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1.
BMC Pharmacol Toxicol ; 22(1): 61, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34674775

RESUMO

BACKGROUND: The emergence and rapid spread of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in thelate 2019 has caused a devastating global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19). Although vaccines have been and are being developed, they are not accessible to everyone and not everyone can receive these vaccines. Also, it typically takes more than 10 years until a new therapeutic agent is approved for usage. Therefore, repurposing of known drugs can lend itself well as a key approach for significantly expediting the development of new therapies for COVID-19. METHODS: We have incorporated machine learning-based computational tools and in silico models into the drug discovery process to predict Adsorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles of 90 potential drugs for COVID-19 treatment identified from two independent studies mainly with the purpose of mitigating late-phase failures because of inferior pharmacokinetics and toxicity. RESULTS: Here, we summarize the cardiotoxicity and general toxicity profiles of 90 potential drugs for COVID-19 treatment and outline the risks of repurposing and propose a stratification of patients accordingly. We shortlist a total of five compounds based on their non-toxic properties. CONCLUSION: In summary, this manuscript aims to provide a potentially useful source of essential knowledge on toxicity assessment of 90 compounds for healthcare practitioners and researchers to find off-label alternatives for the treatment for COVID-19. The majority of the molecules discussed in this manuscript have already moved into clinical trials and thus their known pharmacological and human safety profiles are expected to facilitate a fast track preclinical and clinical assessment for treating COVID-19.


Assuntos
Antivirais/toxicidade , COVID-19/tratamento farmacológico , Descoberta de Drogas , Reposicionamento de Medicamentos , Animais , Antivirais/efeitos adversos , Captopril/uso terapêutico , Cardiotoxinas/toxicidade , Catecóis/uso terapêutico , Biologia Computacional , Sistema Enzimático do Citocromo P-450/metabolismo , Descoberta de Drogas/métodos , Humanos , Indometacina/uso terapêutico , Linezolida/uso terapêutico , Fígado/efeitos dos fármacos , Camundongos , Modelos Biológicos , Nitrilas/uso terapêutico , Ratos , Reprodução/efeitos dos fármacos , Software , Ácido Valproico/uso terapêutico
2.
Cells ; 10(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34440842

RESUMO

This study aimed to investigate the mechanistic pathway of Naja atra (Taiwan cobra) cardiotoxin 1 (CTX1)-induced death of leukemia cell lines U937 and HL-60. CTX1 increased cytoplasmic Ca2+ and reactive oxygen species (ROS) production, leading to the death of U937 cells. It was found that Ca2+-induced NOX4 upregulation promoted ROS-mediated p38 MAPK phosphorylation, which consequently induced c-Jun and ATF-2 phosphorylation. Using siRNA knockdown, activated c-Jun and ATF-2 were demonstrated to regulate the expression of Fas and FasL, respectively. Suppression of Ca2+-mediated NOX4 expression or ROS-mediated p38 MAPK activation increased the survival of U937 cells exposed to CTX1. FADD depletion abolished CTX1-induced cell death, caspase-8 activation, and t-Bid production, supporting the correlation between the Fas death pathway and CTX1-mediated cytotoxicity. Among the tested N. atra CTX isotoxins, only CTX1 induced Fas and FasL expression. Chemical modification studies revealed that intact Met residues were essential for the activity of CTX1 to upregulate Fas and FasL expression. Taken together, the data in this study indicate that CTX1 induces c-Jun-mediated Fas and ATF-2-mediated FasL transcription by the Ca2+/NOX4/ROS/p38 MAPK axis, thereby activating the Fas death pathway in U937 cells. Furthermore, CTX1 activates Fas/FasL death signaling in the leukemia cell line HL-60.


