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1.
Exp Parasitol ; 210: 107831, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31926147

RESUMO

Babesia (B.) bovis is one of the main etiological agents of bovine babesiosis, causes serious economic losses to the cattle industry. Control of bovine babesiosis has been hindered by the limited treatment selection for B. bovis, thus, new options are urgently needed. We explored the drug library and unbiasedly screened 640 food and drug administration (FDA) approved drug compounds for their inhibitory activities against B. bovis in vitro. The initial screening identified 13 potentially effective compounds. Four potent compounds, namely mycophenolic acid (MPA), pentamidine (PTD), doxorubicin hydrochloride (DBH) and vorinostat (SAHA) exhibited the lowest IC50 and then selected for further evaluation of their in vitro efficacies using viability, combination inhibitory and cytotoxicity assays. The half-maximal inhibitory concentration (IC50) values of MPA, PTD, DBH, SAHA were 11.38 ± 1.66, 13.12 ± 4.29, 1.79 ± 0.15 and 45.18 ± 7.37 µM, respectively. Of note, DBH exhibited IC50 lower than that calculated for the commonly used antibabesial drug, diminazene aceturate (DA). The viability result revealed the ability of MPA, PTD, DBH, SAHA to prevent the regrowth of treated parasite at 4 × and 2 × of IC50. Antagonistic interactions against B. bovis were observed after treatment with either MPA, PTD, DBH or SAHA in combination with DA. Our findings indicate the richness of FDA approved compounds by novel potent antibabesial candidates and the identified potent compounds especially DBH might be used for the treatment of animal babesiosis caused by B. bovis.


Assuntos
Antiprotozoários/farmacologia , Babesia bovis/efeitos dos fármacos , Animais , Antiprotozoários/toxicidade , Babesia bovis/crescimento & desenvolvimento , Babesiose/tratamento farmacológico , Babesiose/parasitologia , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Doenças dos Bovinos/parasitologia , Cães , Doxorrubicina/farmacologia , Doxorrubicina/toxicidade , Aprovação de Drogas , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Concentração Inibidora 50 , Células Madin Darby de Rim Canino/efeitos dos fármacos , Ácido Micofenólico/farmacologia , Ácido Micofenólico/toxicidade , Pentamidina/farmacologia , Pentamidina/toxicidade , Bibliotecas de Moléculas Pequenas , Espectrometria de Fluorescência , Vorinostat/farmacologia , Vorinostat/toxicidade
2.
Chem Commun (Camb) ; 56(7): 1085-1088, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31894779

RESUMO

We report an elastase-responsive, H2S-releasing hydrogel prepared by covalently crosslinking a mixture of carboxymethylcellulose and poly(ethylene glycol) with an elastase-degradable peptide functionalized with an H2S-releasing S-aroylthiooxime (SATO) unit. Addition of elastase triggered a gel-to-sol transition, which exposed SATOs, leading to more and longer H2S release compared to untriggered gels.


Assuntos
Carboximetilcelulose Sódica/farmacologia , Hidrogéis/farmacologia , Sulfeto de Hidrogênio/metabolismo , Elastase de Leucócito/metabolismo , Polietilenoglicóis/farmacologia , Animais , Carboximetilcelulose Sódica/síntese química , Carboximetilcelulose Sódica/metabolismo , Linhagem Celular , Doxorrubicina/toxicidade , Humanos , Hidrogéis/síntese química , Hidrogéis/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oximas/síntese química , Oximas/metabolismo , Oximas/farmacologia , Polietilenoglicóis/síntese química , Polietilenoglicóis/metabolismo , Substâncias Protetoras/síntese química , Substâncias Protetoras/metabolismo , Substâncias Protetoras/farmacologia , Ratos
3.
Toxicol Lett ; 319: 204-212, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760061

RESUMO

Doxorubicin has been indicated to be cardiotoxic and nephrotoxic, and thus it is often used as a model drug. Possible molecular mechanisms of this toxicity have been proposed, however, the systematic investigation of time-related metabolic trajectories specific to renal toxicity has rarely been reported. The present study was designed to assess time-dependent changes in doxorubicin-induced nephropathy through urinary metabolomics and to reveal the molecular mechanism based on key pathways. Urinary metabolomics revealed that the 14th day was the critical time point for model construction. Pathway analysis results showed that 5 pathways with impact (>0.1), FDR (<0.1) and p value (<0.05) were important. Furthermore, three pathways, including butanoate metabolism, alanine, aspartate and glutamate metabolism and arginine and proline metabolism, were focused on and validated by partial least squares regression analysis (PLS-RA) and molecular docking techniques. Our findings also showed that robust metabolomics combined with PLS-RA and molecular docking techniques is promising for elucidating time-dependent changes due to doxorubicin toxicity and for clarifying mechanisms, and the results provide a research foundation for the construction of a nephropathy model.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Nefropatias/induzido quimicamente , Nefropatias/urina , Metaboloma/efeitos dos fármacos , Aminoácidos/metabolismo , Animais , Rim/patologia , Nefropatias/patologia , Masculino , Metabolômica , Simulação de Acoplamento Molecular , Proteinúria/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
4.
Food Chem Toxicol ; 135: 111045, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31830546

