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1.
Arch Biochem Biophys ; 712: 109050, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34610336

RESUMO

Doxorubicin (DOX) is an effective and widely used antineoplastic drug. However, its clinical application is limited due to its dose-dependent cardiotoxicity. Great efforts have been made to explore the pathological mechanism of DOX-induced cardiotoxicity (DIC), but new drugs and strategies to alleviate cardiac damage are still needed. Here, we aimed to investigate the effect of nicotinamide mononucleotide (NMN) on DIC in rats. The results of the present study showed that DOX treatment significantly induced cardiac dysfunction and cardiac injury, whereas NMN alleviated these changes. In addition, NMN inhibited Dox-induced activation of nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome-mediated inflammation, as evidenced by decreased caspase 1 and IL-1ß activity. Moreover, NMN treatment increased glutathione (GSH) levels and superoxide dismutase (SOD) activity and decreased the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in DOX-treated rats. Furthermore, NMN treatment mitigated DOX-induced cardiomyocyte apoptosis and cardiac fibrosis. In conclusion, the results indicated that NMN protects against DIC in rats by inhibiting NLRP3 inflammasome activation, oxidative stress, and apoptosis.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Cardiotônicos/uso terapêutico , Cardiotoxicidade/prevenção & controle , Doxorrubicina/toxicidade , Mononucleotídeo de Nicotinamida/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Cardiotoxicidade/metabolismo , Fibrose/prevenção & controle , Coração/efeitos dos fármacos , Inflamassomos/metabolismo , Inflamação/metabolismo , Inflamação/prevenção & controle , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Disfunção Ventricular Esquerda/prevenção & controle
2.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502073

RESUMO

Though effective in treating various types of cancer, the chemotherapeutic doxorubicin (DOX) is associated with skeletal muscle wasting and fatigue. The purpose of this study was to assess muscle function in situ following DOX administration in mice. Furthermore, pre-treatments with exercise (EX) or metformin (MET) were used in an attempt to preserve muscle function following DOX. Mice were assigned to the following groups: control, DOX, DOX + EX, or DOX + MET, and were given a single injection of DOX (15 mg/kg) or saline 3 days prior to sacrifice. Preceding the DOX injection, DOX + EX mice performed 60 min/day of running for 5 days, while DOX + MET mice received 5 daily oral doses of 500 mg/kg MET. Gastrocnemius-plantaris-soleus complex function was assessed in situ via direct stimulation of the sciatic nerve. DOX treatment increased time to half-relaxation following contractions, indicating impaired recovery (p < 0.05). Interestingly, EX prevented any increase in half-relaxation time, while MET did not. An impaired relaxation rate was associated with a reduction in SERCA1 protein content (p = 0.07) and AMPK phosphorylation (p < 0.05). There were no differences between groups in force production or mitochondrial respiration. These results suggest that EX, but not MET may be an effective strategy for the prevention of muscle fatigue following DOX administration in mice.


Assuntos
Metformina/farmacologia , Fadiga Muscular , Músculo Esquelético/fisiologia , Corrida , Animais , Doxorrubicina/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteínas Quinases/metabolismo
3.
Int Heart J ; 62(5): 1112-1123, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34544967

RESUMO

Doxorubicin (DOX) is a widely used anticancer drug, but its cardiotoxicity largely limits its clinical utilization. Circular RNA spindle and kinetochore-associated protein 3 (circ-SKA3) were found to be differentially expressed in heart failure patients. In this study, we investigated the role and mechanism of circ-SKA3 in DOX-induced cardiotoxicity.The quantitative real-time polymerase chain reaction and western blot assays were applied to measure the expression of circ-SKA3, microRNA (miR) -1303, and toll-like receptor 4 (TLR4). The viability and apoptosis of AC16 cells were analyzed using cell counting kit-8, flow cytometry, and western blot assays. The interaction between miR-1303 and circ-SKA3 or TLR4 was verified using dual-luciferase reporter and RNA immunoprecipitation assays. Exosomes were collected from culture media by the use of commercial kits and then qualified by transmission electron microscopy.The expression of circ-SKA3 and TLR4 was increased, whereas miR-1303 expression was decreased in DOX-treated AC16 cells. DOX treatment promoted cell apoptosis and inhibited cell viability in AC16 cells in vitro, which was partially reversed by circ-SKA3 knockdown, TLR4 silencing, or miR-1303 overexpression. Mechanistically, circ-SKA3 served as a sponge for miR-1303 to upregulate TLR4, which was confirmed to be a target of miR-1303. Additionally, circ-SKA3 contributed to DOX-induced cardiotoxicity through the miR-1303/TLR4 axis. Further studies suggested that circ-SKA3 was overexpressed in exosomes extracted from DOX-mediated AC16 cells, which could be internalized by surrounding untreated AC16 cells.Circ-SKA3 enhanced DOX-induced toxicity in AC16 cells through the miR-1303/TLR4 axis. Extracellular circ-SKA3 was packaged into exosomes, and exosomal circ-SKA3 could function as a mediator in intercellular communication between AC16 cells.