Assuntos
Cardiotoxinas/farmacologia , Proteína Ligante Fas/metabolismo , Naja naja/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor fas/metabolismo , Fator 2 Ativador da Transcrição/antagonistas & inibidores , Fator 2 Ativador da Transcrição/genética , Fator 2 Ativador da Transcrição/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular Tumoral , Proteína de Domínio de Morte Associada a Fas/antagonistas & inibidores , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Leucemia/metabolismo , Leucemia/patologia , NADPH Oxidase 4/metabolismo , Fosforilação/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Life Sci ; 283: 119849, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343539

RESUMO

AIMS: Cardiotoxicity of doxorubicin frequently complicates treatment outcome. Aberrantly activated calcium/calmodulin pathway can eventually trigger signaling cascades that mediate cardiotoxicity. Therefore, we tested the hypothesis that trifluoperazine, a strong calmodulin antagonist, may alleviate this morbidity. MATERIALS AND METHODS: Heart failure and cardiotoxicity were assessed via echocardiography, PCR, immunohistochemistry, histopathology, Masson's trichrome staining and transmission electron microscopy. Whereas liver and kidney structural and functional alterations were evaluated histopathologically and biochemically. KEY FINDINGS: Results revealed that combination treatment with trifluoperazine could overcome doxorubicin-induced heart failure with reduced ejection fraction. Moreover, heart weight/body weight ratio and histopathological examination showed that trifluoperazine mitigated doxorubicin-induced cardiac atrophy, inflammation and myofibril degeneration. Transmission electron microscopy further confirmed the marked restoration of the left ventricular ultrastructures by trifluoperazine pretreatment. In addition, Masson's trichrome staining revealed that trifluoperazine could significantly inhibit doxorubicin-induced left ventricular remodeling by fibrosis. Of note, doxorubicin induced the expression of myocardial nuclear NF-κB-p65 and caspase-3 which were markedly inhibited by trifluoperazine, suggesting that cardioprotection conferred by trifluoperazine involved, at least in part, suppression of NF-κB and apoptosis. Furthermore, biochemical and histopathological examinations showed that trifluoperazine improved doxorubicin-induced renal and hepatic impairments both functionally and structurally. SIGNIFICANCE: In conclusion, the present in vivo study is the first to provide evidences underscoring the protective effects of trifluoperazine that may pave the way for repurposing this calmodulin antagonist in ameliorating organ toxicity by doxorubicin.


Assuntos
Apoptose/efeitos dos fármacos , Cardiotoxicidade , Cardiotoxinas/efeitos adversos , Doxorrubicina/efeitos adversos , Miocárdio/metabolismo , Fator de Transcrição RelA/metabolismo , Trifluoperazina/farmacologia , Animais , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/metabolismo , Cardiotoxicidade/patologia , Cardiotoxinas/farmacologia , Caspase 3/metabolismo , Doxorrubicina/farmacologia , Masculino , Camundongos , Miocárdio/patologia
4.
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
5.
Toxicol Appl Pharmacol ; 428: 115696, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34419494

RESUMO

Bisphenol A (BPA) is a well-known endocrine-disrupting chemical that is widely used in a variety of products, including plastics, medical equipment and receipts. Hence, most people are exposed to BPA through the skin, via inhalation and via the digestive system, and such exposure has been linked to cardiovascular diseases including coronary artery disease, hypertension, atherosclerosis, and myocardial infarction. However, the underlying mechanisms of cardiac dysfunction caused by BPA remain poorly understood. In this study, we found that BPA exposure altered cardiac function in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Acute BPA exposure in hiPSC-CMs resulted in reduced field potential, as measured by multielectrode array (MEA). Furthermore, we observed that BPA dose-dependently inhibited ICa, INa or IKr channels. In addition, BPA exposure dose-dependently inhibited calcium transients and contraction in hiPSC-CMs. Our findings suggest that BPA exposure leads to cardiac dysfunction and cardiac risk factors such as arrhythmia.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Compostos Benzidrílicos/toxicidade , Cardiotoxinas/toxicidade , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fenóis/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia
6.
Sci Data ; 8(1): 226, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433823

RESUMO

While gene expression profiling has traditionally been the method of choice for large-scale perturbational profiling studies, proteomics has emerged as an effective tool in this context for directly monitoring cellular responses to perturbations. We previously reported a pilot library containing 3400 profiles of multiple perturbations across diverse cellular backgrounds in the reduced-representation phosphoproteome (P100) and chromatin space (Global Chromatin Profiling, GCP). Here, we expand our original dataset to include profiles from a new set of cardiotoxic compounds and from astrocytes, an additional neural cell model, totaling 5300 proteomic signatures. We describe filtering criteria and quality control metrics used to assess and validate the technical quality and reproducibility of our data. To demonstrate the power of the library, we present two case studies where data is queried using the concept of "connectivity" to obtain biological insight. All data presented in this study have been deposited to the ProteomeXchange Consortium with identifiers PXD017458 (P100) and PXD017459 (GCP) and can be queried at https://clue.io/proteomics .