RESUMO

Cardiotoxicity and nephrotoxicity due to the abnormal production of free radicals have been observed in patients treated with the anticancer antibiotic adriamycin (ADR). The aim of the present study was to evaluate the role of the heart of palm extract in preventing oxidative stress, cardiotoxicity and nephrotoxicity induced by ADR. In this work, an aqueous ethanolic extract of the heart of the Phoenix dactylifera tree (HP) was investigated. The polyphenol content was evaluated by gas chromatography-mass spectrometry (GC-MS) and High-performance liquid chromatography (HPLC). The protective effect of the HP-extract (250 and 500 mg/kg, p.o.) was evaluated along with ADR administration (cumulative dose 15 mg/kg, IP) in rats. The HP-extract (500 mg/kg) treated group showed significant reductions in cardiotoxicity and nephrotoxicity serum markers, apoptotic percentage, and caspase-3 and cyclooxygenase-2 level, with an improvement in antioxidant enzymes in both heart and kidney homogenate, compared with the ADR-induction group. The cardiac and kidney programmed cell death protein-1 (PD-1) was increased in high dose HP-extract treated rats after being inhibited by ADR administration. In conclusion, the HP-extract might be a promising food supplement for preventing the cardiotoxicity and nephrotoxicity induced by ADR administration.


Assuntos
Apoptose/efeitos dos fármacos , Doxorrubicina/toxicidade , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Phoeniceae/química , Extratos Vegetais/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Masculino , Extratos Vegetais/química , Polifenóis/metabolismo , Ratos , Ratos Sprague-Dawley
6.
Life Sci ; 239: 117070, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31751580

RESUMO

Doxorubicin (DOX) induced cardiotoxicity is a life-threatening side effect of chemotherapy and decreased cardiac function can present years after treatment. Despite the investigation of a broad range of pharmacologic interventions, to date the only drug shown to reduce DOX-related cardiotoxicity in preclinical studies and limited clinical trials is the iron chelating agent, dexrazoxane (DRZ), although the mechanisms responsible for DRZ mediated protection from DOX related cardiotoxicity remain unclear. Engineered cardiac tissues (ECTs) can be used for tissue repair strategies and as in vitro surrogate models to test cardiac toxicities and preventative countermeasures. Neonatal murine ECTs display cardiotoxicity in response to the environmental toxin, cadmium, and reduced cadmium toxicity with Zinc co-treatment, in part via the induction of the anti-oxidant Metallothionein (MT). We adapted our in vitro ECT model to determine the feasibility of using the ECT approach to investigate DOX-related cardiac injury and DRZ prevention. We found: (1) DOX induced dose and time dependent cell death in ECTs; (2) Zinc did not show protection from DOX cardiotoxicity; (3) MT overexpression induced by Zinc, low dose Cd pretreatment, or MT-overexpression (MT-TG) did not reduce ECT DOX cardiotoxicity; (4) DRZ reduced ECT DOX induced cell death; and (5) The mechanism of DRZ ECT protection from DOX cardiotoxicity was topoisomerase 2B (TOP2B) inhibition rather than reduced reactive oxygen species. Our data support the feasibility of ECTs as an in vitro platform technology for the investigation of drug induced cardiotoxicities including the role of TOP2B in DOX toxicity and DRZ mediated DOX toxicity prevention.


