate DMZ toxicity in vitro. The impact of 20-days DMZ treatment (1 mg/kg) was also investigated in uninfected and T. cruzi-infected mice as follows: control uninfected and untreated, uninfected treated with DMZ, infected untreated and infected treated with DMZ. DMZ had low toxicity on cardiomyocytes, induced dose-dependent antiparasitic activity on T. cruzi trypomastigotes, and reduced parasite load but not infection rates in cardiomyocytes. DMZ increased ACE2 activity and angiotensin-(1-7) plasma levels but exerted no interference on angiotensin-converting enzyme (ACE) activity, ACE, ACE2 and angiotensin II levels in uninfected and infected mice. DMZ treatment also reduced IFN-γ and IL-2 circulating levels but was ineffective in attenuating parasitemia, MCP-1, IL-10, anti-T. cruzi IgG, nitrite/nitrate and malondialdehyde production, myocarditis and skeletal myositis compared to infected untreated animals. As the antiparasitic effect of DMZ in vitro did not manifest in vivo, this drug exhibited limited relevance to the treatment of Chagas disease. Although DMZ is effective in upregulating angiotensin-(1-7) levels, this molecule does not act as a potent modulator of T. cruzi infection, which can establish heart and skeletal muscle parasitism, lipid oxidation and inflammatory damage, even in the presence of high concentrations of this RAS effector.


Assuntos
Cardiomiopatia Chagásica/tratamento farmacológico , Doença de Chagas/tratamento farmacológico , Diminazena/análogos & derivados , Miócitos Cardíacos/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina I/metabolismo , Animais , Linhagem Celular , Cardiomiopatia Chagásica/parasitologia , Doença de Chagas/parasitologia , Diminazena/administração & dosagem , Diminazena/farmacologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/tratamento farmacológico , Miocardite/parasitologia , Miócitos Cardíacos/parasitologia , Miosite/tratamento farmacológico , Miosite/parasitologia , Fragmentos de Peptídeos/metabolismo , Ratos , Tripanossomicidas/administração & dosagem , Tripanossomicidas/farmacologia
3.
Life Sci ; 253: 117749, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32380079

RESUMO

AIM: This work aims to explore the role of diminazene aceturate (DIZE) in the enhancement of angiotensin-converting enzyme-2 (ACE2) to prevent the inflammatory and fibrotic response induced by γ-irradiation through activating the protective axis ACE2/angiotensin (1-7)/Mas receptor (ACE2/Ang(1-7)/Mas). METHODS: Male rats were injected i.p. with 15 mg/kg DIZE daily for 7 days pre and post-irradiation, where 7.5 Gy of γ-radiation as a single dose was used. KEY FINDINGS: Gamma radiation induced a significant elevation of renal biochemical parameters: urea, creatinine and blood urea nitrogen (BUN) in serum with a significant disturbance in oxidative stress markers: elevation in malondialdehyde (MDA) associated with a depletion of reduced glutathione (GSH) and superoxide dismutase (SOD). Beside elevation in the level of angiotensin II (AngII) that lead to remarkably increases in the levels of the renal inflammatory mediators: tumor necrosis factor-α (TNF-α), nuclear factor kappa B (NF-κB) and interleukin-1ß (IL-1ß) as well as renal fibrogenic markers: transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor (CTGF), and hydroxyproline content in the renal tissues. DIZE caused marked expansion in the expression of ACE2 consequently decreased the expression of AngII and increased the expression of Ang(1-7) which through its Mas receptor ameliorates the biochemical and histopathological damage induced by radiation. SIGNIFICANCE: DIZE-induced stimulation of ACE2 subdues the renal deleterious consequences induced by γ-radiation via activation of ACE2/Ang(1-7)/Mas axis in rats.


Assuntos
Angiotensina II/metabolismo , Diminazena/análogos & derivados , Raios gama/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Angiotensina I/metabolismo , Angiotensina II/administração & dosagem , Animais , Diminazena/farmacologia , Glutationa/metabolismo , Masculino , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
4.
Int J Mol Med ; 46(2): 467-488, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32468014

RESUMO

The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID­19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID­19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , Internalização do Vírus/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/classificação , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Bromoexina/farmacologia , Bromoexina/uso terapêutico , Clorpromazina/farmacologia , Clorpromazina/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Diminazena/farmacologia , Diminazena/uso terapêutico , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/normas , Reposicionamento de Medicamentos/tendências , Gabexato/análogos & derivados , Gabexato/farmacologia , Gabexato/uso terapêutico , Humanos , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Peptidil Dipeptidase A/uso terapêutico , Pneumonia Viral/epidemiologia , Pneumonia Viral/mortalidade , Receptor Tipo 1 de Angiotensina/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
5.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L873-L887, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32160007