Assuntos
Proteínas de Ciclo Celular/genética , Doxorrubicina/toxicidade , Proteínas Associadas aos Microtúbulos/genética , Miócitos Cardíacos/efeitos dos fármacos , Inibidores da Topoisomerase II/toxicidade , Apoptose/efeitos dos fármacos , Cardiotoxicidade/genética , Proteínas de Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Exossomos/genética , Insuficiência Cardíaca/genética , Humanos , MicroRNAs/genética , Microscopia Eletrônica de Transmissão/métodos , Proteínas Associadas aos Microtúbulos/efeitos dos fármacos , Miócitos Cardíacos/patologia , RNA Circular/genética , Receptor 4 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Transfecção/métodos , Regulação para Cima
4.
Redox Biol ; 46: 102120, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34479089

RESUMO

The dose-dependent toxicity to cardiomyocytes has been well recognized as a central characteristic of doxorubicin (DOX)-induced cardiotoxicity (DIC), however, the pathogenesis of DIC in the cardiac microenvironment remains elusive. Irisin is a new hormone-like myokine released into the circulation in response to exercise with distinct functions in regulating apoptosis, inflammation, and oxidative stress. Recent advances revealed the role of irisin as a novel therapeutic method and an important mediator of the beneficial effects of exercise in cardioprotection. Here, by using a low-dose long-term mouse DIC model, we found that the perivascular fibrosis was involved in its myocardial toxicity with the underlying mechanism of endothelial-to-mesenchymal transition (EndMT). Irisin treatment could partially reverse DOX-induced perivascular fibrosis and cardiotoxicity compared to endurance exercise. Mechanistically, DOX stimulation led to excessive accumulation of ROS, which activated the NF-κB-Snail pathway and resulted in EndMT. Besides, dysregulation of autophagy was also found in DOX-treated endothelial cells. Restoring autophagy flux could ameliorate EndMT and eliminate ROS. Irisin treatment significantly alleviated ROS accumulation, autophagy disorder, NF-κB-Snail pathway activation as well as the phenotype of EndMT by targeting uncoupling protein 2 (UCP2). Our results also initially found that irisin was mainly secreted by cardiomyocytes in the cardiac microenvironment, which was significantly reduced by DOX intervention, and had a protective effect on endothelial cells in a paracrine manner. In summary, our study indicated that DOX-induced ROS accumulation and autophagy disorders caused an EndMT in CMECs, which played a role in the perivascular fibrosis of DIC. Irisin treatment could partially reverse this phenomenon by regulating UCP2. Cardiomyocytes were the main source of irisin in the cardiac microenvironment. The current study provides a novel perspective elucidating the pathogenesis and the potential treatment of DIC.


Assuntos
Doxorrubicina , Células Endoteliais , Animais , Apoptose , Autofagia , Doxorrubicina/toxicidade , Fibrose , Camundongos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
5.
Langmuir ; 37(39): 11484-11492, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34565150

RESUMO

This paper reports the facile preparation of dual stimuli-responsive gel particles that simultaneously respond to weakly acidic and reducing stimuli and the application of these gel particles as a drug delivery carrier. The dual stimuli-responsive gel particles composed of a pH-responsive polymer network cross-linked with reduction stimuli-responsive disulfide cross-links, and biocompatible poly(ethylene glycol) cross-links were prepared by soap-free emulsion polymerization. The resulting gel particles were colloidally stable at physiological ionic strength and had a diameter of approximately 200 nm with a narrow size distribution. The resulting gel particles slightly swelled in an acidic environment. On the other hand, the gel particles drastically swelled under simultaneous weakly acidic and reducing conditions because of the ionization of tertiary amino groups in the gel network and a decrease in the cross-linking density resulting from cleavage of the disulfide cross-links. When cells were treated with the gel particles, they were taken up by cells via the endocytosis pathway and distributed in the cytosol after endosomal escape by the proton sponge effect. In addition, a hydrophobic drug, doxorubicin (Dox), was loaded into the gel particles through hydrophobic interactions. Dox was released from the gel particles under weakly acidic and reducing conditions, while the Dox release was inhibited at neutral pH. The weakly acidic pH- and reduction stimuli-responsive release of Dox from gel particles was attributed to the drastic swelling of these particles. The fascinating properties of the dual stimuli-responsive gel particles suggest that they can provide a useful platform for designing intracellular drug delivery carriers.


Assuntos
Doxorrubicina , Portadores de Fármacos , Doxorrubicina/toxicidade , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Micelas
6.
Res Vet Sci ; 140: 242-250, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34536813