Assuntos
Antineoplásicos/toxicidade , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Cardiotoxinas/toxicidade , Inibidores de Proteínas Quinases/toxicidade , Proteômica , Linhagem Celular Tumoral , Humanos , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteoma
7.
Biomolecules ; 11(8)2021 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-34439837

RESUMO

Repeated mechanical stress causes injuries in the adult skeletal muscle that need to be repaired. Although muscle regeneration is a highly efficient process, it fails in some pathological conditions, compromising tissue functionality. This may be caused by aberrant cell-cell communication, resulting in the deposition of fibrotic and adipose infiltrates. Here, we investigate in vivo changes in the profile of skeletal muscle secretome during the regeneration process to suggest new targetable regulatory circuits whose failure may lead to tissue degeneration in pathological conditions. We describe the kinetic variation of expression levels of 76 secreted proteins during the regeneration process. In addition, we profile the gene expression of immune cells, endothelial cells, satellite cells, and fibro-adipogenic progenitors. This analysis allowed us to annotate each cell-type with the cytokines and receptors they have the potential to synthetize, thus making it possible to draw a cell-cell interaction map. We next selected 12 cytokines whose receptors are expressed in FAPs and tested their ability to modulate FAP adipogenesis and proliferation. We observed that IL1α and IL1ß potently inhibit FAP adipogenesis, while EGF and BTC notably promote FAP proliferation. In addition, we characterized the cross-talk mediated by extracellular vesicles (EVs). We first monitored the modulation of muscle EV cargo during tissue regeneration. Using a single-vesicle flow cytometry approach, we observed that EVs differentially affect the uptake of RNA and proteins into their lumen. We also investigated the EV capability to interact with SCs and FAPs and to modulate their proliferation and differentiation. We conclude that both cytokines and EVs secreted during muscle regeneration have the potential to modulate adipogenic differentiation of FAPs. The results of our approach provide a system-wide picture of mechanisms that control cell fate during the regeneration process in the muscle niche.


Assuntos
Adipogenia/genética , Vesículas Extracelulares/metabolismo , Interleucina-1alfa/genética , Interleucina-1beta/genética , Músculo Esquelético/efeitos dos fármacos , Regeneração/genética , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Cardiotoxinas/toxicidade , Comunicação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/classificação , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Vesículas Extracelulares/química , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Mioblastos/citologia , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Proteoma/classificação , Proteoma/genética , Proteoma/metabolismo , Regeneração/efeitos dos fármacos , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo
8.
Nat Commun ; 12(1): 3253, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059674

RESUMO

Muscle stem cell function has been suggested to be regulated by Acetyl-CoA and NAD+ availability, but the mechanisms remain unclear. Here we report the identification of two acetylation sites on PAX7 that positively regulate its transcriptional activity. Lack of PAX7 acetylation reduces DNA binding, specifically to the homeobox motif. The acetyltransferase MYST1 stimulated by Acetyl-CoA, and the deacetylase SIRT2 stimulated by NAD +, are identified as direct regulators of PAX7 acetylation and asymmetric division in muscle stem cells. Abolishing PAX7 acetylation in mice using CRISPR/Cas9 mutagenesis leads to an expansion of the satellite stem cell pool, reduced numbers of asymmetric stem cell divisions, and increased numbers of oxidative IIA myofibers. Gene expression analysis confirms that lack of PAX7 acetylation preferentially affects the expression of target genes regulated by homeodomain binding motifs. Therefore, PAX7 acetylation status regulates muscle stem cell function and differentiation potential to facilitate metabolic adaptation of muscle tissue.