RESUMO

Tenacious mucus produced by tracheal and bronchial submucosal glands is a defining feature of several airway diseases, including cystic fibrosis (CF). Airway acidification as a driving force of CF airway pathology has been controversial. Here we tested the hypothesis that transient airway acidification produces pathologic mucus and impairs mucociliary transport. We studied pigs challenged with intra-airway acid. Acid had a minimal effect on mucus properties under basal conditions. However, cholinergic stimulation in acid-challenged pigs revealed retention of mucin 5B (MUC5B) in the submucosal glands, decreased concentrations of MUC5B in the lung lavage fluid, and airway obstruction. To more closely mimic a CF-like environment, we also examined mucus secretion and transport following cholinergic stimulation under diminished bicarbonate and chloride transport conditions ex vivo. Under these conditions, airways from acid-challenged pigs displayed extensive mucus films and decreased mucociliary transport. Pretreatment with diminazene aceturate, a small molecule with ability to inhibit acid detection through blockade of the acid-sensing ion channel (ASIC) at the doses provided, did not prevent acid-induced pathologic mucus or transport defects but did mitigate airway obstruction. These findings suggest that transient airway acidification early in life has significant impacts on mucus secretion and transport properties. Furthermore, they highlight diminazene aceturate as an agent that might be beneficial in alleviating airway obstruction.


Assuntos
Ácido Acético/administração & dosagem , Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia , Canais Iônicos Sensíveis a Ácido/genética , Obstrução das Vias Respiratórias/induzido quimicamente , Fibrose Cística/induzido quimicamente , Diminazena/análogos & derivados , Canais Iônicos Sensíveis a Ácido/metabolismo , Obstrução das Vias Respiratórias/tratamento farmacológico , Obstrução das Vias Respiratórias/metabolismo , Obstrução das Vias Respiratórias/patologia , Animais , Animais Recém-Nascidos , Bicarbonatos/metabolismo , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Brônquios/patologia , Líquido da Lavagem Broncoalveolar/química , Cloretos/metabolismo , Fibrose Cística/tratamento farmacológico , Fibrose Cística/metabolismo , Fibrose Cística/patologia , Diminazena/farmacologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Concentração de Íons de Hidrogênio , Masculino , Mucina-5AC/genética , Mucina-5AC/metabolismo , Mucina-5B/genética , Mucina-5B/metabolismo , Depuração Mucociliar/efeitos dos fármacos , Muco/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Suínos , Traqueia/efeitos dos fármacos , Traqueia/metabolismo , Traqueia/patologia
6.
PLoS One ; 15(2): e0228996, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32053698

RESUMO

BACKGROUND: The plenteous resistance to and undesirable consequences of the existing antipiroplasmic therapies have emphasized the urgent need for new chemotherapeutics and drug targets for both prophylaxis and chemotherapy. Hydroxyurea (HYD) is an antineoplastic agent with antitrypanosomal activity. Eflornithine (α-difluoro-methyl ornithine, DFMO) is the best choice therapy for the treatment of late-stage Gambian human African trypanosomiasis. METHODS: In this study, the inhibitory and combination efficacy of HYD and DFMO with existing babesicidal drugs (diminazene aceturate (DA), atovaquone (ATV), and clofazimine (CLF)) deoxyribonucleotide in vitro against the multiplication of Babesia and Theileria. As well as, their chemotherapeutic effects were assessed on B. microti strain that infects rodents. The Cell Counting Kits-8 (CCK-8) test was used to examine their cytotoxicity on human foreskin fibroblast (HFF), mouse embryonic fibroblast (NIH/3T3), and Madin-Darby bovine kidney (MDBK) cells. FINDINGS: HYD and DFMO suppressed the multiplication of all tested species (B. bigemina, B. bovis, B. caballi, B. divergens, and T. equi) in a dose-related manner. HFF, NIH/3T3, or MDBK cell viability was not influenced by DFMO at 1000 µM, while HYD affected the MDBK cell viability at EC50 value of 887.5±14.4 µM. The in vitro combination treatments of DFMO and HYD with CLF, DA, and ATV exhibited synergistic and additive efficacy toward all tested species. The in vivo experiment revealed that HYD and DFMO oral administration at 100 and 50 mg/kg inhibited B. microti multiplication in mice by 60.1% and 78.2%, respectively. HYD-DA and DFMO-DA combined treatments showed higher chemotherapeutic efficacy than their monotherapies. CONCLUSION: These results indicate the prospects of HYD and DFMO as drug candidates for piroplasmosis treatment, when combined mainly with DA, ATV, and CLF. Therefore, further studies are needed to combine HYD or DFMO with either ATV or CLF and examine their impact on B. microti infection in mice.