RESUMO

Doxorubicin (DOX) is known to cause cognitive impairments in patients submitted to long-term chemotherapy (deficits also known as chemobrain). Therefore, there is an urgent need for therapeutic strategies capable of returning cancer survivors back to their previous quality of life. The present study investigated whether resveratrol (RSV) or curcumin (CUR) administration could affect mnemonic function and brain morphological changes following DOX administration in rats. Male Wistar rats were divided into 4 groups: DOX group (2.5 mg/kg/week for 4 weeks, i.p., plus distilled water for 28 days, oral gavage - OG), DOX + RSV group (DOX, 2.5 mg/kg/week for 4 weeks, i.p., plus RSV, 10 mg/kg/day for 28 days, OG), DOX + CUR group (DOX, 2.5 mg/kg/week for 4 weeks, i.p., plus CUR, 100 mg/kg/day for 28 days, OG) and control (CTR) group (0.9% saline solution weekly for 4 weeks, i.p., plus distilled water for 28 days, OG). Behavioral analyses (open field - OF - and the novel object recognition test - NORT) were performed. Brains were collected and analyzed by hematoxylin-eosin and luxol fast blue staining techniques and by immunohistochemistry for GFAP (glial fibrillary acidic protein) expression in astrocytes and Iba1 (ionized calcium-binding adaptor molecule 1) expression in microglia. DOX-injected rats presented short-term and long-term memory impairments as seen in the NORT at 3 and 24 h after habituation and increased GFAP and Iba1 expression, respectively, in astrocytes and microglia of the frontal cortex, hypothalamus and hippocampus. Such cognitive deficits were prevented by CUR at both periods and by RSV at 24 h. DOX-induced astrogliosis and microgliosis were avoided by RSV and CUR. No signs of demyelination or neuronal loss were found in any group. Thus, CUR and RSV prevented memory loss, astrogliosis and microgliosis induced by DOX monotherapy.


Assuntos
Disfunção Cognitiva , Curcumina , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Curcumina/farmacologia , Curcumina/uso terapêutico , Doxorrubicina/toxicidade , Masculino , Qualidade de Vida , Ratos , Ratos Wistar , Resveratrol
7.
Anat Histol Embryol ; 50(6): 908-917, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34494664

RESUMO

Cancer is a lethal disease that is characterized by uncontrolled cell division and proliferation, and it results in death in many organisms. Doxorubicin (DOX) is a therapeutic agent used for treatment of many cancer types, but it induces serious hepatotoxicity. In this study, we aimed to determine possible hepato-therapeutic effects of thymoquinone (THQ) on DOX-induced hepatotoxicity in rats. Rats were divided into five groups (n = 8): Control, THQ (10 mg/kg/day/i.p for 14 days), Olive Oil (equal volume with THQ for 14 days), DOX (single dose, 15 mg/kg/i.p on 7th day) and DOX + THQ (10 mg/kg/day/i.p and DOX 15 mg/kg/i.p on 7th day). At the end of the experiment, liver tissues were extracted and evaluated histopathologically. eNOS, iNOS and Cas-3 immunostaining were performed to determine the expression levels. TUNEL method was used to determine apoptotic index. Furthermore, liver tissue total antioxidant status (TAS), total oxidant status (TOS), TNF-α and TGF-ß levels were measured by ELISA assay. The DOX group showed histopathological deterioration compared to Control group. Moreover, apoptotic index, eNOS, iNOS and Cas-3 expressions increased in DOX group. While TAS level of the DOX group decreased, TOS level increased. TNF-α and TGF-ß levels increased in DOX group. However, there was improvement in DOX + THQ group compared to DOX group. Moreover, apoptotic cell number, eNOS, iNOS and Cas-3 expressions decreased in DOX + THQ group compared to DOX group. We concluded that thymoquinone can be used as a phytotherapeutic for reducing DOX-induced liver damage.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Doenças dos Roedores , Animais , Antibióticos Antineoplásicos/farmacologia , Antibióticos Antineoplásicos/uso terapêutico , Apoptose , Benzoquinonas , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/veterinária , Doxorrubicina/toxicidade , Inflamação/tratamento farmacológico , Inflamação/veterinária , Estresse Oxidativo , Ratos
8.
Eur J Pharm Sci ; 166: 105977, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34416387

RESUMO

Chemotherapy has several adverse effects to patients, some of which are life-threatening. We hypothesized that Doxorubicin induced microbiome imbalance and intestinal damage may contribute to Doxorubicin induced cardiac dysfunction. Male adult (2-3 months) C57BL/6 mice were administered 3 mg/kg, 5 mg/kg, 7.5 mg/kg,15 mg/kg, 20 mg/kg doses of Doxorubicin. Echocardiography was performed at 7 and 14 days after Doxorubicin administration. 16S rRNA amplicon sequencing was used to characterize microbiome changes. Fecal microbiota transplantation (FMT) was performed to evaluate the role of the microbiota on Doxorubicin induced cardiac dysfunction. Doxorubicin dose dependently increases mortality rate and induces cardiac dysfunction. 5 mg/kg-Doxorubicin significantly induces decreased left ventricular ejection fraction (LVEF) and fraction shortening (FS) as well as increased cardiac fibrosis, inflammation and oxidative stress respond without increasing mortality. 5 mg/kg-Doxorubicin induces significant decreased colorectum length, increased loss of goblet cells, numbers of ulcers and infiltration of lymphocyte clusters and decreased tight junction protein ZO-1, as well as increased plasma endotoxin level measured by ELISA assay. 16S rRNA microbiota analysis shows that Doxorubicin-induced microbiota dysbiosis with decreased community richness compared with normal control mice. FMT to Doxorubicin-5 mg treated mice significantly improved cardiac function by increasing LVEF and FS as well as decreased perivascular and interstitial fibrosis; increased colorectum length, decreased the loss of goblet cells,infiltration of lymphocyte clusters,the number of ulcers and plasma endotoxin level; improved microbiota composition, function and diversity with increased abundance of Alloprevotella, Prevotellaceae_UCG-001 and Rikenellaceae_RC9_gut_group. We find that normal fecal transplantation improves cardiac function, decreases gut damage and alter microbiota composition induced by Doxorubicin. The microbiota appears to contribute to heart-gut interaction.