Assuntos
Autorrenovação Celular/genética , Músculo Esquelético/lesões , Fator de Transcrição PAX7/metabolismo , Regeneração/genética , Células Satélites de Músculo Esquelético/fisiologia , Acetilação , Animais , Células COS , Sistemas CRISPR-Cas , Cardiotoxinas/administração & dosagem , Cardiotoxinas/toxicidade , Diferenciação Celular/genética , Chlorocebus aethiops , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Mutagênese , Cultura Primária de Células , Regiões Promotoras Genéticas , Células Sf9 , Sirtuína 2/genética , Sirtuína 2/metabolismo , Spodoptera , Ativação Transcricional
9.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071003

RESUMO

Superoxide dismutase (SOD) is a major antioxidant enzyme for superoxide removal, and cytoplasmic SOD (SOD1) is expressed as a predominant isoform in all cells. We previously reported that renal SOD1 deficiency accelerates the progression of diabetic nephropathy (DN) via increasing renal oxidative stress. To evaluate whether the degree of SOD1 expression determines regeneration capacity and sarcopenic phenotypes of skeletal muscles under incipient and advanced DN conditions, we investigated the alterations of SOD1 expression, oxidative stress marker, inflammation, fibrosis, and regeneration capacity in cardiotoxin (CTX)-injured tibialis anterior (TA) muscles of two Akita diabetic mouse models with different susceptibility to DN, DN-resistant C57BL/6-Ins2Akita and DN-prone KK/Ta-Ins2Akita mice. Here, we report that KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, exhibit delayed muscle regeneration after CTX injection, as demonstrated by the finding indicating significantly smaller average cross-sectional areas of regenerating TA muscle myofibers relative to KK/Ta-wild-type mice. Furthermore, we observed markedly reduced SOD1 expression in CTX-injected TA muscles of KK/Ta-Ins2Akita mice, but not C57BL/6-Ins2Akita mice, along with increased inflammatory cell infiltration, prominent fibrosis and superoxide overproduction. Our study provides the first evidence that SOD1 reduction and the following superoxide overproduction delay skeletal muscle regeneration through induction of overt inflammation and fibrosis in a mouse model of progressive DN.


Assuntos
Nefropatias Diabéticas/complicações , Músculo Esquelético/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Sarcopenia/etiologia , Superóxido Dismutase-1/efeitos dos fármacos , Animais , Cardiotoxinas/toxicidade , Colágeno Tipo I/biossíntese , Colágeno Tipo I/genética , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Progressão da Doença , Indução Enzimática/efeitos dos fármacos , Fibrose , Regulação Enzimológica da Expressão Gênica , Predisposição Genética para Doença , Mesângio Glomerular/patologia , Inflamação , Insulina/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase-1/biossíntese , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/fisiologia , Superóxidos/metabolismo
10.
Ecotoxicol Environ Saf ; 220: 112394, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34091186

RESUMO

Arsenic (As) and antimony (Sb) are known as an environmental contaminant with cardiotoxicity properties. The endoplasmic reticulum (ER) is the largest calcium reservoir in the cell, and its calcium homeostasis disorder plays a vital role in endoplasmic reticulum stress (ERS) and apoptosis. The objective of this study was to investigate whether As and Sb induced apoptosis via endoplasmic reticulum stress (ERS) linked to calcium homeostasis disturbance. In this study, thirty-two adult mice were gavage-fed daily with As2O3 (4 mg/kg), SbCl3 (15 mg/kg) and co-treat with SbCl3 (15 mg/kg) and As2O3 (4 mg/kg) daily for 60 days. It was observed that As or/and Sb caused histopathological lesions and ER expansion of the heart. Meanwhile, the gene expression of ER Ca2+ release channels (RyR2 and IP3R) and calmodulin-dependent protein kinase II (CaMKII) increased while the levels of mRNA and protein of ER Ca2+ uptake channel (SERCA2) downregulated significantly compared to the controls. Then, As or/and Sb induced ERS and triggered the ER apoptotic pathway by activating unfolded protein response (UPR)-associated genes ((PERK, ATF6, IRE1, XBP1, JNK, GRP78), and apoptosis-related genes (Caspase12, Caspase3, p53, CHOP). Above indicators in As + Sb group became more severe than that of As group and Sb group. Overall, our results proved that the cardiotoxicity caused by As or/and Sb might be concerning disturbing calcium homeostasis, which induced apoptosis through the ERS pathway.


