RESUMO
This study aimed to investigate the effects and possible mechanisms of adenylate cyclase 1 (ADCY1) on pirarubicin-induced cardiomyocyte injury. HL-1 cells were treated with pirarubicin (THP) to induce intracellular toxicity, and the extent of damage to mouse cardiomyocytes was assessed using CCK-8, Edu, flow cytometry, ROS, ELISA, RT-qPCR and western blotting. THP treatment reduced the viability of HL-1 cells, inhibited proliferation, induced apoptosis and triggered oxidative stress. In addition, the RT-qPCR results revealed that ADCY1 expression was significantly elevated in HL-1 cells, and molecular docking showed a direct interaction between ADCY1 and THP. Western blotting showed that ADCY1, phospho-protein kinase A and GRIN2D expression were also significantly elevated. Knockdown of ADCY1 attenuated THP-induced cardiotoxicity, possibly by regulating the ADCY1/PKA/GRIN2D pathway.
Assuntos
Adenilil Ciclases , Cardiotoxicidade , Doxorrubicina , Técnicas de Silenciamento de Genes , Miócitos Cardíacos , Adenilil Ciclases/metabolismo , Adenilil Ciclases/genética , Animais , Camundongos , Cardiotoxicidade/genética , Doxorrubicina/toxicidade , Doxorrubicina/farmacologia , Doxorrubicina/análogos & derivados , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Linhagem Celular , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Simulação de Acoplamento Molecular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/toxicidadeRESUMO
Doxorubicin (DOX) is an anthracycline antibiotic widely employed to treat carcinoma. Nevertheless, severe cardiotoxic side effects restrict its clinical use. Esculetin, a natural flavonoid, is found abundantly in plants. This study evaluated the protective effects of esculetin against DOX-induced hepatotoxicity in rat livers. Forty-eight rats were randomly divided into six groups with eight rats in each group: control (I), DOX (II), esculetin (III, 50 mg/kg), esculetin (IV, 100 mg/kg), DOX+esculetin 50 (V, DOX+esculetin 50 mg/kg), and DOX+esculetin 100 (VI, DOX+esculetin 100 mg/kg). The administration of esculetin effectively mitigated alterations in the measured biochemical parameters induced by DOX. Gene expression analyses demonstrated that esculetin treatment significantly reduced the DOX-induced expression of Foxo1, Hspa1a, Hsp4a, Hsp5a, Casp3, and Casp9 while increasing the DOX-induced expression of Foxo3. These findings suggest that esculetin, with its antioxidant and anti-inflammatory effects, might be a therapeutic option for protecting against DOX-induced hepatotoxicity.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Doxorrubicina , Umbeliferonas , Animais , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Umbeliferonas/farmacologia , Ratos , Masculino , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Fatores de Transcrição Forkhead/metabolismo , Caspases/metabolismo , Antibióticos Antineoplásicos/toxicidade , Antibióticos Antineoplásicos/efeitos adversos , Transdução de Sinais/efeitos dos fármacosRESUMO
This study assessed the protective potential of ascorbic acid against doxorubicin-induced spleen tissue damage in rats. Twenty-eight male Sprague-Dawley rats were divided into four groups. The control group received saline every other day at a dose of 1mL throughout the experiment. The ascorbic acid group was administered 50mg/kg of ascorbic acid daily for 10 days. The doxorubicin group received a single dose of 15mg/kg of doxorubicin on day 7. The ascorbic acid + doxorubicin group received both 50mg/kg of ascorbic acid daily for 10 days and a single dose of 15mg/kg of doxorubicin on day 7. After the experiment, splenic tissue samples were examined histopathologically and immunohistochemically. Histopathological analysis revealed edema, destruction and degeneration in the doxorubicin group, but these changes were alleviated in the ascorbic acid-treated group, approaching control group levels. Immunohistochemical analysis showed increased CD4+ and CD8+ cell immunopositivity in the ascorbic acid + doxorubicin group compared to the doxorubicin group. Biochemical tests indicated that doxorubicin reduced superoxide dismutase activity and increased malondialdehyde levels, whereas ascorbic acid mitigated these effects. The findings suggest that ascorbic acid may have a protective role against doxorubicin-induced spleen injury in rats.