Assuntos
Cardiotoxicidade/metabolismo , Dexrazoxano/farmacologia , Miócitos Cardíacos/metabolismo , Animais , Animais Recém-Nascidos , Cardiotoxicidade/prevenção & controle , DNA Topoisomerases Tipo II/metabolismo , Dexrazoxano/metabolismo , Modelos Animais de Doenças , Doxorrubicina/toxicidade , Quelantes de Ferro/farmacologia , Metalotioneína/metabolismo , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Engenharia Tecidual/métodos
7.
J Environ Pathol Toxicol Oncol ; 38(2): 143-152, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679277

RESUMO

The current study evaluated the cardioprotective activity of genistein in cases of doxorubicin-(Dox) induced cardiac toxicity and a probable mechanism underlying this protection, such as an antioxidant pathway in cardiac tissues. Animals used in this study were categorized into four groups. The first group was treated with sodium carboxymethylcellulose (0.3%; CMC-Na) solution. The second group received Dox (3.0 mg/kg, i.p.) on days 6, 12, 18, and 24. The third and fourth groups received Dox (3 mg/kg, i.p.) on days 6, 12, 18, and 24 and received protective doses of genistein (100 [group 3] and 200 [group 4] mg/kg/day, p.o.) for 30 days. Treatment with genistein significantly improved the altered cardiac function markers and oxidative stress markers. This was coupled with significant improvement in cardiac histopathological features. Genistein enhanced the Nrf2 and HO-1 expression, which showed protection against oxidative insult induced by Dox. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed substantial inhibition of apoptosis by genistein in myocardia. The study showed that genistein has a strong reactive oxygen species scavenging property and potentially (P ≤ .001) decreases the lipid peroxidation as well as inhibits DNA damage in cardiac toxicity induced by Dox. In conclusion, the potential antioxidant effect of genistein may be because of its modulatory effect on Nrf2/HO-1 signalling pathway and by this means exhibits cardioprotective effects from Dox-induced oxidative injury.


Assuntos
Cardiotônicos/farmacologia , Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , Genisteína/farmacologia , Heme Oxigenase-1/genética , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Animais , Cardiotoxicidade/etiologia , Heme Oxigenase-1/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar
8.
J Environ Pathol Toxicol Oncol ; 38(2): 153-163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679278

RESUMO

Chemobrain is a significant post-chemotherapy complication for which no approved treatments are available. We had previously identified that rutin inhibits doxorubicin (Dox-) -induced cognitive decline in healthy rats. However, it was important to also establish that it does so in rats with mammary carcinoma without compromising Dox's antitumor potential. Mammary carcinoma was induced in female rats by intraperitonial administration of N-methyl-N-nitrosourea (i.p.). Rats that developed mammary carcinoma were treated with Dox after pretreatment with vehicle or rutin. After Dox exposure (50 days), episodic and spatial memory was assessed using the novel object recognition task and the Morris water maze, respectively. Tumor progression was evaluated by measurement of tumor weight and volume and histological analysis. Blood samples were collected to estimate hematological parameters. Oxidative status and TNF-α levels were estimated in brain homogenates. Dox treatment significantly reduced tumor size and volume. Pretreatment with rutin did not significantly alter Dox's tumor suppression potential, suggesting that it does not influence Dox's anticancer activity. In addition, rutin ameliorated Dox-induced cognitive decline, myelosuppression, and brain oxidative stress. The present study indicates that rutin protects against Dox-induced cognitive decline and myelosuppression without affecting its antitumor potential.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/induzido quimicamente , Doxorrubicina/farmacologia , Metilnitrosoureia/toxicidade , Substâncias Protetoras/farmacologia , Rutina/farmacologia , Animais , Disfunção Cognitiva/induzido quimicamente , Doxorrubicina/toxicidade , Feminino , Ratos , Ratos Sprague-Dawley
9.
BMC Complement Altern Med ; 19(1): 317, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744501

RESUMO

BACKGROUND: Doxorubicin (DOX) is a chemotherapy drug for malignant tumors. The clinical application of DOX is limited due to its dosage relative cardiotoxicity. Oxidative damage and cardiac inflammation appear to be involved in DOX-related cardiotoxicity. Shenmai injection (SMI), which mainly consists of Panax ginsengC.A.Mey.and Ophiopogon japonicus (Thunb.) Ker Gawl, is widely used for the treatment of atherosclerotic coronary heart disease and viral myocarditis in China. In this study, we investigated the protective effect of Shenmai injection on doxorubicin-induced acute cardiac injury via the regulation of inflammatory mediators. METHODS: Male ICR mice were randomly divided into seven groups: control, DOX (10 mg/kg), SMI (5 g/kg), DOX with pretreatment with SMI (0.5 g/kg, 1.5 g/kg or 5 g/kg) and DOX with post-treatment with SMI (5 g/kg). Forty-eight hours after the last DOX administration, all mice were anesthetized for ultrasound echocardiography. Then, serum was collected for biochemical and inflammatory cytokine detection, and heart tissue was collected for histological and Western blot detection. RESULTS: A cumulative dose of DOX (10 mg/kg) induced acute cardiotoxicity in mice manifested by altered echocardiographic outcome, and increased tumor necrosis factor, interleukin 6 (IL-6), monocyte chemotactic protein 1, interferon-γ, and serum AST and LDH levels, as well as cardiac cytoplasmic vacuolation and myofibrillar disarrangement. DOX also caused the increase in the expression of IKK-α and iNOS and produced a large amount of NO, resulting in the accumulation of nitrotyrosine in the heart tissue. Pretreatment with SMI elicited a dose-dependent cardioprotective effect in DOX-dosed mice as evidenced by the normalization of serum inflammatory mediators, as well as improve dcardiac function and myofibril disarrangement. CONCLUSIONS: SMI could recover inflammatory cytokine levels and suppress the expression of IKK-α and iNOS in vivo, which was increased by DOX. Overall, there was evidence that SMI could ameliorate DOX-induced cardiotoxicity by inhibiting inflammation and recovering heart dysfunction.