Assuntos
Antimônio/toxicidade , Arsênio/toxicidade , Cálcio/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Coração/efeitos dos fármacos , Animais , Antimônio/metabolismo , Apoptose , Arsênio/metabolismo , Canais de Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiotoxicidade/metabolismo , Cardiotoxinas , Caspase 3/metabolismo , Morte Celular , Regulação para Baixo , Retículo Endoplasmático/metabolismo , Poluentes Ambientais/toxicidade , Homeostase/efeitos dos fármacos , Masculino , Metais Pesados/toxicidade , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Resposta a Proteínas não Dobradas
11.
Toxicol Appl Pharmacol ; 423: 115577, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34019861

RESUMO

Lenvatinib is a tyrosine kinase inhibitor (TKI) approved for the treatment of resistant differentiated thyroid cancer, advanced renal cell carcinoma, unresectable hepatocellular carcinoma, and endometrial carcinoma. Although it is successful in cancer treatment, it can cause life-threatening side effects such as cardiotoxicity. The molecular mechanism of cardiotoxicity caused by lenvatinib is not fully known. In this study, the molecular mechanism of lenvatinib's cardiotoxicity was investigated focusing on mitochondrial toxicity in the H9c2 cardiomyoblastic cell line. Lenvatinib inhibited cell viability at 48 and 72 h exposure with three selected concentrations (1.25 µM, 5 µM and 10 µM); and inhibited intracellular ATP after 72 h exposure compared to the control group. Mitochondrial membrane potential was decreased after 48 h and did not show significant changes after 72 h exposure. Evaluated with real-time PCR, mitochondrial dynamics (Mfn1, Mfn2, OPA1, DRP1, Fis1) expression levels after lenvatinib treatment significantly changed. Lenvatinib triggered the tendency from fusion to fission in mitochondria after 48 h exposure, and increased both fusion and fission after 72 h. The mtDNA ratio increased after 48 h and decreased after 72 h. ASK1, JNK and AMPKα2 increased. UCP2 showed downregulation, SOD2 level showed upregulation and Cat levels decreased after drug treatment. Nrf1 and Nrf2 also changed concentration-dependently. Protein carbonyl levels increased significantly after lenvatinib treatments indicating oxidative stress. The protein levels of the electron transport chain complexes, LONP1, UCP2, and P21 showed significant differences after lenvatinib treatment. The outcome of our study is expected to be a contribution to the understanding of the molecular mechanisms of TKI-induced cardiotoxicity.


Assuntos
Antineoplásicos/toxicidade , Cardiotoxinas/toxicidade , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Compostos de Fenilureia/toxicidade , Quinolinas/toxicidade , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Dinâmica Mitocondrial/fisiologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Ratos
12.
Mol Cell Biochem ; 476(8): 3099-3109, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33835331

RESUMO

While anthracyclines (ACs) are a class of chemotherapeutic agents that have improved the prognosis of many women with breast cancer, it is one of the most cardiotoxic agents used to treat cancer. Despite their reported dose-dependent cardiotoxicity, AC-based chemotherapy has become the mainstay of breast cancer therapy due to its efficacy. Elucidating the mechanisms of anthracycline-mediated cardiotoxicity and associated therapeutic interventions continue to be the main focus in the field of cardio-oncology. Herein, we summarized the current literature surrounding the mechanisms of anthracycline-induced cardiotoxicity, including the role of topoisomerase II inhibition, generation of reactive oxygen species, and elevations in free radicals. Furthermore, this review highlights the molecular mechanisms of potential cardioprotective interventions in this setting. The benefits of pharmaceuticals, including dexrazoxane, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, statins, and antioxidants in this setting, are reviewed. Finally, the mechanisms of emerging preventative interventions within this patient population including nutraceuticals and aerobic exercise are explored.