Assuntos
Ácido Ascórbico , Doxorrubicina , Malondialdeído , Ratos Sprague-Dawley , Baço , Animais , Doxorrubicina/toxicidade , Ácido Ascórbico/farmacologia , Masculino , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Malondialdeído/metabolismo , Imuno-Histoquímica , Ratos , Antioxidantes/farmacologia , Superóxido Dismutase/metabolismo , Antibióticos Antineoplásicos/toxicidade , Esplenopatias/induzido quimicamente , Esplenopatias/patologia , Esplenopatias/tratamento farmacológico , Esplenopatias/metabolismoRESUMO
PURPOSE: Doxorubicin is an antibiotic drug used clinically to treat infectious diseases and tumors. Unfortunately, it is cardiotoxic. Autophagy is a cellular self-decomposition process that is essential for maintaining homeostasis in the internal environment. Accordingly, the present study was proposed to characterize the autophagy-related signatures of doxorubicin-induced cardiotoxicity. METHODS: Datasets related to doxorubicin-induced cardiotoxicity were retrieved by searching the GEO database and differentially expressed genes (DEGs) were identified. DEGs were taken to intersect with autophagy-related genes to obtain autophagy-related signatures, and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein-protein interaction (PPI) network were performed on them. Further, construction of miRNA-hub gene networks and identification of target drugs to reveal potential molecular mechanisms and therapeutic strategies. Animal models of doxorubicin-induced cardiotoxicity were constructed to validate differences in gene expression for autophagy-related signatures. RESULTS: PBMC and heart samples from the GSE37260 dataset were selected for analysis. There were 995 and 2357 DEGs in PBMC and heart samples, respectively, and they had 23 intersecting genes with autophagy-related genes. RT-qPCR confirmed the differential expression of 23 intersecting genes in doxorubicin-induced cardiotoxicity animal models in general agreement with the bioinformatics results. An autophagy-related signatures consisting of 23 intersecting genes is involved in mediating processes and pathways such as autophagy, oxidative stress, apoptosis, protein ubiquitination and phosphorylation. Moreover, Akt1, Hif1a and Mapk3 are hub genes in autophagy-associated signatures and their upstream miRNAs are mainly rno-miR-1188-5p, rno-miR-150-3p and rno-miR-326-3p, and their drugs are mainly CHEMBL55802, Carboxyamidotriazole and 3-methyladenine. CONCLUSION: This study identifies for the first-time autophagy-related signatures in doxorubicin's cardiotoxicity, which could provide potential molecular mechanisms and therapeutic strategies for doxorubicin-induced cardiotoxicity.
Assuntos
Autofagia , Cardiotoxicidade , Doxorrubicina , Doxorrubicina/toxicidade , Autofagia/efeitos dos fármacos , Animais , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Masculino , Mapas de Interação de Proteínas , Antibióticos Antineoplásicos/toxicidade , Redes Reguladoras de Genes/efeitos dos fármacos , Camundongos , Perfilação da Expressão Gênica/métodos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismoRESUMO
BACKGROUND: To investigate the protective effect and mechanism of Ghrelin on Doxorubicin (Dox) hydrochloride induced heart failure (HF) and myocardial injury in rats. METHODS: 45 rats were randomly divided into control group, HF group and Ghrelin group. Dox hydrochloride was injected intraperitoneally to establish the model of HF in rats of HF group and Ghrelin group. Rats in the Ghrelin group were given intraperitoneal injection of Ghrelin twice a day, and rats in the HF group and control group were given equal volume of normal saline for a total of 6 weeks. The changes of echocardiography, cardiac hemodynamics, myocardial histology and plasma inflammatory factors were observed. RESULTS: After the Ghrelin intervention, compared with the HF group, the left ventricular end-diastolic diameter (LVDD) and left ventricular end-systolic diameter (LVSD) in the Ghrelin group was markedly reduced (P < 0.05), and left ventricular ejection fraction (LVEF) was significantly increased (P < 0.05). Compared with HF group, the left ventricular systolic pressure (LVSP), maximum rate of increase in left ventricular pressure (+ dP/dtmax) and maximum rate of decrease in left ventricular pressure (- dP/dtmax) of Ghrelin group was remarkedly increased (P < 0.05), left ventricular diastolic pressure (LVDP) decreased (P < 0.05). In the Ghrelin group, the degree and extent of cardiomyocyte degeneration and necrosis were remarkedly reduced compared with the HF group. The levels of TNF-α and iNOS in Ghrelin group were notably lower than those in HF group (P < 0.05), the IL-10 level increased markedly (P < 0.05). CONCLUSION: Ghrelin may reduce Dox-induced myocardial injury and improve cardiac function in rats by regulating inflammation and oxidative stress.