Assuntos
Antineoplásicos/toxicidade , Cardiotoxicidade/prevenção & controle , Doxorrubicina/toxicidade , Medicamentos de Ervas Chinesas/administração & dosagem , Mediadores da Inflamação/metabolismo , Animais , Cardiotoxicidade/etiologia , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Coração/efeitos dos fármacos , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ophiopogon/química , Panax/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
Drug Des Devel Ther ; 13: 3321-3329, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571833

RESUMO

Objective: This study aimed to evaluate the effect of quercetin and/or sitagliptin on testicular damage induced by doxorubicin (DOX). Methodology: Twenty-five male Wistar rats, weighing 240±20 g, were randomly divided into five groups as follows: a negative control group; that was treated with 1 mL of 0.9% sodium chloride; a DOX-treated group received Intraperitoneal (I.P.) DOX injection (3 mg/kg); a group treated with quercetin 80 mg/kg + sitagliptin 10 mg/kg + DOX; a group treated with quercetin 80 mg/kg + DOX; and a group treated with sitagliptin 10 mg/kg+ DOX. All treatment were given orally daily for 21 days with I.P. DOX 3 mg/kg injection for the treatment groups at days 8, 10, 12, 15, 17, and 19. On day 22, blood was collected for analysis of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), glutathione peroxidase (GPx), and total antioxidant capacity (TAOC). The testes were also removed and sent for histopathological examination. Results: The study revealed that the combination of quercetin with sitagliptin produced a significant increase in testosterone and FSH levels with a non-significant increase in LH level. This combination also non-significantly decreased the level of ALP and LDH and restored the GPx level with enhancing TAOC. Conclusion: The results suggest quercetin/sitagliptin combination as a promising therapeutic modality for attenuation of DOX-induced testicular toxicity in rats, and the main mechanism involved in such effect could be due to the antioxidant and anti-inflammatory properties of both agents.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Quercetina/farmacologia , Fosfato de Sitagliptina/farmacologia , Testículo/efeitos dos fármacos , Fosfatase Alcalina/sangue , Animais , Antioxidantes/metabolismo , Hormônio Foliculoestimulante/sangue , Glutationa Peroxidase/sangue , L-Lactato Desidrogenase/sangue , Hormônio Luteinizante/sangue , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Testículo/patologia , Testosterona/sangue
11.
Food Chem Toxicol ; 134: 110834, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31577924

RESUMO

Doxorubicin (DOX), is a very effective chemotherapeutic agent against cancer whose clinical use is limited by toxicity. Different strategies have been proposed to attenuate toxicity, including combined therapy with bioactive compounds. This review update mechanisms of action and toxicity of doxorubicin and the role of nutrients like vitamins (A, C, E), minerals (selenium) and n-3 polyunsaturated fatty acids. Protective activities against DOX toxicity in liver, kidney, skin, bone marrow, testicles or brain have been reported, but these have not been evaluated for all of the reviewed nutrients. In most cases oxidation-related effects were present either, by reducing ROS levels and/or increasing antioxidant defenses. Antiapoptotic and anti-inflammatory mechanisms are also commonly reported. In some cases, interferences with autophagy and calcium homeostasis also have shown to be affected. Notwithstanding, there is a wide variety in duration and doses of treatment tested for both, compounds and DOX, which make difficult to compare the results of the studies. In spite of the reduction of DOX cardiotoxicity in health models, DOX anti-cancer activity in cancer cell lines or xenograft models usually did not result compromised when this has been evaluated. Importantly, clinical studies are needed to confirm all the observed effects.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Morte Celular/efeitos dos fármacos , Doxorrubicina/toxicidade , Nutrientes/farmacologia , Animais , Autofagia/efeitos dos fármacos , Humanos
12.
Trans Am Clin Climatol Assoc ; 130: 88-99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31516171