Assuntos
Microbioma Gastrointestinal , Animais , Cardiotoxicidade , Doxorrubicina/toxicidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/genética , Volume Sistólico , Função Ventricular Esquerda
9.
Chem Biol Interact ; 347: 109599, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34343525

RESUMO

BACKGROUND: Geraniol, a natural monoterpene, is a component of many plant essential oils. It contains many medicinal and pharmacological properties. Doxorubicin is an anticancer drug; however, its clinical usage is limited due to its cumulative and dose-dependent cardiotoxicity. This study investigates geraniol as a protective agent against doxorubicin-induced cardiotoxicity and explores possible underlying mechanisms of action. METHODS: Male Sprague-Dawley rats were allocated into five groups. Groups 1 and 2 were administered saline and geraniol 200 mg/kg/day/orally, respectively, for 15 days. Group 3 was administered intraperitoneal doxorubicin (5 mg/kg/IP on the 5th, 10th and 15th days to achieve a cumulative dose of 15 mg/kg) to induce cardiotoxicity. The fourth and fifth groups were treated with either geraniol 100 mg/kg or 200 mg/kg orally and doxorubicin to equal the doxorubicin dose administered to Group 3. RESULTS: Treatment with geraniol significantly ameliorated cardiac damage and restored serum cardiac injury marker levels in doxorubicin treated animals. Geraniol upregulated Nrf2 and HO-1 expression, elevated total antioxidant capacity, decreased the nuclear accumulation of kappa-light-chain enhancer of activated B cells (NF-κB), decreased the phosphorylation and degradation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα), suppressed tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin-18 (IL-18) levels, and restored the levels of Bax and caspase-3 and 9 in heart tissue. CONCLUSION: Geraniol may function as a potential activator of nuclear factor erythroid 2-related factor 2 (Nrf2), which subsequently improves Nrf2-dependent antioxidative signaling, diminishes apoptosis and subdues the inflammatory response. The downstream result is protection of the heart from doxorubicin-induced cardiotoxicity.


Assuntos
Monoterpenos Acíclicos/uso terapêutico , Cardiotônicos/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Cymbopogon/química , Doxorrubicina/toxicidade , Transdução de Sinais/efeitos dos fármacos , Animais , Cardiotoxicidade/patologia , Eletrocardiografia/efeitos dos fármacos , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Miocárdio/patologia , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley
10.
Am J Physiol Renal Physiol ; 321(4): F480-F493, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34423678

RESUMO

Proteolytic activation of the renal epithelial Na+ channel (ENaC) involves cleavage events in its α- and γ-subunits and is thought to mediate Na+ retention in nephrotic syndrome (NS). However, the detection of proteolytically processed ENaC in kidney tissue from nephrotic mice has been elusive so far. We used a refined Western blot technique to reliably discriminate full-length α-ENaC and γ-ENaC and their cleavage products after proteolysis at their proximal and distal cleavage sites (designated from the NH2-terminus), respectively. Proteolytic ENaC activation was investigated in kidneys from mice with experimental NS induced by doxorubicin or inducible podocin deficiency with or without treatment with the serine protease inhibitor aprotinin. Nephrotic mice developed Na+ retention and increased expression of fragments of α-ENaC and γ-ENaC cleaved at both the proximal cleavage site and, more prominently, the distal cleavage site, respectively. Treatment with aprotinin but not with the mineralocorticoid receptor antagonist canrenoate prevented Na+ retention and upregulation of the cleavage products in nephrotic mice. Increased expression of cleavage products of α-ENaC and γ-ENaC was similarly found in healthy mice treated with a low-salt diet, sensitive to mineralocorticoid receptor blockade. In human nephrectomy specimens, γ-ENaC was found in the full-length form and predominantly cleaved at its distal cleavage site. In conclusion, murine experimental NS leads to aprotinin-sensitive proteolytic activation of ENaC at both proximal and, more prominently, distal cleavage sites of its α- and γ-subunit, most likely by urinary serine protease activity or proteasuria.NEW & NOTEWORTHY This study demonstrates that murine experimental nephrotic syndrome leads to aprotinin-sensitive proteolytic activation of the epithelial Na+ channel at both the α- and γ-subunit, most likely by urinary serine protease activity or proteasuria.