Assuntos
Modelos Animais de Doenças , Doxorrubicina , Grelina , Insuficiência Cardíaca , Ratos Sprague-Dawley , Animais , Grelina/farmacologia , Doxorrubicina/toxicidade , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/fisiopatologia , Ratos , Masculino , Antibióticos Antineoplásicos/toxicidade , Ecocardiografia , Miocárdio/patologia , Miocárdio/metabolismo , Hemodinâmica/efeitos dos fármacosRESUMO
Oxidative stress contributes greatly to doxorubicin (DOX)-induced cardiotoxicity. Down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key factor in DOX-induced myocardial oxidative injury. Recently, we found that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)-dependent k48-linked ubiquitination was responsible for down-regulation of myocardial Nrf2 in DOX-treated mice. Micafungin, an antifungal drug, was identified as a potential MALT1 inhibitor. This study aims to explore whether micafungin can reduce DOX-induced myocardial oxidative injury and if its anti-oxidative effect involves a suppression of MALT1-dependent k48-linked ubiquitination of Nrf2. To establish the cardiotoxicity models in vivo and in vitro, mice were treated with a single dose of DOX (15 mg/kg, i.p.) and cardiomyocytes were incubated with DOX (1 µM) for 24 h, respectively. Using mouse model of DOX-induced cardiotoxicity, micafungin (10 or 20 mg/kg) was shown to improve cardiac function, concomitant with suppression of oxidative stress, mitochondrial dysfunction, and cell death in a dose-dependent manner. Similar protective roles of micafungin (1 or 5 µM) were observed in DOX-treated cardiomyocytes. Mechanistically, micafungin weakened the interaction between MALT1 and Nrf2, decreased the k48-linked ubiquitination of Nrf2 while elevated the protein levels of Nrf2 in both DOX-treated mice and cardiomyocytes. Furthermore, MALT1 overexpression counteracted the cardioprotective effects of micafungin. In conclusion, micafungin reduces DOX-induced myocardial oxidative injury via suppression of MALT1, which decreases the k48-linked ubiquitination of Nrf2 and elevates Nrf2 protein levels. Thus, micafungin may be repurposed for treating DOX-induced cardiotoxicity.
Assuntos
Doxorrubicina , Micafungina , Camundongos Endogâmicos C57BL , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Ubiquitinação , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Doxorrubicina/toxicidade , Ubiquitinação/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Masculino , Micafungina/farmacologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/metabolismo , Cardiotoxicidade/etiologia , Miocárdio/metabolismo , Miocárdio/patologiaRESUMO
Doxorubicin-induced cardiotoxicity (DIC) poses a significant challenge, impeding its widespread application. Emerging evidence suggests the involvement of ferroptosis in the DIC. While the downregulation of SLC7A11 expression has been linked to the promotion of ferroptosis, the precise regulatory mechanism remains unclear. Recent studies, including our own, have highlighted abnormal levels of autophagy adapter protein P62 and autophagy in DIC development. Thus, our study aimed to further investigate the role of autophagy and ferroptosis in DIC, elucidating underlying molecular mechanisms across molecular, cellular, and whole-organ levels utilizing gene knockdown, immunoprecipitation, and mass spectrometry techniques. The results of our findings unveiled cardiomyocyte damage, heightened autophagy levels, and ferroptosis in DOX-treated mouse hearts. Notably, inhibition of autophagy levels attenuated DOX-induced ferroptosis. Mechanistically, we discovered that the autophagy adaptor protein P62 mediates the entry of SLC7A11 into the autophagic pathway for degradation. Furthermore, the addition of autophagy inhibitors (CQ or BAF) could elevate SLC7A11 and GPX4 protein expression, reduce the accumulation of Fe2+ and ROS in cardiomyocytes, and thus mitigate DOX-induced ferroptosis. In summary, our findings underscore the pivotal role of the P62-autophagy pathway in SLC7A11 degradation, modulating ferroptosis to exacerbate DIC. This finding offers significant insights into the underlying molecular mechanisms of DOX-induced ferroptosis and identifies new targets for reversing DIC.
Assuntos
Sistema y+ de Transporte de Aminoácidos , Autofagia , Cardiotoxicidade , Doxorrubicina , Ferroptose , Miócitos Cardíacos , Proteína Sequestossoma-1 , Animais , Masculino , Camundongos , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Antibióticos Antineoplásicos/toxicidade , Antibióticos Antineoplásicos/efeitos adversos , Autofagia/efeitos dos fármacos , Cardiotoxicidade/metabolismo , Cardiotoxicidade/etiologia , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Ferroptose/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Espécies Reativas de Oxigênio/metabolismo , Proteína Sequestossoma-1/metabolismo , Proteína Sequestossoma-1/genéticaRESUMO
Evidence concerning the osteotoxic effects of chemotherapy (doxorubicin) has been previously described. Periodontitis also progressively increases in patients receiving chemotherapy; however, the beneficial effects of melatonin and metformin on the alleviation of doxorubicin-induced osteotoxicity have never been investigated. Therefore, we investigated the negative impact of doxorubicin on alveolar bone homeostasis and the benefits of melatonin and metformin on the attenuation of doxorubicin-induced alveolar bone toxicity. Male Wistar rats were divided into 4 groups to receive either 1 mL of normal saline solution as a control group, 3 mg/kg of doxorubicin, 3 mg/kg of doxorubicin plus 10 mg/kg of melatonin, or 3 mg/kg of doxorubicin plus 250 mg/kg of metformin. Doxorubicin treatment was given on days 0, 4, 8, 15, 22, and 29, while interventions were given daily on days 0 to 29. Following euthanasia, blood and alveolar bones were collected for evaluation of oxidative stress, bone remodeling, inflammation, microarchitecture, and periodontal condition. We found that doxorubicin increased systemic oxidative stress, decreased antioxidative capacity, increased inflammation, decreased bone formation, increased bone reabsorption, impaired microarchitecture, and impaired periodontal condition of the alveolar bone. Although cotreatment with melatonin or metformin resulted in some improvement in these parameters, cotreatment with melatonin was more effective than cotreatment with metformin in terms of decreasing oxidative stress, reducing bone resorption, and improving microarchitecture and periodontal condition. All of these findings highlight the potential for antioxidants, especially melatonin, to ameliorate doxorubicin-induced alveolar bone toxicity.