Assuntos
Babesia/efeitos dos fármacos , Eflornitina/efeitos adversos , Eflornitina/farmacologia , Hidroxiureia/efeitos adversos , Hidroxiureia/farmacologia , Theileria/efeitos dos fármacos , Animais , Antineoplásicos , Antiprotozoários/administração & dosagem , Antiprotozoários/farmacologia , Atovaquona/efeitos adversos , Atovaquona/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Clofazimina/efeitos adversos , Clofazimina/farmacologia , Diminazena/efeitos adversos , Diminazena/análogos & derivados , Diminazena/farmacologia , Cães , Prepúcio do Pênis/citologia , Humanos , Masculino , Camundongos , Células NIH 3T3
7.
Hypertens Res ; 42(12): 1883-1893, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31506648

RESUMO

The aim of this study was to investigate whether treatment with diminazene aceturate (DIZE), a putative ACE2 activator, or with angiotensin-(1-7) during pregnancy could attenuate the development of cardiovascular dysfunction in the adult offspring of spontaneously hypertensive rats (SHRs). For this, pregnant SHRs received DIZE or Ang-(1-7) throughout gestation. The systolic blood pressure (SBP) was measured in the male offspring from the 6th to16th weeks of age by tail-cuff plethysmography. Thereafter, the left ventricular contractile function and coronary reactivity were evaluated by the Langendorff technique. Samples of the left ventricles (LVs) and kidneys were collected for histology and western blot assay in another batch of adult rat offspring. Maternal treatment with DIZE or Ang-(1-7) during pregnancy attenuated the increase in SBP in adult offspring. In addition, both DIZE and Ang-(1-7) treatments reduced the cardiomyocyte diameter and fibrosis deposition in the LV, and treatment with Ang-(1-7) also reduced the fibrosis deposition in the kidneys. Maternal treatment with DIZE, as well as Ang-(1-7), improved the coronary vasodilation induced by bradykinin in isolated hearts from adult offspring. However, no difference was observed in the contractile function of the LVs of these animals. The expression levels of AT1 and Mas receptors, ACE, ACE2, SOD, and catalase in the LV were not modified by maternal treatment with Ang-(1-7), but this treatment elicited a reduction in AT2 expression. These data show that treatment with DIZE or Ang-(1-7) during gestation promoted beneficial effects of attenuating hypertension and cardiac remodeling in adult offspring.


Assuntos
Angiotensina I/farmacologia , Doenças Cardiovasculares/prevenção & controle , Diminazena/análogos & derivados , Ativadores de Enzimas/farmacologia , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Diminazena/farmacologia , Feminino , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Masculino , Contração Miocárdica , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Função Ventricular Esquerda
8.
QJM ; 112(12): 914-924, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31393582

RESUMO

OBJECTIVE: To investigate the role of angiotensin-converting enzyme 2 (ACE2) in hyperoxic lung injury. METHODS: Adult mice were exposed to 95% O2 for 72 h to induce hyperoxic lung injury, and simultaneously treated with ACE2 agonist diminazene aceturate (DIZE) or inhibitor MLN-4760. ACE2 expression/activity in lung tissue and angiotensin (Ang)-(1-7)/Ang II in bronchoalveolar lavage fluid (BALF), and the severity of hyperoxic lung injury were evaluated. The levels of inflammatory factors in BALF and lung tissue and the expression levels of phospho-p65, p65 and IkBα were measured. Oxidative parameter and antioxidant enzyme levels in lung tissue were measured to assess oxidative stress. Finally, the expression levels of nuclear factor-erythroid-2-related factor (Nrf2), NAD(P)H quinine oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) were measured using Western blotting. RESULTS: Hyperoxia treatment significantly decreased lung ACE2 expression/activity and increased the Ang II/Ang-(1-7) ratio, while co-treatment with hyperoxia and DIZE significantly increased lung ACE2 expression/activity and decreased the Ang II/Ang-(1-7) ratio. By contrast, co-treatment with hyperoxia and MLN-4760 significantly decreased lung ACE2 expression/activity and increased the Ang II/Ang-(1-7) ratio. Hyperoxia treatment induced significant lung injury, inflammatory response and oxidative stress, which were attenuated by DIZE but aggravated by MLN-4760. The NF-κB pathways were activated by hyperoxia and MLN-4760 but inhibited by DIZE. The Nrf2 pathway and its downstream proteins NQO1 and HO-1 were activated by DIZE but inhibited by MLN-4760. CONCLUSION: Activation of ACE2 can reduce the severity of hyperoxic lung injury by inhibiting inflammatory response and oxidative stress. ACE2 can inhibit the NF-κB pathway and activate the Nrf2/HO-1/NQO1 pathway, which may be involved in the underlying mechanism.


Assuntos
Lesão Pulmonar/patologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Angiotensina I/análise , Animais , Líquido da Lavagem Broncoalveolar/química , Diminazena/análogos & derivados , Diminazena/farmacologia , Hiperóxia/patologia , Imidazóis/farmacologia , Leucina/análogos & derivados , Leucina/farmacologia , Lesão Pulmonar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/análise
9.
Vet Parasitol ; 270: 40-46, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31213240