Assuntos
Antraciclinas/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiotônicos/uso terapêutico , Cardiotoxicidade/prevenção & controle , Animais , Neoplasias da Mama/patologia , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Cardiotoxinas/efeitos adversos , Feminino , Humanos , Prognóstico , Fatores de Risco
13.
Rev. urug. cardiol ; 36(1): e36107, abr. 2021. ilus, tab
Artigo em Espanhol | LILACS, BNUY, UY-BNMED | ID: biblio-1252372

RESUMO

Las nuevas terapias oncológicas han logrado aumentar la sobrevida del paciente con cáncer, observando, sin embargo, un incremento de la morbilidad y mortalidad vinculadas a sus efectos secundarios. El desarrollo de eventos cardiovasculares adversos impacta negativamente en el pronóstico durante el tratamiento del cáncer, pero también en los supervivientes al cáncer, donde las enfermedades cardiovasculares (ECV) y las segundas neoplasias son la principal causa de muerte1-5. La cardiotoxicidad inducida por el tratamiento del cáncer se define como el conjunto de ECV derivadas de los tratamientos oncológicos. Su manifestación es variada e incluye el desarrollo de disfunción ventricular, insuficiencia cardíaca (IC), isquemia miocárdica, hipertensión arterial y arritmias, entre otras. Puede ser consecuencia tanto del efecto directo del tratamiento sobre la estructura y función cardíacas, como del desarrollo acelerado de ECV6-9. Frecuentemente se utiliza el término cardiotoxicidad como sinónimo de disfunción ventricular por quimioterapia (DV-QT). Dado que la cardiotoxicidad abarca un espectro más amplio de afectación cardiovascular, creemos conveniente hablar de DV-QT para referirnos a la afectación de la función sistólica del ventrículo izquierdo. La DV-QT y el desarrollo de IC representan una de las complicaciones más temidas por su impacto pronóstico en la esfera cardiovascular y oncológica, dado que limitan el arsenal terapéutico para el tratamiento del cáncer5,10. Han sido creadas diversas sociedades de cardio-onco-hematología con el fin de generar recomendaciones de práctica clínica y formar profesionales capacitados para el manejo de las complicaciones cardiovasculares del tratamiento del cáncer11. La cardio-oncología es una disciplina en creciente y continuo desarrollo. Creemos que es fundamental realizar tareas de formación médica continua, así como también estimular el trabajo conjunto de diversas especialidades para brindar una mejor asistencia. Este texto es el resultado del trabajo de un equipo multidisciplinario que incluye cardiólogos, hematólogos y oncólogos, y pretende brindar información a los integrantes del equipo de salud involucrados en la asistencia de pacientes oncológicos. Debido a su extensión, hemos decidido fraccionar el contenido en tres partes para facilitar su publicación.


New oncological therapies have been successful in increasing cancer patient survival, but they have also led to an increase in morbidity and mortality linked to their side effects. During cancer treatment, the development of cardiovascular side effects has a negative impact in prognosis, but also in cancer survivors, in whom cardiovascular diseases and secondary malignancies are the main cause of death. Cancer related cardiotoxicity is defined as the development of cardiovascular diseases related to cancer treatment. Clinical presentation is broad involving ventricular dysfunction, heart failure, myocardial ischemia, arterial hypertension and arrhythmias among others. This may result from the direct cardiovascular effect of a cancer treatment or accelerated development of cardiovascular diseases. Frequently, in the literature cardiotoxicity and chemotherapy related ventricular dysfunction are used as synonyms. However, cardiotoxicity includes a broad spectrum of cardiovascular manifestations, thus in this text we refer to chemotherapy related ventricular dysfunction as the presence of left ventricular systolic impairment. Chemotherapy related ventricular dysfunction and heart failure are two of the most feared complications of cancer treatment due to its impact on cardiovascular and oncological prognosis, affecting treatment options. Numerous worldwide cardio-onco-hematology societies have emerged to generate clinical practice guidelines and improve the diagnosis and evaluation of cardiovascular cancer treatment side effects. Cardio-Oncology is a discipline in continuous growth and development. We strongly believe that continuum medical education and a multidisciplinary approach is necessary to provide a quality health care. This text is the result of a multidisciplinary work involving cardiologists, hematologists and oncologists. It is our goal to provide information to the health care team involved in the assistance of cancer patients. Due to its extension, it will be published in three parts.