Assuntos
Perda do Osso Alveolar , Processo Alveolar , Antioxidantes , Doxorrubicina , Melatonina , Metformina , Estresse Oxidativo , Ratos Wistar , Melatonina/farmacologia , Melatonina/uso terapêutico , Animais , Metformina/farmacologia , Metformina/uso terapêutico , Doxorrubicina/toxicidade , Masculino , Ratos , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Perda do Osso Alveolar/prevenção & controle , Processo Alveolar/efeitos dos fármacos , Antibióticos Antineoplásicos/toxicidade , Remodelação Óssea/efeitos dos fármacos , Microtomografia por Raio-XRESUMO
The present study investigated the effect of adding allopathic doxorubicin (DOX 0.3⯵g/mL), the vehicle of ultradiluted/dynamized doxorubicin (0.2â¯% ethanol), different dynamizations of ultradiluted/dynamized doxorubicin (DOX 6CH, DOX 12CH and DOX 30CH), both in the absence or presence of chemical stress induced by doxorubicin at 0.3⯵g/mL on follicular survival and activation, antioxidant capacity of the medium, Catalase activity (CAT), production of reactive protein thiol, maintenance of type I and III collagen fibers and accumulation of lipofuscin in porcine ovarian tissue cultured in vitro for 48â¯hours. To do this, part of the ovarian tissue fragments was fixed for the uncultured control and the rest were cultured in: MEM (cultured control), DOX 0.3⯵g/mL, Ethanol, DOX 6CH, DOX 12CH, DOX 30CH, DOX (0.3⯵g/mL) + DOX 6CH, DOX (0.3⯵g/mL) + DOX 12CH, DOX (0.3⯵g/mL) + DOX 30CH treatments. The results showed that, in general, ultradiluted/dynamized doxorubicin (DOX 6CH, DOX 12CH and DOX 30CH) mitigated the toxic effect of allopathic doxorubicin (0.3⯵g/mL) on the morphology of preantral follicles, the content of type I and III collagen fibers, and the production of lipofuscin in the tissue. However, only DOX (0.3⯵g/mL) + DOX 6CH attenuated the oxidative stress induced by DOX (0.3⯵g/mL), maintaining adequate CAT activity that was similar to the uncultured control. Additionally, when the three isolated ultradiluted/dynamized doxorubicin were considered, only DOX 12CH increased the reduced thiol levels compared to the uncultured control and MEM. In conclusion, supplementing the culture medium with ultradiluted/dynamized DOX (DOX 6CH, DOX 12CH and DOX 30CH) attenuated the toxicity induced by allopathic doxorubicin during the in vitro culture of pig preantral follicles enclosed in ovarian tissue.
Assuntos
Antibióticos Antineoplásicos , Doxorrubicina , Folículo Ovariano , Animais , Doxorrubicina/toxicidade , Feminino , Suínos , Antibióticos Antineoplásicos/toxicidade , Folículo Ovariano/efeitos dos fármacos , Catalase/metabolismo , Técnicas de Cultura de Tecidos , Lipofuscina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/farmacologia , Colágeno Tipo I/metabolismo , Ovário/efeitos dos fármacos , Compostos de Sulfidrila/metabolismo , Colágeno Tipo III/metabolismoRESUMO
Irreversible cardiotoxicity limits the clinical application of doxorubicin (DOX). DOX-induced cardiotoxicity has been associated with induction of senescence and activation of the p38 MAPK pathway. Losmapimod (LOSM), an orally active p38 MAPK inhibitor, is an anti-inflammatory agent with cardioprotective effects. Nevertheless, the effect of LOSM against DOX-induced cardiotoxicity has not been reported. In this study, we determined the effects of LOSM on DOX-induced chronic cardiotoxicity in C57BL/6â¯N mice. Five-week-old C57BL/6â¯N mice were fed diet containing LOSM (estimated daily intake 12â¯mg/kg/day) or a control diet for four days. Thereafter, mice were randomized to receive six weekly intraperitoneal injections of either DOX (4â¯mg/kg) or saline. Three days after the last injection, cardiac function was assessed by trans-thoracic echocardiography. Activation of p38, JNK, and ERK1/2 MAPKs were assessed by immunoblotting in the heart and liver. Gene expressions of senescence, inflammatory, oxidative stress, and mitochondrial function markers were quantified using real-time PCR and serum inflammatory markers were assessed by Luminex. Our results demonstrated that LOSM attenuated p38 MAPK activation, ameliorated DOX-induced cardiac dysfunction, and abrogated DOX-induced expression of the senescence marker p21Cip1. Additionally, LOSM demonstrated anti-inflammatory effects, with reduced cardiac Il-1α and Il-6 gene expression in DOX-treated mice. Systemic inflammation, assessed by serum cytokine levels, showed decreased IL-6 and CXCL1 in both DOX-treated mice and mice on LOSM diet. LOSM significantly increased mitofusin2 gene expression, which may enhance mitochondrial fusion. These findings underscore the potential therapeutic efficacy of p38 MAPK inhibition, exemplified by LOSM, in ameliorating DOX-induced cardiotoxicity, senescence, and inflammation.