RESUMO

We have found that calcium calmodulin kinase IV is increased in T cells, podocytes, and mesangial cells from patients with systemic lupus erythematosus, as well as in lupus-prone mice, podocytes of patients with focal segmental glomerulosclerosis, and in mice injected with doxorubicin. We showed that this accounts for aberrant T cell function and glomerular damage. Using nanoparticles (nlg) loaded with a small drug inhibitor of calcium calmodulin kinase IV and tagged with antibodies directed to CD4 we have been able to show inhibition of autoimmunity and lupus nephritis. Also, using nlg tagged with antibodies to nephrin, we showed suppression of nephritis in lupus-prone mice and of glomerular damage in mice exposed to doxorubicin. We propose the development of approaches to deliver drugs to cells in a targeted and precise manner.


Assuntos
Benzilaminas/administração & dosagem , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Nefrite Lúpica/tratamento farmacológico , Nanopartículas , Inibidores de Proteínas Quinases/administração & dosagem , Sulfonamidas/administração & dosagem , Linfócitos T/imunologia , Animais , Antibióticos Antineoplásicos/toxicidade , Benzilaminas/uso terapêutico , Antígenos CD4 , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/imunologia , Metilação de DNA , Modelos Animais de Doenças , Doxorrubicina/toxicidade , Sistemas de Liberação de Medicamentos , Glomerulosclerose Segmentar e Focal/induzido quimicamente , Glomerulosclerose Segmentar e Focal/imunologia , Humanos , Lúpus Eritematoso Sistêmico , Nefrite Lúpica/imunologia , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos MRL lpr , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/uso terapêutico , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
13.
Chem Biol Interact ; 311: 108777, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31376360

RESUMO

Nicorandil ameliorated doxorubicin-induced nephrotoxicity; this study aimed to show and explain the mechanism of this protection. A precise method was elucidated to study the effect of nicorandil on doxorubicin-induced nephrotoxicity in rats depending on the critical inflammation pathway TLR4/MAPK P38/NFκ-B. Adult male rats were subdivided into four groups. The 1st group was normal control, the 2nd group received nicorandil (3 mg/kg; p.o., for 4 weeks), the 3rd group received doxorubicin (2.6 mg/kg, i.p., twice per week for 4 weeks), and the fourth group was combination of doxorubicin and nicorandil for 4 weeks. Nephrotoxicity was assessed by biochemical tests through measuring Kidney function biomarkers such as [serum levels of urea, creatinine, albumin and total protein] besides renal kidney injury molecule-1 (KIM-1) and cystatin C], oxidative stress parameters such as [renal tissue malondialdehyde (MDA), reduced glutathione (GSH), SOD, catalase and nrf-2], mediators of inflammation such as [Toll like receptor 4 (TLR-4), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), p38 MAPK, Interleukin 1 beta (IL-1 ß), and Tumor necrosis factor alpha (TNF-α)] and markers of apoptosis [BAX and Bcl-2 in renal tissue]. Finally, our data were supported by histopathology examination. Nicorandil pretreatment resulted in a significant decrease in nephrotoxicity biomarkers, oxidative stress markers, inflammatory mediators and prevented apoptosis through decreasing BAX and increasing Bcl-2 in renal tissues. Nicorandil prevented all the histological alterations caused by doxorubicin. Nicorandil is a promising antidote against doxorubicin-induced nephrotoxicity by neutralizing all toxicity mechanisms caused by doxorubicin through normalizing inflammatory cascade of TLR4/MAPK P38/NFκ-B.


Assuntos
Doxorrubicina/toxicidade , Rim/efeitos dos fármacos , Nicorandil/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Nitrogênio da Ureia Sanguínea , Moléculas de Adesão Celular/sangue , Creatinina/sangue , Glutationa/metabolismo , Interleucina-1beta/metabolismo , Rim/metabolismo , Rim/patologia , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
14.
Food Funct ; 10(9): 5587-5604, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31432062