Assuntos
Canais Epiteliais de Sódio/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/metabolismo , Aldosterona/farmacologia , Animais , Antibióticos Antineoplásicos/toxicidade , Aprotinina/farmacologia , Doxorrubicina/toxicidade , Canais Epiteliais de Sódio/genética , Feminino , Humanos , Rim/metabolismo , Masculino , Camundongos , Subunidades Proteicas , Proteólise , Triantereno/farmacologia
11.
Toxicology ; 460: 152881, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34358621

RESUMO

Myocardial apoptosis and necroptosis are the major etiological factor during doxorubicin (DOX) induced cardiotoxicity, and one of the important reasons that limit the drug's clinical application. Up to date, its mechanism has not been fully elucidated. The protective role of phosphocreatine (PCr) in heart surgery and medical cardiology has been observed in numerous clinical trials. This study aimed to evaluate cardioprotective actions of PCr against DOX-induced cardiotoxicity and investigate the underlying mechanism involving in transforming growth factor ß-activated kinase 1 (TAK1) mediated myocardial survive signaling pathway. Male Sprague-Dawleyrats were intraperitoneally (ip) injected with normal saline (NS) or DOX (2 mg/kg) alone or DOX with PCr (200 mg/kg) used as animal model. The data showed that DOX significantly impaired cardiac function and structure, induced oxidative stress, myocardial apoptosis and necroptosis, and dramatically down-regulated the expression level of TAK1, while the intervention of PCr obviously attenuated cardiac dysfunction, oxidative stress, myocardial apoptosis and necroptosis, especially alleviated the decrease of TAK1 expression. In vitro analysis, after H9c2 cells were pretreated with or without PCr (0.5 mM) or N-Acetyl-L-cysteine (NAC, 0.5 mM) or 5Z-7-oxozeaenol (5z-7-Ox, 1 µM) for 1 h, subsequently treated with DOX (1 µM) for 24 h. The results revealed that inhibition of TAK1 further deteriorated apoptotic and necroptotic cell death induced by DOX in H9c2 cells, but didn't affect oxidative stress. While the pretreatment of PCr or NAC enhanced antioxidant activity to reduce oxidative stress, significantly alleviated apoptotic and necroptotic cell death induced by DOX in H9c2 cells. Consistent with the results in vivo, PCr or NAC significantly inhibited the decrease of TAK1 expression induced by DOX. In conclusion, oxidative stress induced by DOX inhibits the expression of TAK1, and leads to myocardial apoptotic and necroptotic death, while the intervention of PCr increases antioxidant activity to alleviate oxidative stress, which in turn activates TAK1 signaling pathway to promote myocardial survival, and finally attenuate DOX-induced cardiotoxicity.


Assuntos
Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , MAP Quinase Quinase Quinases/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfocreatina/farmacologia , Animais , Antibióticos Antineoplásicos/toxicidade , Antioxidantes/farmacologia , Masculino , Miocárdio/patologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley
12.
Biomed Res Int ; 2021: 9979670, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34409109

RESUMO

Oncotherapeutics like doxorubicin can affect male gonads; as a result, it leads to infertility. This work was conducted to demonstrate the toxic effects of doxorubicin on testes of male albino rats. Fifty male albino rats aged 5-7 weeks were used in this study. The animals were randomly separated into 5 sets (each set containing ten rats). Group I received saline (i.p.) for 4 weeks. Group II was given doxorubicin (DOX), 5 mg/kg BW (i.p.) once/week for 4 weeks. Groups III and IV were treated in the same way as the DOX group, left for one week without medication, and then injected with mesenchymal stromal cells (MSCs) or human placental extract (HPE) therapy in a single dose of 5 × 106 in 200 ml PRP/week or 40 µl placental extract for 4 weeks via the caudal vein. Group V rats were treated in the same way as the DOX group also, left for one week without medication, and then injected with MSC+HPE. A significant decrease in serum testosterone, FSH, and LH levels was observed in rats treated with DOX compared to the control group. A significant elevation was recorded in rats treated with DOX+MSC or DOX+HPE when compared with the DOX group only. Rats that were given MSC+HPE after DOX intoxication showed a significant increase in hormone levels when compared to rats treated with either MSC or HPE. Light and electron microscopic examinations revealed that DOX intoxication initiated degenerative and necrotic changes in seminiferous tubules associated with partial or complete cessation of spermatogenesis. These effects were reversed by the effect of MSC or HPE. Coadministration of MSC and HPE even showed further improvement. Finally, we can say that doxorubicin has a deleterious impact on rat testes; however, therapeutic effects can be induced through MSC and/or HPE administration.


Assuntos
Doxorrubicina/toxicidade , Transplante de Células-Tronco Mesenquimais/métodos , Extratos Placentários/administração & dosagem , Testículo/fisiologia , Animais , Terapia Combinada , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Masculino , Camundongos , Extratos Placentários/farmacologia , Gravidez , Ratos , Testículo/efeitos dos fármacos , Testosterona/sangue
13.
Andrologia ; 53(11): e14225, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34431122

RESUMO

This study was conducted to evaluate the protective role of Pleurotus eryngii extract (PE) and Pleurotus eryngii extract-loaded chitosan nanoparticles (PE-CSNP) against doxorubicin (DOX)-induced testicular toxicity in rats. Male rats were divided into six groups: control (DMSO/ethanol), PE (200 mg/kg PE), PE-CSNP (30 mg/kg PE-CSNP), DOX (10 mg/kg DOX, a single dose, i.p), DOX+PE (10 mg/kg DOX+200 mg/kg PE) and DOX+PE-CSNP (10 mg/kg DOX+30 mg/kg PE-CSNP). PE and PE-CSNP were administered by oral gavage every other day for 21 days. DOX-treated rats showed histopathological impairment compared with the control group. There was an increase in the apoptotic index, caspase 3 (CASP3), BCL2-associated X apoptosis regulator (BAX), dynamin-related protein 1 (DRP1) expression and total oxidative status (TOS) in the DOX group, while mitofusin-2 (MFN2), total antioxidative status (TAS) and serum testosterone levels of the DOX group reduced when compared with the other groups. PE and PE-CSNP treatments provided significant protection against DOX-induced oxidative stress by reducing TOS levels and increasing TAS levels. CASP3, BAX, apoptotic index and DRP1-MFN2 expressions were restored by PE and PE-CSNP. However, the PE-CSNP showed higher antioxidant and anti-apoptotic efficacy compared with PE. Thus, our results provide evidence that CSNP and PE could synergistically have a potent antioxidant and anti-apoptotic therapy against DOX-induced testicular damage in male rats.