Assuntos
Cardiotoxicidade , Doxorrubicina , Inflamação , Camundongos Endogâmicos C57BL , Animais , Doxorrubicina/toxicidade , Doxorrubicina/efeitos adversos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Masculino , Piridinas/farmacologia , Senescência Celular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Anti-Inflamatórios/farmacologia , CiclopropanosRESUMO
Chemotherapy-related cognitive impairments (CRCIs) encompass cognitive deficits in memory, attention, and executive function that arise during and following chemotherapy. CRCI symptoms are predominantly reported by female cancer patients but also occur in males. These impairments may involve reduced estradiol levels, which then increases vulnerability to the impact of tumors and chemotherapy on cognition. This study utilized the MMTV-PyVT mouse model of breast cancer to test the hypothesis that impaired ovarian function and associated estradiol levels play a critical role in CRCI susceptibility. Mice were either ovariectomized (OVX) or underwent sham surgery. The OVX group then received supplemental estradiol (E2) ad libitum in the drinking water to maintain physiological hormone levels. After tumor development, mice were trained in the Morris water maze to assess spatial memory, and subsequently, they received weekly injections of either saline or a combination of cyclophosphamide (CYP; 66.7â mg/kg, i.v.) and doxorubicin (DOX; 6.7â mg/kg, i.v.) for 4â weeks. Spatial memory was reassessed 10â d and then 35â d, after the final injections. Results demonstrated a significant disruption of normal ovarian cycling in sham-operated mice treated with CYP + DOX, as well as significant spatial memory impairments when compared with OVX mice supplemented with E2 This study suggests that chemotherapy-induced ovarian damage and the consequent drop in circulating estrogens significantly contribute to vulnerability to CRCIs, underscoring the importance of estradiol in mitigating CRCI risks.
Assuntos
Ciclofosfamida , Doxorrubicina , Estradiol , Transtornos da Memória , Ovariectomia , Memória Espacial , Animais , Ciclofosfamida/toxicidade , Feminino , Estradiol/farmacologia , Estradiol/administração & dosagem , Doxorrubicina/toxicidade , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Memória Espacial/efeitos dos fármacos , Camundongos Transgênicos , Camundongos , Modelos Animais de Doenças , Comprometimento Cognitivo Relacionado à Quimioterapia , Aprendizagem em Labirinto/efeitos dos fármacosRESUMO
Doxorubicin (DOX), which is frequently used in cancer treatment, has limited clinical use due to adverse effects on healthy tissues, especially the liver. Therefore, it is necessary to research the molecular basis of DOX-induced organ and tissue damage and protective agents. In this study, we aimed to examine the protective effects of tannic acid (TA) against DOX-induced hepatoxicity in experimental rat models. Rats were randomly divided into four experimental groups: the untreated control, DOX, TA, and cotreatment (DOX + TA) groups. We investigated the antioxidant system's main components and oxidative stress indicators. Moreover, we examined alterations in the mRNA expression of critical regulators that modulate apoptosis, inflammation, and cell metabolism to better understand the underlying factors of DOX-induced liver toxicity. The results showed that DOX exposure caused an increase in MDA levels and a significant depletion of GSH content in rat liver tissues. Consistent with oxidative stress-related metabolites, DOX was found to significantly suppress both mRNA expression and enzyme activities of antioxidant system components. Moreover, DOX exposure had significant adverse effects on regulating the other regulatory genes studied. However, it was determined that TA could alleviate many of the negative changes caused by DOX. The results of the present study indicated that TA might be considered a versatile candidate that could prevent DOX-induced hepatotoxicity, possibly by preserving cell physiology, viability, and especially redox balance.