RESUMO

Doxorubicin is a powerful anticancer agent used to treat a variety of human neoplasms. However, the clinical use of doxorubicin is hampered by cardiotoxicity and effective cardioprotective adjuvants do not exist. Dietary zinc, an essential nutrient, is required to maintain steady-state tissue zinc levels and intestinal homeostasis and may yield therapeutic benefits in diseases associated with zinc dysregulation or gut dysbiosis. Here, we investigated the effects of dietary Zn(ii)-curcumin (ZnCM) solid dispersions on gut dysbiosis and zinc dyshomeostasis during doxorubicin-induced cardiotoxicity in rats. Rats were injected with multiple low doses of doxorubicin and orally administered ZnCM daily over four weeks. Daily administration of ZnCM not only alleviated Dox-induced gut dysbiosis-as indicated by the increased Firmicutes-to-Bacteroidetes ratio and the maintenance of the relative abundances of major beneficial bacteria including Clostridium_XIVa, Clostridium_IV, Roseburia, Butyricicoccus and Akkermansia-but also maintained intestinal barrier integrity and decreased the lipopolysaccharide (LPS) contents of feces and plasma. ZnCM also significantly attenuated doxorubicin-induced zinc dyshomeostasis, which was mirrored by preservation of zinc levels and expression of zinc-related transporters. Furthermore, ZnCM significantly improved heart function and reduced cardiomyocyte apoptosis and myocardial injury in doxorubicin-treated rats. Notably, the regulation of zinc homeostasis and cardioprotective and microbiota-modulating effects of ZnCM were transmissible through horizontal feces transfer from ZnCM-treated rats to normal rats. Thus, ZnCM supplementation has potential as an effective therapeutic strategy to alleviate gut dysbiosis and zinc dyshomeostasis during doxorubicin-induced cardiotoxicity.


Assuntos
Antineoplásicos/toxicidade , Cardiotoxicidade/tratamento farmacológico , Curcumina/administração & dosagem , Doxorrubicina/toxicidade , Disbiose/tratamento farmacológico , Zinco/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Cardiotônicos/administração & dosagem , Cardiotoxicidade/etiologia , Cardiotoxicidade/microbiologia , Cardiotoxicidade/fisiopatologia , Suplementos Nutricionais/análise , Disbiose/etiologia , Disbiose/microbiologia , Fezes/microbiologia , Homeostase/efeitos dos fármacos , Humanos , Masculino , Miocárdio/citologia , Ratos , Ratos Sprague-Dawley
15.
Cell Physiol Biochem ; 53(2): 388-399, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31403269

RESUMO

BACKGROUND/AIMS: Doxorubicin, a chemotherapy drug used successfully for years, could induce cardiotoxicity. Euterpe oleracea Mart. (açai) is a fruit high in antioxidant properties. The aim of this study was to evaluate doxorubicin-induced cardiotoxicity prevention after açai administration. METHODS: A total of 64 male Wistar rats were allocated into 4 groups: control (C), açai (A), doxorubicin (D) and açai-doxorubicin (DA). Rats received regular chow (C and D groups) or chow supplemented with açai 5% (A and DA groups) for 4 weeks. Subsequently, rats received doxorubicin 20 mg/kg (D and DA groups) or saline (C and A groups). Euthanasia was performed 48 hours after doxorubicin injection. Left ventricular function was evaluated by echocardiography in vivo and by isolated heart study ex vivo. Oxidative stress, myocardial metabolism and nitric oxide metabolite were evaluated by spectrophotometry, MMP-2 activity by zymography and caspase-3 and Bcl-2 protein expression by Western blot. RESULTS: Doxorubicin induced decreases in body weight, food and water ingestion. We observed decreases in left ventricular fractional shortening in rats treated with doxorubicin. Additionally, the same rats showed lower +dP/dt and -dP/dt during isolated heart study than those who did not receive doxorubicin. Doxorubicin injection increased caspase-3 protein expression, myocardium lipid hydroperoxide concentration, MMP-2 activity, phosphofructokinase and lactate dehydrogenase activity, and decreased ß-hydroxyacyl-CoA dehydrogenase, pyruvate dehydrogenase, citrate synthase, complex I, complex II and ATP synthase activity in myocardium. Açai supplementation improved left ventricular fractional shortening, decreased myocardium lipid hydroperoxide concentration, MMP-2 activity, and improved ß-hydroxyacyl-CoA dehydrogenase, phosphofructokinase, citrate synthase, complex II and ATP synthase enzymatic activities. We did not observe differences in nitric oxide metabolite concentrations between groups. CONCLUSION: Doxorubicin induced left ventricular dysfunction, increases in oxidative stress, changes in myocardium metabolism and MMP-2 activation. Açai supplementation was able to prevent these alterations.