Assuntos
Quitosana , Nanopartículas , Pleurotus , Animais , Antioxidantes/farmacologia , Apoptose , Doxorrubicina/toxicidade , Masculino , Nanopartículas/toxicidade , Estresse Oxidativo , Ratos
14.
J Food Biochem ; 45(9): e13901, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34396545

RESUMO

The nephroprotective effect of standardized aqueous root extract of Vetiveria zizanioides (L.) Nash (Family: Poaceae) was investigated in doxorubicin-induced (20 mg/kg, ip) experimental nephrotoxicity model of Wistar rats. The freeze-dried aqueous refluxed (4 hr) root extract of V. zizanioides (25, 50; equivalent human therapeutic dose and 100 mg/kg) was administered separately to nephrotoxic Wistar rats (n = 6/group). Supplement of V. zizanioides resulted a dose-dependent reduction in raised serum creatinine, ß2 -microglobulin, and blood urea nitrogen and a subsequent increase in serum total protein and albumin in nephrotoxic rats (p < .05). An attenuation of the doxorubicin-induced features of renal parenchymal injury was observed on H- and E-stained sections of the kidney tissues. Nootkatone, dehydroaromadendrene, isokhusenic acid, α-vetivone, and isolongifolene were identified in the methanol extract of V. zizanioides based on the GC-MS chromatogram analysis. The findings revealed that the supplement of standardized aqueous root extract of V. zizanioides had a significant dose-dependent nephroprotective activity against doxorubicin-induced experimental nephrotoxicity. PRACTICAL APPLICATIONS: Vetiveria zizanioides is a medicinal plant with a variety of therapeutic applications in kidney-related diseases. Apparently, it is used as a food ingredient due to its fresh and elegant scent and potential bioactivities. The aqueous root extract of V. zizanioides exerted relatively high antioxidant potential in vitro, substantiating the health effects of the plant pertaining to kidney diseases as a potential source of dietary antioxidant. The administration of the plant extract resulted in significant nephroprotection against doxorubicin-induced experimental nephrotoxicity revealing the significance of V. zizanioides as a promising dietary supplement in the management of kidney disease.


Assuntos
Vetiveria , Animais , Antioxidantes , Suplementos Nutricionais , Doxorrubicina/toxicidade , Ratos , Ratos Wistar
15.
Biochem Pharmacol ; 192: 114743, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34453902

RESUMO

Doxorubicin (Dox) is widely used in chemotherapy regimens for several malignant conditions. Unfortunately, cumulative and irreversible cardiotoxicity of Dox is the most prominent adverse effect which limits its use. Several pharmacological interventions which exert antioxidant properties, including melatonin and metformin, have demonstrated beneficial effects against various cardiac pathological conditions. However, the exact molecular mechanisms underlying their cardioprotective effects are not completely understood. We hypothesized that treatment with either melatonin or metformin provides cardioprotection against Dox-induced cardiotoxicity through mitochondrial protection. Thirty-two male Wistar rats received 6 doses of either 0.9% normal saline solution (0.9% NSS, n = 8) or Dox (3 mg/kg, i.p., n = 24). The Dox-treated rats (n = 8/group) were co-treated with: 1) Vehicle (0.9% NSS), 2) Melatonin (10 mg/kg/day), and 3) Metformin (250 mg/kg/day) for 30 consecutive days via oral gavage. Following the treatment, left ventricular (LV) function, oxidative stress, inflammation, mitochondrial function, dynamics, biogenesis and bioenergetics, mitophagy, autophagy, and apoptosis were determined. Dox induced excessive oxidative stress, inflammation, autophagy, apoptosis, reduced mitochondrial function, dynamics balance, biogenesis, and bioenergetics leading to LV dysfunction. Treatment with either melatonin or metformin exerted equal measures of cardioprotection via reducing oxidative stress, inflammation, autophagy, apoptosis, and improved mitochondrial function, dynamics balance, biogenesis, and bioenergetics in the Dox-treated rats. Melatonin and metformin exerted both anti-cancer and cardioprotective properties, suggesting they have potential roles in concomitant therapy in cancer patients receiving Dox treatment.