RESUMO

Parasitic nematodes pose a major threat to livestock production worldwide. The blood-feeding parasite Haemonchus contortus is a key small-ruminant pathogen that causes anaemia, and thereby seriously impacts animal health and production. Control of this parasite relies largely upon broad-spectrum anthelmintics, but new drugs are urgently needed to combat the threat of widespread multidrug resistance. Repurposing drugs can accelerate the development pipeline by reducing costs and risks, and can be an effective way of quickly bringing new antiparasitic drugs to market. Diarylamidine compounds such as pentamidine and diminazene have been employed in the treatment of trypanosomiasis and leishmaniasis in both human and veterinary settings, but their activity against parasitic worms has not yet been reported. We screened a small panel of diarylamidine compounds against H. contortus to assess their potential to be repurposed as anthelmintic drugs. Pentamidine and diminazene inhibited H. contortus larval development at low micromolar concentrations (IC50 4.9 µM and 16.1 µM, respectively, in a drug-susceptible isolate) with no existing cross-resistance in two multidrug resistant isolates and a monepantel-resistant isolate. Combinations of pentamidine with commercial anthelmintics showed additive activity, with no significant synergism detected. Pentamidine and diminazene showed different life-stage patterns of activity; both were active against early stage larvae in development assays, but only diminazene was active against the infective L3 stage in migration assays. This suggests some differences in uptake of the two drugs across the nematode cuticle, or differences in the nature and expression patterns of their molecular targets. As pentamidine and diminazene have been reported to be potent inhibitors of mammalian acid-sensing ion channels (ASIC), we tested the activity of known ASIC inhibitors against H. contortus to probe whether these channels may represent potential anthelmintic targets in nematodes. Remarkably, the spider-venom peptide Hi1a, a potent inhibitor of ASIC1a, inhibited H. contortus larval development with an IC50 of 22.9 ± 1.9 µM. This study highlights the potential use of diarylamidines as anthelmintics, although their activity needs to be confirmed in vivo. In addition, our demonstration that ASIC inhibitors have anthelmintic activity raises the possibility that this family of ion channels may represent a novel anthelmintic target.


Assuntos
Anti-Helmínticos/farmacologia , Diminazena/farmacologia , Haemonchus/efeitos dos fármacos , Pentamidina/farmacologia , Animais , Antiprotozoários/farmacologia , Técnicas In Vitro , Concentração Inibidora 50
10.
PLoS One ; 14(5): e0216078, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31048849

RESUMO

African trypanosomiasis remains a lethal disease to both humans and livestock. The disease persists due to limited drug availability, toxicity and drug resistance, hence the need for a better understanding of the parasite's biology and provision of alternative forms of therapy. In this study, the in vitro effects of phenolic acids were assessed for their trypanocidal activities against Trypanosoma brucei brucei. The effect of the phenolic acids on Trypanosoma brucei brucei was determined by the alamarBlue assay. The cell cycle effects were determined by flow cytometry and parasite morphological analysis was done by microscopy. Effect on cell proliferation was determined by growth kinetic analysis. Reverse Transcriptase quantitative Polymerase Chain Reaction was used to determine expression of iron dependent enzymes and iron distribution determined by atomic absorption spectroscopy. Gallic acid gave an IC50 of 14.2±1.5 µM. Deferoxamine, gallic acid and diminazene aceturate showed a dose dependent effect on the cell viability and the mitochondrion membrane integrity. Gallic acid, deferoxamine and diminazene aceturate caused loss of kinetoplast in 22%, 26% and 82% of trypanosomes respectively and less than 10% increase in the number of trypanosomes in S phase was observed. Gallic acid caused a 0.6 fold decrease, 50 fold increase and 7 fold increase in the expression levels of the transferrin receptor, ribonucleotide reductase and cyclin 2 genes respectively while treatment with deferoxamine and diminazene aceturate also showed differential expressions of the transferrin receptor, ribonucleotide reductase and cyclin 2 genes. The data suggests that gallic acid possibly exerts its effect on T. brucei via iron chelation leading to structural and morphological changes and arrest of the cell cycle. These together provide information on the cell biology of the parasite under iron starved conditions and provide leads into alternative therapeutic approaches in the treatment of African trypanosomiasis.


Assuntos
Hidroxibenzoatos/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desferroxamina/farmacologia , Diminazena/análogos & derivados , Diminazena/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Ácido Gálico/farmacologia , Humanos , Ferro/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Tripanossomicidas/farmacologia , Trypanosoma/efeitos dos fármacos , Trypanosoma brucei brucei/patogenicidade , Tripanossomíase Africana/parasitologia
11.
Trop Anim Health Prod ; 51(7): 2091-2094, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30997632

RESUMO

African animal trypanosomiasis is a major cause of mortality and economic losses for the livestock industry in Nigeria. Chemotherapy has been the most reliable option for cattle herders, and the most commonly found drug on the market is diminazene aceturate. To ascertain the long-term efficacy of this compound, we sampled a cattle herd in Ogun State, Nigeria, 2 months after they were treated with diminazene aceturate. The ITS-PCR results revealed 19 positives for trypanosome DNA out of the 79 samples tested (24.1%, 95% CI 16.0-34.5). Seventeen out of the total 19 positives were Trypanosoma congolense (21.5%, 95% CI 13.9-31.8). Mixed infections were also observed. Therefore, the persistence of bovine trypanosomiasis at this Nigerian cattle farm despite treatment could be due to diminazene aceturate resistant trypanosomes being present in the herd.