O desenvolvimento de novas terapias oncológicas levou a um aumento na sobrevida dos pacientes, mas ao mesmo tempo traz consigo morbidades relacionadas aos tratamentos. O desenvolvimento de efeitos cardiovasculares adversos tem um impacto negativo no prognóstico dos pacientes em tratamento, bem como nos pacientes considerados curados, nos quais doença cardiovascular e malignidades secundárias são as principais causas de morte. Cardiotoxicidade relacionada ao câncer é definida como o desenvolvimento de doença cardiovascular secundária ao tratamento. A gama de apresentações clínicas é ampla, podendo se manifestar como disfunção ventricular, insuficiência cardíaca, isquemia miocárdica, hipertensão arterial, arritmias, entre outras. Isto pode ser resultante de desenvolvimento e progressão acelerados de doença cardiovascular ou por efeito direto das terapias. Frequentemente é dito na literatura que cardiotoxicidade e disfunção ventricular relacionada à quimioterapia são sinônimos. Entretanto, cardiotoxicidade engloba um amplo espectro de manifestações cardiovasculares. Neste texto, portanto, nos referimos à disfunção ventricular causada por quimioterápicos exclusivamente como a presença de disfunção sistólica ventricular esquerda. Disfunção ventricular relacionada à quimioterapia e insuficiência cardíaca são duas das mais temidas complicações do tratamento oncológico devido ao seu impacto no prognóstico cardiovascular e oncológico, podendo afetar ainda a escolha e manutenção das opções terapêuticas. Diversas sociedades cardio-onco-hematológicas surgiram ao redor do mundo com o objetivo de gerar diretriz clínicas práticas e melhorar o diagnóstico e tratamento das complicações cardiovasculares resultantes das terapias oncológicas. A cardio-oncologia é uma disciplina em contínuo crescimento e desenvolvimento. Nós acreditamos fortemente que educação médica continuada e uma abordagem multidisciplinar são necessárias para um cuidado médico de qualidade. Este texto é o resultado de um trabalho multidisciplinar envolvendo cardiologistas, hematologistas e oncologistas. Nosso objetivo é de oferecer informação à equipe de cuidados em saúde envolvido na assistência destes pacientes. Devido à sua extensão, este texto será publicado em três partes.


Assuntos
Humanos , Disfunção Ventricular/induzido quimicamente , Disfunção Ventricular/prevenção & controle , Disfunção Ventricular/diagnóstico por imagem , Cardiotoxinas/efeitos adversos , Cardiotoxinas/farmacologia , Antineoplásicos/efeitos adversos , Biomarcadores , Medição de Risco , Assistência ao Paciente/normas , Insuficiência Cardíaca/induzido quimicamente
14.
Pediatr Hematol Oncol ; 38(5): 497-503, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33715575

RESUMO

BACKGROUND: Anthracycline chemotherapy is used to treat a variety of cancers. However, late cardiac effects of anthracycline chemotherapy, such as subclinical left ventricular dilatation and/or dysfunction, have been observed in more than half of long-term survivors of childhood cancers. A major risk factor for anthracycline cardiotoxicity is intrauterine growth restriction (IUGR). We assessed the significance of IUGR as an important risk factor for late cardiotoxic effects of anthracycline therapy in asymptomatic long-term survivors of childhood cancers. MATERIALS AND METHODS: The study included 61 survivors of childhood cancers. Cardiac functions were prospectively studied using both conventional and non-conventional echocardiographic methods (two-dimensional speckle tracking echocardiography) after completion of the treatment. The patients were divided into two groups based on their birth weights: Group 1 (patients with IUGR) and Group 2 (patients with normal birth weight). RESULTS: Conventional echocardiography revealed a similar and normal range of left ventricle systolic and diastolic functions in both groups. However, global longitudinal and circumferential strain values demonstrated subclinical left ventricular systolic dysfunction in both groups as compared with normal reference strain values. Furthermore, Group 1 patients had significantly lower global longitudinal and circumferential strain and strain rate values than those in Group 2 patients. CONCLUSION: Asymptomatic long-term survivors of childhood cancers with a history of IUGR may have an increased risk of anthracycline cardiotoxicity due to the low content of mitochondrial DNA (mtDNA). IUGR is a risk factor for late anthracycline cardiotoxicity.