Assuntos
Cardiotônicos/uso terapêutico , Cardiotoxicidade/prevenção & controle , Doxorrubicina/toxicidade , Melatonina/uso terapêutico , Metformina/uso terapêutico , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/toxicidade , Cardiotônicos/farmacologia , Cardiotoxicidade/metabolismo , Linhagem Celular , Relação Dose-Resposta a Droga , Masculino , Melatonina/farmacologia , Metformina/farmacologia , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/fisiologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Ratos Wistar
16.
J Pharm Biomed Anal ; 203: 114177, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198197

RESUMO

Doxorubicin (DOX) is widely used against cancer but carries the risk of a progressive cardiomyopathy. Astragalus polysaccharides (ASP) is the main active ingredient of Astragalus membranaceus Bunge. It has been proved to be effective against DOX-induced cardiomyopathy. However, its therapeutic mechanism is not yet well explored. In this study, a metabolomics approach based on hydrophilic interaction liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HILIC-Q-TOFMS) was developed to characterize the metabolic fluctuations associated with DOX cardiomyopathy and elucidate the underlying mechanisms of the protective effects of ASP. By the combination of HILIC-Q-TOFMS and multivariate and univariate data analysis, we identified 22 polar serum metabolites associated with DOX cardiomyopathy, 12 of which were significantly reversed when the animals were co-treated with ASP through two main metabolic pathways, i.e., sphingolipid and glycerophospholipid metabolism. Furthermore, it was found that ASP could alleviate DOX-induced cardiomyopathy by decreasing the levels of acid sphingomyelinase, acid ceramidase and phospholipase A2 and increasing the levels of sphingomyelin synthase to regulate the sphingolipid and glycerophospholipid metabolic disorder. These results revealed that sphingolipid and glycerophospholipid metabolism may be significantly responsible for DOX cardiomyopathy, which is also a major mechanism for the action of ASP against DOX cardiomyopathy.


Assuntos
Cardiomiopatias , Esfingolipídeos , Animais , Biomarcadores , Cardiomiopatias/induzido quimicamente , Doxorrubicina/toxicidade , Glicerofosfolipídeos , Homeostase , Metabolômica , Polissacarídeos/farmacologia
17.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299059

RESUMO

BACKGROUND: Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), but its use may be limited by its cardiotoxicity mediated by the production of reactive oxygen species. We evaluated whether vitamin D may prevent Dox-induced cardiotoxicity in a mouse TNBC model. METHODS: Female Balb/c mice received rodent chow with vitamin D3 (1500 IU/kg; vehicle) or chow supplemented with additional vitamin D3 (total, 11,500 IU/kg). the mice were inoculated with TNBC tumors and treated with intraperitoneal Dox (6 or 10 mg/kg). Cardiac function was evaluated with transthoracic echocardiography. The cardiac tissue was evaluated with immunohistochemistry and immunoblot for levels of 4-hydroxynonenal, NAD(P)H quinone oxidoreductase (NQO1), C-MYC, and dynamin-related protein 1 (DRP1) phosphorylation. RESULTS: At 15 to 18 days, the mean ejection fraction, stroke volume, and fractional shortening were similar between the mice treated with vitamin D + Dox (10 mg/kg) vs. vehicle but significantly greater in mice treated with vitamin D + Dox (10 mg/kg) vs. Dox (10 mg/kg). Dox (10 mg/kg) increased the cardiac tissue levels of 4-hydroxynonenal, NQO1, C-MYC, and DRP1 phosphorylation at serine 616, but these increases were not observed with vitamin D + Dox (10 mg/kg). A decreased tumor volume was observed with Dox (10 mg/kg) and vitamin D + Dox (10 mg/kg). CONCLUSIONS: Vitamin D supplementation decreased Dox-induced cardiotoxicity by decreasing the reactive oxygen species and mitochondrial damage, and did not decrease the anticancer efficacy of Dox against TNBC.


Assuntos
Cardiotoxicidade/prevenção & controle , Citoproteção/efeitos dos fármacos , Doxorrubicina/toxicidade , Substâncias Protetoras/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Vitamina D/farmacologia , Vitaminas/farmacologia , Animais , Antibióticos Antineoplásicos/toxicidade , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias de Mama Triplo Negativas/induzido quimicamente , Neoplasias de Mama Triplo Negativas/patologia
18.
Toxicology ; 459: 152852, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34246718

RESUMO

Current cancer therapies are successfully increasing the lifespan of cancer patients. Nevertheless, cardiotoxicity is a serious chemotherapy-induced adverse side effect. Doxorubicin (DOX) and mitoxantrone (MTX) are cardiotoxic anticancer agents, whose toxicological mechanisms are still to be identified. This study focused on DOX and MTX's cardiac mitochondrial damage and their molecular mechanisms. As a hypothesis, we also sought to compare the cardiac modulation caused by 9 mg/kg of DOX or 6 mg/kg of MTX in young adult mice (3 months old) with old control mice (aged control, 18-20 months old) to determine if DOX- and MTX-induced damage had common links with the aging process. Cardiac homogenates and enriched mitochondrial fractions were prepared from treated and control animals and analyzed by immunoblotting and enzymatic assays. Enriched mitochondrial fractions were also characterized by mass spectrometry-based proteomics. Data obtained showed a decrease in mitochondrial density in young adults treated with DOX or MTX and aged control, as assessed by citrate synthase (CS) activity. Furthermore, aged control had increased expression of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and manganese superoxide dismutase (MnSOD). Regarding the enriched mitochondrial fractions, DOX and MTX led to downregulation of proteins related to oxidative phosphorylation, fatty acid oxidation, amino acid metabolic process, and tricarboxylic acid cycle. MTX had a greater impact on malate dehydrogenase (MDH2) and pyruvate dehydrogenase E1 component subunit α (PDHA1). No significant proteomic changes were observed in the enriched mitochondrial fractions of aged control when compared to young control. To conclude, DOX and MTX promoted changes in several mitochondrial-related proteins in young adult mice, but none resembling the aged phenotype.