Assuntos
Diminazena/análogos & derivados , Tripanossomicidas/uso terapêutico , Trypanosoma congolense/genética , Tripanossomíase Africana/veterinária , Tripanossomíase Bovina/tratamento farmacológico , Animais , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/parasitologia , DNA Intergênico , Diminazena/farmacologia , Resistência a Medicamentos , Fazendas , Nigéria , Reação em Cadeia da Polimerase
12.
Protein Pept Lett ; 26(7): 523-531, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30950337

RESUMO

BACKGROUND: Angiotensin Converting Enzyme (ACE) 2 is an important modulator of the Renin Angiotensin System (RAS) and the RAS plays a central role in renovascular hypertension. Very few studies investigated the role of components of the counterregulatory RAS axis (ACE2, Ang-(1-7) and Mas receptor) in renovascular hypertension and the results are controversial. OBJECTIVE: The aim of this study was to investigate the effects of Diminazene Aceturate (DIZE) administration on renal function and renal inflammation parameters in 2K1C hypertensive rats. METHODS: Male Wistar rats were divided into three experimental groups: sham-operated animals, 2K1C+saline and 2K1C+DIZE orally (1 mg/kg/day). At the end of the 30 days of treatment, renal function was analyzed and kidneys from all the groups were collected and processed separately for measurement of N-acetyl-beta-D-glucosaminidase (NAG) and Myeloperoxidase (MPO) activities, cytokines, chemokines and nitric oxide levels. RESULTS: Oral DIZE administration for 4 weeks in hypertensive rats attenuated renal dysfunction and reduced the levels of MPO and NAG, cytokines and chemokines (IL1ß, IL-6, TNF-α and MCP-1) and increased urinary nitrate/nitrite levels in 2K1C hypertensive rats. CONCLUSION: Our findings showed that ACE2 activation may effectively improve renal alterations and inflammation induced by renovascular hypertension.


Assuntos
Diminazena/análogos & derivados , Ativadores de Enzimas/farmacologia , Hipertensão Renovascular/tratamento farmacológico , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Acetilglucosaminidase/metabolismo , Angiotensina I/metabolismo , Animais , Citocinas/metabolismo , Diminazena/farmacologia , Diminazena/uso terapêutico , Ativadores de Enzimas/uso terapêutico , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/metabolismo , Peroxidase/metabolismo , Ratos Wistar
13.
Can J Physiol Pharmacol ; 97(7): 638-646, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30840489

RESUMO

Myocardial infarction is a major cause of cardiac dysfunction. All components of the cardiac renin-angiotensin system (RAS) are upregulated in myocardial infarction. Angiotensin-converting enzyme (ACE) and ACE2 are key enzymes involved in synthesis of components of RAS and provide a counter-regulatory mechanism within RAS. We compared the cardioprotective effect of the ACE2 activator diminazene aceturate (DIZE) versus the ACE inhibitor enalapril on post acute myocardial infarction (AMI) ventricular dysfunction in rats. Adult male rats received subcutaneous injections of either saline (control) or isoproterenol (85 mg/kg) to induce AMI. Rats with AMI confirmed biochemically and by ECG, were either left untreated (AMI) or administered DIZE (AMI + DIZE) or enalapril (AMI + enalapril) daily for 4 weeks. DIZE caused a significant activation of cardiac ACE2 compared with enalapril. DIZE caused a significantly greater enhancement of cardiac hemodynamics. DIZE also caused greater reductions in heart-type fatty acid binding protein (H-FABP), ß-myosin heavy chain (ß-MYH), and in heart mass to total body mass ratio. These results indicated that activation of cardiac ACE2 by DIZE enhanced the protective axis of RAS and improved myocardial function following AMI, whereas enalapril was not sufficient to restore all cardiac parameters back to normal.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Cardiotônicos/farmacologia , Diminazena/análogos & derivados , Enalapril/farmacologia , Infarto do Miocárdio/fisiopatologia , Peptidil Dipeptidase A/metabolismo , Doença Aguda , Animais , Diminazena/farmacologia , Ativação Enzimática/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Hipertrofia Ventricular Direita/complicações , Masculino , Infarto do Miocárdio/complicações , Ratos , Ratos Wistar
14.
Artigo em Inglês | MEDLINE | ID: mdl-30785049