Assuntos
Anti-Inflamatórios , Antioxidantes , Apoptose , Doença Hepática Induzida por Substâncias e Drogas , Doxorrubicina , Fígado , Polifenóis , Animais , Masculino , Ratos , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/farmacologia , Ratos Sprague-DawleyRESUMO
BACKGROUND: Adriamycin (ADR) is a widely used chemotherapy drug in clinical practice and it causes toxicity in the myocardium affecting its clinical use. miR-432-5p is a miRNA primarily expressed in myocardial cells and has a protective effect in the myocardium. We aim to explore the protective effect of miR-432-5p on ADR-caused impaired mitochondrial ATP metabolism and endoplasmic reticulum stress (ERs). METHOD: The primary cardiomyocytes were obtained from neonatal mice and the ADR was added to cells, meanwhile, a mice model was constructed through intravenous ADR challenge, and expression levels of miR-432-5p were examined. Subsequently, the miR-432-5p was introduced in vitro and in vivo to explore its effect on the activity of mitochondrial ATP synthesis, autophagy, and ER stress. The bioinformatics analysis was performed to explore the target of miR-432-5p. RESULTS: ADR decreased the expression of miR-432-5p in cardiomyocytes. It also decreases mitochondrial ATP production and activates the ER stress pathway by increasing the expression of LC3B, Beclin 1, cleaved caspase 3, and induces cardiac toxicity. miR-432-5p exogenous supplementation can reduce the cardiotoxicity caused by ADR, and its protective effect on cardiomyocytes depends on the down-regulation of the RTN3 signaling pathway in ER. CONCLUSION: ADR can induce the low expression of miR-432-5p, and activate the RTN3 pathway in ER, increase the expression of LC3B, Beclin 1, cleaved caspase 3, CHOP, and RTN3, and induce cardiac toxicity.
Assuntos
Cardiotoxicidade , Regulação para Baixo , Doxorrubicina , Estresse do Retículo Endoplasmático , MicroRNAs , Miócitos Cardíacos , Transdução de Sinais , Animais , MicroRNAs/metabolismo , MicroRNAs/genética , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Doxorrubicina/toxicidade , Doxorrubicina/efeitos adversos , Cardiotoxicidade/metabolismo , Cardiotoxicidade/genética , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , MasculinoRESUMO
The study aimed to examine effects of (-)-epigallocatechin-3-gallate (EGCG) on energy metabolism and mitochondrial dynamics in mouse model of renal injury caused by doxorubicin (DOX). Here, mice were divided into Control group, EGCG-only treated group, DOX group, and three doses of EGCG plus DOX groups. Our results showed that EGCG behaved beneficial effects against kidney injury via attenuation of pathological changes in kidney tissue, which was confirmed by reducing serum creatinine (SCr), blood urea nitrogen (BUN), and apoptosis. Subsequently, changes in reactive oxygen species generation, malondialdehyde content, and activities of antioxidant enzymes were considerably ameliorated in EGCG + DOX groups when compared to DOX group. Furthermore, EGCG-evoked renal protection was associated with increases of mitochondrial membrane potential and decreases of mitochondrial fission protein Dynamin-related protein 1 (Drp1). Moreover, changing glycolysis into mitochondrial oxidative phosphorylation was observed, evidenced by controlling activities of malate dehydrogenase (MDH) and hexokinase (HK) in EGCG + DOX groups when compared to DOX group, indicating that reprogramming energy metabolism was linked to EGCG-induced renal protection in mice. Therefore, EGCG was demonstrated to have a protective effect against kidney injury by reducing oxidative damage, metabolic disorders, and mitochondrial dysfunction, suggesting that EGCG has potential as a feasible strategy to prevent kidney injury.
Assuntos
Catequina , Doxorrubicina , Dinaminas , Dinâmica Mitocondrial , Animais , Catequina/análogos & derivados , Catequina/farmacologia , Camundongos , Dinâmica Mitocondrial/efeitos dos fármacos , Masculino , Doxorrubicina/toxicidade , Dinaminas/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Homeostase/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/induzido quimicamente , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Metabolismo Energético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Antioxidantes/farmacologiaRESUMO
Doxorubicin (Dox) is extensively used as an antitumor agent, but its severe cardiotoxicity significantly limits its clinical use. Current treatments for Dox-induced cardiotoxicity are inadequate, necessitating alternative solutions. This study evaluated the effects of sarmentosin, a compound from Sedum sarmentosum, on Dox-induced cardiotoxicity and dysfunction. Sarmentosin was administered as a pretreatment to both mice and H9c2 cells before Dox exposure. Subsequently, markers of Dox-induced cardiotoxicity and ferroptosis in serum and cell supernatants were measured. Western blot analysis was utilized to detect levels of ferroptosis, oxidative stress, and autophagy proteins. Additionally, echocardiography, hematoxylin-eosin staining, ROS detection, and immunofluorescence techniques were employed to support our findings. Results demonstrated that sarmentosin significantly inhibited iron accumulation, lipid peroxidation, and oxidative stress, thereby reducing Dox-induced ferroptosis and cardiotoxicity in C57BL/6 mice and H9c2 cells. The mechanism involved the activation of autophagy and the Nrf2 signaling pathway. These findings suggest that sarmentosin may prevent Dox-induced cardiotoxicity by mitigating ferroptosis. The study underscores the potential of compounds like sarmentosin in treating Dox-induced cardiotoxicity.