Assuntos
Envelhecimento/efeitos dos fármacos , Antibióticos Antineoplásicos/toxicidade , Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitoxantrona/toxicidade , Proteoma/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Citrato (si)-Sintase/metabolismo , Masculino , Camundongos , Mitocôndrias Cardíacas/enzimologia , Miócitos Cardíacos/patologia , Tamanho do Órgão/efeitos dos fármacos
19.
EBioMedicine ; 69: 103456, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34233258

RESUMO

BACKGROUND: Doxorubicin, an anthracycline chemotherapeutic agent, is widely used in the treatment of many cancers. However, doxorubicin posts a great risk of adverse cardiovascular events, which are thought to be caused by oxidative stress. We recently reported that the ubiquitin E3 ligase TRIM21 interacts and ubiquitylates p62 and negatively regulates the p62-Keap1-Nrf2 antioxidant pathway. Therefore, we sought to determine the role TRIM21 in cardiotoxicity induced by oxidative damage. METHODS: Using TRIM21 knockout mice, we examined the effects of TRIM21 on cardiotoxicity induced by two oxidative damage models: the doxorubicin treatment model and the Left Anterior Descending (LAD) model. We also explored the underlying mechanism by RNA-sequencing of the heart tissues, and by treating the mouse embryonic fibroblasts (MEFs), immortalized rat cardiomyocyte line H9c2, and immortalized human cardiomyocyte line AC16 with doxorubicin. FINDINGS: TRIM21 knockout mice are protected from heart failure and fatality in both the doxorubicin and LAD models. Hearts of doxorubicin-treated wild-type mice exhibit deformed mitochondria and elevated level of lipid peroxidation reminiscent of ferroptosis, which is alleviated in TRIM21 knockout hearts. Mechanistically, TRIM21-deficient heart tissues and cultured MEFs and H9c2 cells display enhanced p62 sequestration of Keap1 and are protected from doxorubicin-induced ferroptosis. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient TRIM21 mutants impedes the protection from doxorubicin-induced cell death. INTERPRETATION: Our study demonstrates that TRIM21 ablation protects doxorubicin-induced cardiotoxicity and illustrates a new function of TRIM21 in ferroptosis, and suggests TRIM21 as a therapeutic target for reducing chemotherapy-related cardiotoxicity. FUNDING: NIH (CA129536; DK108989): data collection, analysis. Shanghai Pujiang Program (19PJ1401900): data collection. National Natural Science Foundation (31971161): data collection. Department of Veteran Affairs (BX004083): data collection. Tianjin Science and Technology Plan Project (17ZXMFSY00020): data collection.


Assuntos
Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Ferroptose , Cardiopatias/genética , Miócitos Cardíacos/efeitos dos fármacos , Ribonucleoproteínas/genética , Animais , Cardiotoxicidade/genética , Linhagem Celular , Células Cultivadas , Cardiopatias/etiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Ratos
20.
Chem Asian J ; 16(17): 2552-2558, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34296823

RESUMO

A pH-responsive smart nanocarrier with significant components was synthesized by conjugating the non-emissive anticancer drug methyl orange and polyethylene glycol derived folate moiety to the backbone of polynorbornene. Complete synthesis procedure and characterization methods of three monomers included in the work: norbornene-derived Chlorambucil (Monomer 1), norbornene grafted with polyethylene glycol, and folic acid (Monomer 2) and norbornene attached methyl orange (Monomer 3) connected to the norbornene backbone through ester linkage were clearly discussed. Finally, the random copolymer CHO PEG FOL METH was synthesized by ring-opening metathesis polymerization (ROMP) using Grubbs' second-generation catalyst. Advanced polymer chromatography (APC) was used to find the final polymer's molecular weight and polydispersity index (PDI). Dynamic light scattering, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) were utilized to explore the prodrug's size and morphology. Release experiments of the anticancer drug, Chlorambucil and the coloring agent, methyl orange, were performed at different pH and time. Cell viability assay was carried out for determining the rate of survived cells, followed by the treatment of our final polymer named CHO PEG FOL METH.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Ácido Fólico/análogos & derivados , Plásticos/química , Polietilenoglicóis/química , Pró-Fármacos/química , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Compostos Azo/síntese química , Compostos Azo/química , Compostos Azo/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Clorambucila/síntese química , Clorambucila/química , Clorambucila/toxicidade , Corantes/síntese química , Corantes/química , Corantes/toxicidade , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/toxicidade , Doxorrubicina/síntese química , Doxorrubicina/química , Doxorrubicina/toxicidade , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Ácido Fólico/síntese química , Ácido Fólico/química , Ácido Fólico/toxicidade , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Plásticos/síntese química , Plásticos/toxicidade , Polietilenoglicóis/síntese química , Polietilenoglicóis/toxicidade , Polimerização , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidade
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