RESUMO

Diminazene aceturate (DA) is commonly used in the treatment of bovine babesiosis caused by Babesia bovis. In this study, we attempted to develop resistance in B. bovis in vitro to DA and clofazimine (CF, a novel antibabesial agent) using short- and long-term drug pressures. In the short term, we found that 6.7 ±â€¯2 (0.54 ±â€¯0.16 µM)-, 12.9 ±â€¯8.6 (1.05 ±â€¯0.7 µM)-, and 14 ±â€¯5.9 (1.14 ±â€¯0.48 µM)-fold increases in the half-maximal inhibitory concentration (IC50) of DA were demonstrated on B. bovis cultivated with 0.04 µM of DA pressure for 4, 8, and 12 days, respectively, as compared to that on parental culture (0.08 ±â€¯0.0065 µM) before drug pressure was initiated. However, in B. bovis cultivated with 0.04 µM of DA pressure after 16 days, the parasites could not tolerate 0.8 µM of DA. In the long term, 7.6 ±â€¯3.5-, 20.5 ±â€¯0.1-, and 26.8 ±â€¯5.5-fold increases in the IC50 of DA were demonstrated on parasites from subcultures at days 8, 3, and 5 post-cultivation, respectively, in a drug-free medium, where these subcultures were obtained from B. bovis cultivated with DA pressure with changing doses for 30, 60, and 90 days, respectively. However, the second and third times, no increase was demonstrated on B. bovis from these subcultures at days 15 and 30 post-cultivation in a drug-free medium. In addition, in B. bovis cultivated with drug pressure after 90 days, the parasites tolerate up to 0.64 µM DA. All findings demonstrated that DA resistance in B. bovis is unstable and lost within 15 days of drug withdrawal. However, treatment with subtherapeutic doses of DA in cattle might result in the development of resistance in B. bovis, which may not even respond to subsequent treatments with high doses of DA. Thus, if the bovine babesiosis caused by B. bovis is unresponsive to DA, treatment with other antibabesial agents might be recommended.


Assuntos
Antiprotozoários/farmacologia , Babesia bovis/efeitos dos fármacos , Diminazena/análogos & derivados , Resistência a Medicamentos , Animais , Babesiose/tratamento farmacológico , Bovinos , Diminazena/farmacologia , Eritrócitos/parasitologia , Concentração Inibidora 50
15.
Life Sci ; 221: 159-167, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30769114

RESUMO

AIMS: Renin-angiotensin system (RAS) and natriuretic peptides system (NPS) perturbations govern the development of diabetic nephropathy (DN). Hence, in search of a novel therapy against DN, present study targeted both, NPS and RAS simultaneously using a neprilysin inhibitor (NEPi) in combination with either angiotensin receptor blocker (ARB) or angiotensin-converting enzyme 2 (ACE2) activator. METHODS: We induced diabetes in male Wistar rats by a single dose of streptozotocin (55 mg/kg, i.p.). After four weeks, we treated diabetic rats with thiorphan, telmisartan or diminazene aceturate (Dize) 0.1, 10, 5 mg/kg/day, p.o. alone as monotherapy, or both thiorphan/telmisartan or thiorphan/Dize as combination therapy, for four weeks. Then, plasma and urine biochemistry were performed, and kidneys from all the groups were collected and processed separately for histopathology, ELISA and Western blotting. KEY FINDINGS: Proposed combination therapies attenuated metabolic perturbations, prevented renal functional decline, and normalised adverse alterations in renal ACE, ACE2, Ang-II, Ang-(1-7), neprilysin and cGMP levels in diabetic rats. Histopathological evaluation revealed a significant reduction in glomerular and tubulointerstitial fibrosis by combination therapies. Importantly, combination therapies inhibited inflammatory, profibrotic and apoptotic signalling, way better than respective monotherapies, in preventing DN. CONCLUSION: Renoprotective potential of thiorphan (NEPi)/telmisartan (ARB) and thiorphan/Dize (ACE2 activator) combination therapies against the development of DN is primarily attributed to normalisation of RAS and NPS components and inhibition of pathological signalling related to inflammation, fibrosis, and apoptosis. Hence, we can conclude that NEPi/ARB and NEPi/ACE2 activator combination therapies might be new therapeutic strategies in preventing DN.


Assuntos
Nefropatias Diabéticas/metabolismo , Neprilisina/metabolismo , Sistema Renina-Angiotensina/fisiologia , Animais , Apoptose , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/prevenção & controle , Diminazena/análogos & derivados , Diminazena/metabolismo , Diminazena/farmacologia , Fibrose , Inflamação , Rim/patologia , Masculino , Neprilisina/antagonistas & inibidores , Peptidil Dipeptidase A , Ratos , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos , Estreptozocina , Telmisartan/metabolismo , Telmisartan/farmacologia , Tiorfano/metabolismo , Tiorfano/farmacologia
16.
Neuropharmacology ; 148: 366-376, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30716415