Assuntos
Doxorrubicina/toxicidade , Euterpe/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Suplementos Nutricionais , Ecocardiografia , Euterpe/metabolismo , Cardiopatias/etiologia , Cardiopatias/prevenção & controle , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Miocárdio/metabolismo , Óxido Nítrico/sangue , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Função Ventricular Esquerda/efeitos dos fármacos
16.
Biomed Res Int ; 2019: 5269074, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31317032

RESUMO

Adriamycin (Adr) is a cytotoxic anthracycline agent that is utilized to manage many types of tumors, but its clinical use is undesirable due to severe cardiotoxicity. The present study aimed to investigate the cardioprotective effect of Achillea fragrantissima (A. fragrantissima) against Adr-induced cardiotoxicity through the antioxidant and anti-inflammatory metabolic pathways. A single dose of Adr was injected in rats to induce cardiotoxicity. Rats are divided into 5 groups, control, A. fragrantissima 800, Adr, A. fragrantissima 400 + Adr, and A. fragrantissima 800 + Adr. 72 h after Adr administration, electrocardiographic (ECG) study was performed for all rats. Serum and hearts were then collected for biochemical and histopathological studies. A. fragrantissima ameliorated Adr-induced ST-segment elevation. It reduced Adr-induced elevation in lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), thiobarbituric acid reactive substance (TBARS), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), and IL-6. It also protected against Adr-induced histopathological changes. Pretreatment with the extract increased heart tissue contents of glutathione peroxidase (GSH-PX) and reduced glutathione (GSH). Phytochemical analysis of the extract revealed that it is rich in phenolic and flavonoid active constituents. The results of this study revealed that A. fragrantissima extract ameliorates Adr-induced cardiotoxicity via an antioxidant and anti-inflammatory mechanisms. Further studies are warranted in order to recognize the precise active constituents of this natural extract which are responsible for the antioxidant and anti-inflammatory actions.


Assuntos
Achillea/química , Antioxidantes/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Cardiotoxicidade/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Antioxidantes/química , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/patologia , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Doxorrubicina/toxicidade , Glutationa , Coração/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos
17.
Med Sci Monit ; 25: 5327-5335, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31317882

RESUMO

BACKGROUND Previous studies of human and animal models indicate that inflammation alters lipid metabolism. The pro-protein convertase subtilisin kexin type 9 (PCSK9) plays an important role in lipid metabolism. MATERIAL AND METHODS We examined the effect of inflammation on PCSK9 expression and lipid deposition in the kidneys of mice with Adriamycin-induced nephropathy. RESULTS The results indicated an increased expression of inflammatory cytokines and lipid deposition over 12 weeks. During this time, the expression of PCSK9 and its transcriptional activator (hepatocyte nuclear factor 1alpha, HNF1alpha) decreased, and the expression of the low-density lipoprotein receptor (LDLR) and its transcriptional activator (sterol regulatory element binding protein-2, SREBP-2) increased. Exogenous inflammation appeared to further aggravate this process. CONCLUSIONS Our mouse model of nephropathy suggests that a key step in the inflammation-induced deposition of lipids in the kidneys is the downregulation renal PCSK9 expression.


Assuntos
Doxorrubicina/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Síndrome Nefrótica/induzido quimicamente , Síndrome Nefrótica/metabolismo , Pró-Proteína Convertase 9/metabolismo , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Doxorrubicina/farmacologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Inflamação/metabolismo , Rim/metabolismo , Nefropatias , Lipídeos/fisiologia , Lipoproteínas LDL/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nefrite/induzido quimicamente , Nefrite/metabolismo , Pró-Proteína Convertase 9/biossíntese , Pró-Proteína Convertases/metabolismo , Pró-Proteína Convertases/farmacologia , Receptores de LDL/genética , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
18.
Eur J Pharmacol ; 858: 172467, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31216443