Assuntos
Cardiotoxicidade , Doxorrubicina , Ferroptose , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2 , Transdução de Sinais , Animais , Ferroptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Camundongos , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Autofagia/efeitos dos fármacos , Proteína Sequestossoma-1/metabolismoRESUMO
Doxorubicin (DOX) is restricted due to its severe cardiotoxicity. There is still a lack of viable and effective drugs to prevent or treat DOX-induced cardiotoxicity(DIC). Vericiguat is widely used to treat heart failure with reduced ejection fraction. However, it is not clear whether vericiguat can improve DIC. In the present study, we constructed a DIC model using mice and neonatal rat cardiomyocytes and found that vericiguat ameliorated DOX-induced cardiac insufficiency in mice, restored DOX-induced mitochondrial dysfunction in neonatal rat cardiomyocytes, and inhibited the expression of inflammatory factors. Further studies showed that vericiguat improved mitochondrial dysfunction and reduced mtDNA leakage into the cytoplasm by up-regulating PRKG1, which activated PINK1 and then inhibited the STING/IRF3 pathway to alleviate DIC. These findings demonstrate for the first time that vericiguat has therapeutic potential for the treatment of DIC.
Assuntos
Cardiotoxicidade , Doxorrubicina , Proteínas de Membrana , Miócitos Cardíacos , Proteínas Quinases , Animais , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/etiologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos , Proteínas Quinases/metabolismo , Ratos , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
Doxorubicin (DOX), a chemotherapy drug widely recognized for its efficacy in cancer treatment, unfortunately, has significant nephrotoxic effects leading to kidney damage. This study explores the nephroprotective potential of Phosphocreatine (PCr) in rats, specifically examining its influence on Nrf2 (Nuclear factor erythroid 2-related factor 2) and PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) pathways, its role in apoptosis inhibition, and effectiveness in preserving mitochondrial function. The research employed in vivo experiments in rats, focusing on PCr's capacity to protect renal function against doxorubicin-induced damage. The study entailed evaluating Nrf2 and PGC-1α pathway activation, apoptosis rates, and mitochondrial health in renal tissues. A significant aspect of this research was the use of high-resolution respirometry (HRR) to assess the function of isolated kidney mitochondria, providing in-depth insights into mitochondrial bioenergetics and respiratory efficiency under the influence of PCr and doxorubicin. Results demonstrated that PCr treatment significantly enhanced the activation of Nrf2 and PGC-1α pathways, reduced apoptosis, and preserved mitochondrial structure in doxorubicin-affected kidneys. Observations included upregulated expression of Nrf2 and PGC-1α target genes, stabilization of mitochondrial membranes, and a notable improvement in cellular antioxidant defense, evidenced by the activities of enzymes like superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) This study positions phosphocreatine as a promising agent in mitigating doxorubicin-induced kidney damage in rats. The findings, particularly the insights from HRR on isolated kidney mitochondria, highlight PCr's potential in enhancing mitochondrial function and reducing nephrotoxic side effects of chemotherapy. These encouraging results pave the way for further research into PCr's applications in cancer treatment, aiming to improve patient outcomes by managing chemotherapy-related renal injuries.
Assuntos
Apoptose , Doxorrubicina , Rim , Mitocôndrias , Fator 2 Relacionado a NF-E2 , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fosfocreatina , Doxorrubicina/toxicidade , Animais , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Apoptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Masculino , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fosfocreatina/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/tratamento farmacológico , Nefropatias/patologiaRESUMO
Doxorubicin (Dox), a chemotherapeutic agent frequently used to treat cancer, elicits cardiotoxicity, a condition referred to as Dox-induced cardiotoxicity (DIC), and ferroptosis plays a contributory role in its pathophysiology. Fucoidan, a polysaccharide with various biological activities and safety profile, has potential therapeutic and pharmaceutical applications. This study aimed to investigate the protective effects and underlying mechanisms of fucoidan in DIC. Echocardiography, biomarkers of cardiomyocyte injury, serum creatine kinase, creatine kinase isoenzyme and lactate dehydrogenase, as well as histological staining results, revealed that fucoidan significantly reduced myocardial damage and improved cardiac function in DIC mice. Transmission electron microscopy; levels of lipid reactive oxygen species, glutathione, and malondialdehyde; ferroptosis-related markers; and regulatory factors such as glutathione peroxidase 4 (GPX4), transferrin receptor protein-1, ferritin heavy chain-1, heme oxygenase-1 in the heart tissue were measured to explore the effect of fucoidan on Dox-induced ferroptosis. These results suggested that fucoidan could inhibit cardiomyocyte ferroptosis caused by Dox. In vitro experiments revealed that silencing nuclear factor-erythroid 2-related factor 2 (Nrf2) in cardiomyocytes reduced the inhibitory effect of fucoidan on ferroptosis. Hence, fucoidan has the potential to ameliorate DIC by inhibiting ferroptosis via the Nrf2/GPX4 pathway.