RESUMO

Acid-sensing ion channels (ASICs) are proton-activated, sodium-permeable channels, highly expressed in both central and peripheral nervous systems. ASIC1a is the most abundant isoform in the central nervous system and is credited to be involved in several neurological disorders including stroke, multiple sclerosis, and epilepsy. Interestingly, the affinity of ASIC1a for two antagonists, diminazene and amiloride, has recently been proposed to be voltage sensitive. Based on this evidence, it is expected that the pharmacology of ASIC1cannot be properly characterized by single-cell voltage-clamp, an experimental condition in which membrane potential is maintained close to resting values. In particular, these measurements do not take into account the influence of the membrane potential depolarization induced by ASIC1a activation during acidosis or neuronal activity. We show here the voltage-dependence of some small molecules antagonists (diminazene, amiloride and a new patented drug from Merck), but not of Psalmotoxin 1, a peptide binding to regions other than the pore. We also demonstrate that the opening of ASIC1a induced by moderate acidosis determines a depolarization sufficient to change the affinity of small molecule antagonists. The characterization of this mechanism was performed on CHO-K1 expressing ASIC1a and further confirmed in hippocampal neurons in culture. Finally, perforated-patch experiments indicate that intracellular modulations do not play a role in the voltage-dependent binding of small molecules. Since ASIC1a activation promotes a membrane depolarization that may influence the binding of small molecules, we propose to adopt experimental methods that do not interfere with the membrane potential for the drug screening of ASIC1a modulators.


Assuntos
Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia , Canais Iônicos Sensíveis a Ácido/fisiologia , Potenciais da Membrana/fisiologia , Acidose/fisiopatologia , Amilorida/farmacologia , Animais , Células Cultivadas , Cricetinae , Diminazena/farmacologia , Hipocampo/fisiologia , Neurônios/fisiologia , Venenos de Aranha/farmacologia
17.
Cell Biol Toxicol ; 35(2): 147-159, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30673990

RESUMO

Manganese exposure is among the many environmental risk factors linked to the progression of neurodegenerative diseases, such as manganese-induced parkinsonism. In animal models, chronic exposure to manganese causes loss of cell viability, neurodegeneration, and functional deficits. Polyamines, such as spermine, have been shown to rescue animals from age-induced neurodegeneration in an autophagy-dependent manner; nonetheless, it is not understood whether polyamines can prevent manganese-induced toxicity. In this study, we used two model systems, the Caenorhabditis elegans UA44 strain and SK-MEL-28 cells, both expressing the protein alpha-synuclein (α-syn) to determine whether spermine could ameliorate manganese-induced toxicity. Manganese caused a substantial reduction in the viability of SK-MEL-28 cells and hastened neurodegeneration in the UA44 strain. Spermine protected both the SK-MEL-28 cells and the UA44 strain from manganese-induced toxicity. Spermine also reduced the age-associated neurodegeneration observed in the UA44 strain compared with a control strain without α-syn expression and led to improved avoidance behavior in a functional assay. Treatment with berenil, an inhibitor of polyamine catabolism, which leads to increased intracellular polyamine levels, also showed similar cellular protection against manganese toxicity. While both translation blocker cycloheximide and autophagy blocker chloroquine caused a reduction in the cytoprotective effect of spermine, transcription blocker actinomycin D had no effect. This study provides new insights on the effect of spermine in preventing manganese-induced toxicity, which is most likely via translational regulation of several candidate genes, including those of autophagy. Thus, our results indicate that polyamines positively influence neuronal health, even when exposed to high levels of manganese and α-syn, and supplementing polyamines through diet might delay the onset of diseases involving degeneration of dopaminergic neurons.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Manganês/toxicidade , Fármacos Neuroprotetores/farmacologia , Espermina/farmacologia , Animais , Caenorhabditis elegans/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diminazena/análogos & derivados , Diminazena/farmacologia , Humanos , Degeneração Neural/prevenção & controle , alfa-Sinucleína/metabolismo
18.
Biomed Pharmacother ; 107: 212-218, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30092400

RESUMO

Diminazene aceturate (DIZE) has been reported to enhance the catalytic efficiency of ACE-2 and presumably increases angiotensin 1-7 generation, interfering with cardiac remodeling after myocardial infarction (MI). Our aim was to investigate the chronic effects of DIZE on cardiac dysfunction post-MI. Male Wistar rats underwent myocardial infarction (MI) or SHAM surgery (SO) and were divided into groups treated with DIZE 15 mg/kg/day, s.c. or vehicle (Control). After 4 weeks, the hemodynamic variables were recorded by cardiac catheterism. Hearts were then arrested to obtain the left ventricular (LV) pressure-volume curves in situ. Cardiomyocyte hypertrophy and collagen content were determined by histology. DIZE prevented LV end-diastolic pressure increases in MI rats (MI: 26 ± 3.3 vs. MI-DIZE: 15 ± 1.6 mmHg, P < 0.001) without a significant effect on LV systolic pressure (LVSP). Moreover, DIZE improved LV contractility (+dP/dt, MI: 3014 ± 161 vs. MI-DIZE: 3884 ± 104 mmHg/s, P < 0.001) and relaxation (-dP/dt, MI: -2333 ± 91 vs. MI-DIZE: -2798 ± 120 mmHg/s, P < 0.05). Right ventricular SP was increased in the MI compared to that in the SO group (40 ± 0.6 vs. 30 ± 1.2 mmHg; P < 0.01), and DIZE partially prevented this augmentation. LV stiffness was reduced in MI-DIZE compared with that in MI (0.64 ± 0.01 vs. 0.78 ± 0.02 mmHg/mL; P < 0.01). DIZE treatment reduced the interstitial collagen content by 18% in the surviving LV myocardium. Cardiomyocyte hypertrophy remained unaffected by DIZE treatment. Our findings show that chronic DIZE treatment post-MI attenuates the morphofunctional changes induced by MI in rats. The effects on LV -dP/dt, chamber stiffness and collagen content suggest this drug can be used as a therapeutic agent to reduce interstitial fibrosis and diastolic dysfunction after MI.