RESUMO

The present study investigates the cardioprotective effect of ß-caryophyllene against doxorubicin-induced acute cardiotoxicity in rats. Doxorubicin (12.5 mg/kg) and ß-caryophyllene (25, 50 or 100 mg/kg) were administered intraperitoneally to male albino Wistar rats. Doxorubicin-treated rats showed elevated levels of creatine kinase-MB in serum and oxidative stress in the myocardium as evidenced by decreased superoxide dismutase, catalase and glutathione with a concomitant rise in malondialdehyde levels. Doxorubicin also induced pro-inflammatory cytokines release following activation of the nuclear factor kappa-B and elevated expressions of inducible nitric oxide synthase and cyclooxygenase-2 in the myocardium. Additionally, doxorubicin also increased expression of γ-H2AX, a marker of DNA damage as well as increased expression of proapoptotic (Bax, p53, and active caspase-3) proteins along with the decreased expression of anti-apoptotic protein, Bcl2 in the myocardium. The histological and ultrastructural studies further revealed edema, inflammation and structural degeneration of cardiomyocytes following doxorubicin injection. However, treatment with ß-caryophyllene showed significant cardioprotective effects as evidenced by favorable improvement of biochemical and molecular parameters along with remarkable preservation of cardiomyocytes in histological and ultrastructural studies. Results of the present study demonstrate that ß-caryophyllene has potential to protect heart against doxorubicin-induced acute cardiotoxicity in rats. Moreover, the antioxidant and free radical scavenging properties of ß-caryophyllene was confirmed by in vitro assays. Provided the anticancer and chemosensitizing properties of ß-caryophyllene, the cardioprotective effects of ß-caryophyllene are suggestive of its multiple properties that provides an additional basis of its possible therapeutic application in chemotherapy-associated cardiotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Dieta , Doxorrubicina/toxicidade , Miocárdio/citologia , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , /farmacologia , Animais , Antioxidantes/metabolismo , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Citoproteção/efeitos dos fármacos , Dano ao DNA , Relação Dose-Resposta a Droga , Radical Hidroxila/metabolismo , Inflamação/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Miocárdio/patologia , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Superóxidos/metabolismo
19.
Nat Commun ; 10(1): 2820, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249297

RESUMO

Bats are unusual mammals, with the ability to fly, and long lifespans. In addition, bats have a low incidence of cancer, but the mechanisms underlying this phenomenon remain elusive. Here we discovered that bat cells are more resistant than human and mouse cells to DNA damage induced by genotoxic drugs. We found that bat cells accumulate less chemical than human and mouse cells, and efficient drug efflux mediated by the ABC transporter ABCB1 underlies this improved response to genotoxic reagents. Inhibition of ABCB1 triggers an accumulation of doxorubicin, DNA damage, and cell death. ABCB1 is expressed at higher levels in several cell lines and tissues derived from bats compared to humans. Furthermore, increased drug efflux and high expression of ABCB1 are conserved across multiple bat species. Our findings suggest that enhanced efflux protects bat cells from DNA damage induced by genotoxic compounds, which may contribute to their low cancer incidence.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Quirópteros/genética , Quirópteros/metabolismo , Dano ao DNA/efeitos dos fármacos , Mutagênicos/toxicidade , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Doxorrubicina/toxicidade , Humanos , Camundongos
20.
Hum Exp Toxicol ; 38(9): 1111-1124, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31179749

RESUMO

Cardiotoxicity is one of the most significant reasons of attrition in drug development. The present study assessed the sensitivity of various endpoints for early monitoring of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiac cells, including precursors as well as mature cardiomyocytes, by correlating changes in cardiac biomarker expression. Directed differentiation was induced and cardiac progenitor cell (CPC) population were treated with cardiotoxic drugs, namely, doxorubicin (Dox) and paclitaxel (Pac), and with noncardiotoxic drug, namely penicillin G. To assess cardiac-specific toxicity, the changes in the expression of key markers of cardiac lineage, such as Nkx2.5, Tbx5, α-myosin heavy chain α-MHC, and cardiac troponin T, were studied using quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry (FC). The half-maximal inhibition in the expression of these cardiac markers was analyzed from the dose-response curves. We also assessed the half-maximal inhibition (IC50) in cardiac cells using propidium iodide dye (IC50 PI) and by measuring disruption in the mitochondrial membrane potential (IC50 MMP). We observed that the most sensitive marker was α-MHC in the case of both Dox and Pac, and the order of sensitivity of the various prediction assays was MMP > protein expression by FC > gene expression by qRT-PCR > cell viability by PI staining. The results could enrich the screening of drug-induced cardiotoxicity in vitro and propose disruption in MMP along with downregulation of α-MHC protein as a potential biomarker of predicting cardiotoxicity earlier during drug safety evaluation.


Assuntos
Cardiotoxicidade/fisiopatologia , Doxorrubicina/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Paclitaxel/toxicidade , Biomarcadores/metabolismo , Cardiotoxicidade/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteína Homeobox Nkx-2.5/genética , Humanos , Miócitos Cardíacos/fisiologia , Cadeias Pesadas de Miosina/genética , Penicilina G/farmacologia , Proteínas com Domínio T/genética
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