Assuntos
Cardiotoxicidade , Doxorrubicina , Ferroptose , Miócitos Cardíacos , Fator 2 Relacionado a NF-E2 , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Polissacarídeos , Transdução de Sinais , Animais , Polissacarídeos/farmacologia , Polissacarídeos/química , Ferroptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Camundongos , Cardiotoxicidade/tratamento farmacológico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , MasculinoRESUMO
Doxorubicin (Dox) is widely used as a chemotherapy drug, while anethole (AN) is primarily known as the main aromatic component in various plant species. This research focused on the impact of AN on the cardiac and renal toxicity induced by Dox and to understand the underlying mechanisms. For cardiac toxicity, Wistar rats were categorized into four groups: a Control group; a Dox group, where rats received 2.5 mg/kg of Dox intraperitoneally every other day; and two Dox + AN groups, where animals were administered Dox (2.5 mg/kg/every other day, IP) along with 125 mg/kg or 250 mg/kg of AN, respectively. The renal toxicity study included similar groups, with the Dox group receiving a single dose of 20 mg/kg of Dox intraperitoneally on the tenth day, and the Dox + AN groups receiving 125 mg/kg and 250 mg/kg of AN for two weeks, alongside the same dose of Dox (20 mg/kg, IP, once on the 10th day). Parameters assessed included ECG, cardiac injury markers (CK, CK-MB, and LDH), and kidney function tests (Cr, BUN, uric acid, LDL, Kim-1, NGAL, and CysC). Antioxidant activity, lipid peroxidation, inflammation, and apoptotic markers were also monitored in heart and renal tissues. Gene expression levels of the TLR4/MyD88/NFκB pathway, along with Bax and Bcl-2, were evaluated. Dox significantly altered ECG, elevated cardiac injury markers, and renal function markers. It also augmented gene expressions of TLR4/MyD88/NFκB, amplified oxidative stress, inflammatory cytokines and apoptotic markers. Conversely, AN reduced cardiac injury markers and kidney function tests, improved ECG, diminished TLR4/MyD88/NFκB gene expression, and alleviated oxidative stress by increasing antioxidant enzyme activities and reducing inflammatory cytokines. AN also enhanced Bcl-2 levels and inhibited Bax and the cleavage of caspase-3 and 9. AN countered the lipid peroxidation, oxidative stress, inflammation, and apoptosis induced by Dox, marking it as a potential preventive strategy against Dox-induced nephrotoxic and cardiotoxic injuries.
Assuntos
Derivados de Alilbenzenos , Anisóis , Doxorrubicina , Rim , Farmacologia em Rede , Ratos Wistar , Animais , Doxorrubicina/toxicidade , Ratos , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Anisóis/farmacologia , Anisóis/toxicidade , Masculino , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/etiologia , Coração/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Antibióticos Antineoplásicos/toxicidade , Antioxidantes/farmacologia , NF-kappa B/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/patologia , Nefropatias/prevenção & controle , Nefropatias/metabolismoRESUMO
Antioxidants given concurrently with chemotherapy offer an effective strategy for reducing the negative effects of the drug. One remaining obstacle to the use of doxorubicin (DOX) in chemotherapy is cardiotoxicity. Using vitamin E (Vit. E) as a reference standard, our study focuses on the potential preventive benefits of oxyresveratrol (ORES) and/or dapagliflozin (DAPA) against DOX-induced cardiac injury. Acute cardiotoxicity was noticed after a single intravenous injection of a male rat's tail vein with 10 mg/kg of DOX. Oral doses of ORES (80 mg/kg), DAPA (10 mg/kg), and Vit. E (1 g/kg) were given, respectively. Pretreatment of animals with Vit. E, ORES and/or DAPA revealed a considerable alleviation of heart damage, as evidenced by histopathological change mitigation and a notable drop in serum AST, LDH, CK, CK-MB, and cardiac contents of MDA and NO2-. Also, serum TAC, tissue GSH, and SOD showed substantial increases. Additionally, tissue caspase-3, serum IL-6, and TNF-α were considerably reduced. Moreover, a downregulation in cardiac gene expression of ATG-5, Keap-1, and NF-κB in addition to an upregulation of Bcl-2 gene expression and HO-1, Nrf-2, and PPAR-γ protein expression clearly appeared. Ultimately, ORES and/or DAPA have an optimistic preventive action against severe heart deterioration caused by DOX.