Assuntos
Diástole , Diminazena/análogos & derivados , Ativadores de Enzimas/uso terapêutico , Infarto do Miocárdio/complicações , Peptidil Dipeptidase A/metabolismo , Disfunção Ventricular/tratamento farmacológico , Disfunção Ventricular/etiologia , Animais , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Colágeno/metabolismo , Diástole/efeitos dos fármacos , Diminazena/farmacologia , Diminazena/uso terapêutico , Ativadores de Enzimas/farmacologia , Hemodinâmica/efeitos dos fármacos , Masculino , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Wistar , Disfunção Ventricular/patologia , Disfunção Ventricular/fisiopatologia , Função Ventricular/efeitos dos fármacos
19.
Sci Rep ; 8(1): 10175, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29977014

RESUMO

There is no established medical therapy to treat biliary fibrosis resulting from chronic inflammation in the biliary tree. We have recently shown that liver-specific over-expression of angiotensin converting enzyme 2 (ACE2) of the renin angiotensin system (RAS) ameliorated liver fibrosis in mice. Diminazene aceturate (DIZE), a small molecule drug approved by the US Food and Drug Administration, which is used to treat human trypanosomiasis, has been shown to have antifibrotic properties by enhancing ACE2 activity. In this study we sought to determine the therapeutic potential of DIZE in biliary fibrosis using bile duct ligated and multiple drug resistant gene-2 knockout mice. Additionally, human hepatic stellate (LX-2) and mouse Kupffer (KUP5) cell lines were used to delineate intracellular pathways. DIZE treatment, both in vivo and in vitro, markedly inhibited the activation of fibroblastic stellate cells which was associated with a reduced activation of Kupffer cells. Moreover, DIZE-inhibited NOX enzyme assembly and ROS generation, activation of profibrotic transcription factors including p38, Erk1/2 and Smad2/3 proteins and proinflammatory and profibrotic cytokine release. These changes led to a major reduction in biliary fibrosis in both models without affecting liver ACE2 activity. We conclude that DIZE has a potential to treat biliary fibrosis.


Assuntos
Diminazena/análogos & derivados , Cirrose Hepática Experimental/tratamento farmacológico , Fígado/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Linhagem Celular , Citocinas/metabolismo , Diminazena/farmacologia , Diminazena/uso terapêutico , Células Estreladas do Fígado , Humanos , Macrófagos do Fígado , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática Experimental/etiologia , Cirrose Hepática Experimental/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Peptidil Dipeptidase A/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Resultado do Tratamento
20.
Exp Gerontol ; 111: 133-140, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30006298

RESUMO

The obesity epidemic is multi-generational and is particularly debilitating in the aging population, necessitating the use of pharmaceutical interventions. Recent evidence suggests that increasing the activity of the angiotensin converting enzyme-2 [ACE2]/angiotensin-(1-7)[Ang-(1-7)]/Mas receptor (MasR) axis in obese animal models leads to significant reductions in body weight. It was hypothesized that activation of ACE2 via diminazene aceturate (DIZE) will significantly reduce body weight of rats fed a high fat diet. Young and old (4 and 23 months, respectively) male Fisher 344 × Brown Norway rats were fed 60% high fat diet for one week, and subsequently given either 15 mg/kg/day DIZE s.c. or vehicle for three weeks. DIZE treatment resulted in a significant reduction of food intake and body weight in both young and old animals. However, that decrease was so dramatic in the older animals that they all nearly stopped eating. Interestingly, the TD-NMR assessments revealed that the weight-loss was primarily a result of decreased body fat percentage, with a relative preservation of lean mass. Tissue weights confirm the significant loss of white adipose tissue (WAT), with no change in muscle weights. Gene expression and serum ACE2 activity analyses implied that increased activation of the ACE2/Ang-(1-7)/MasR axis plays a role in reducing fat mass. Collectively, our results suggest that DIZE may be a useful tool in the study of obesity; however, caution is recommended when using this compound in older animals due to severe anorectic effects, although there is a mechanism by which muscle is preserved.


Assuntos
Adiposidade/efeitos dos fármacos , Angiotensina I/metabolismo , Diminazena/análogos & derivados , Obesidade/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Fatores Etários , Angiotensina I/genética , Animais , Diminazena/farmacologia , Modelos Animais de Doenças , Expressão Gênica , Masculino , Fragmentos de Peptídeos/genética , Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/genética , Ratos , Ratos Endogâmicos F344 , Sistema Renina-Angiotensina/efeitos dos fármacos
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