Assuntos
Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Retardo do Crescimento Fetal , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Peso ao Nascer , Sobreviventes de Câncer , Cardiotoxinas/efeitos adversos , Criança , Estudos Transversais , Retardo do Crescimento Fetal/etiologia , Humanos , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
15.
Aging (Albany NY) ; 13(6): 8454-8466, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33714197

RESUMO

In this study, we investigated the beneficial effects of high endogenous levels of n-3 polyunsaturated fatty acids (PUFAs) on skeletal muscle repair and regeneration using a mouse cardiotoxin (CTX, 20 µM/200 µL) -induced gastrocnemius muscle injury model. Transgenic fat-1 mice expressing the Caenorhabditis elegans fat-1 gene, encoding n-3 fatty acid desaturase, showed higher n-3 PUFA levels and lower n-6/n-3 PUFA ratios in gastrocnemius muscle tissues. Hematoxylin and eosin and Masson's trichrome staining of gastrocnemius sections revealed increased muscle fiber size and reduced fibrosis in fat-1 mice on days 7 and 14 after CTX injections. Gastrocnemius muscle tissues from fat-1 mice showed reduced inflammatory responses and increased muscle fiber regeneration reflecting enhanced activation of satellite cells on day 3 after cardiotoxin injections. Gastrocnemius muscle tissues from cardiotoxin-treated fat-1 mice showed reduced levels of pro-apoptotic proteins (Caspase 3 and Bax) and increased levels of anti-apoptotic proteins (Bcl-2 and Survivin). Moreover, eicosapentaenoic acid (EPA) reduced the incidence of apoptosis among cardiotoxin-treated C2C12 mouse myoblasts. These findings demonstrate that higher endogenous n-3 PUFA levels in fat-1 mice enhances skeletal muscle repair and regeneration following cardiotoxin-induced injury.


Assuntos
Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Músculo Esquelético/lesões , Músculo Esquelético/metabolismo , Regeneração/fisiologia , Animais , Proteínas de Caenorhabditis elegans , Cardiotoxinas/toxicidade , Ácidos Graxos Dessaturases , Camundongos , Camundongos Transgênicos
16.
J Vis Exp ; (167)2021 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-33554972

RESUMO

Despite several advances in cardiac tissue engineering, one of the major challenges to overcome remains the generation of a fully functional vascular network comprising several levels of complexity to provide oxygen and nutrients within bioengineered heart tissues. Our laboratory has developed a three-dimensional in vitro model of the human heart, known as the "cardiac spheroid" or "CS". This presents biochemical, physiological, and pharmacological features typical of the human heart and is generated by co-culturing its three major cell types, such as cardiac myocytes, endothelial cells, and fibroblasts. Human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs or iCMs) are co-cultured at ratios approximating the ones found in vivo with human cardiac fibroblasts (HCFs) and human coronary artery endothelial cells (HCAECs) in hanging drop culture plates for three to four days. The confocal analysis of CSs stained with antibodies against cardiac Troponin T, CD31 and vimentin (markers for cardiac myocytes, endothelial cells and fibroblasts, respectively) shows that CSs present a complex endothelial cell network, resembling the native one found in the human heart. This is confirmed by the 3D rendering analysis of these confocal images. CSs also present extracellular matrix (ECM) proteins typical of the human heart, such as collagen type IV, laminin and fibronectin. Finally, CSs present a contractile activity measured as syncytial contractility closer to the one typical of the human heart compared to CSs that contain iCMs only. When treated with a cardiotoxic anti-cancer agent, such as doxorubicin (DOX, used to treat leukemia, lymphoma and breast cancer), the viability of DOX-treated CSs is significantly reduced at 10 µM genetic and chemical inhibition of endothelial nitric oxide synthase, a downstream target of DOX in HCFs and HCAECs, reduced its toxicity in CSs. Given these unique features, CSs are currently used as in vitro models to study heart biochemistry, pathophysiology, and pharmacology.


Assuntos
Bioengenharia/métodos , Coração/fisiopatologia , Esferoides Celulares/citologia , Animais , Cardiotoxinas/farmacologia , Contagem de Células , Separação Celular , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Colágeno/farmacologia , Doxorrubicina/farmacologia , Doxorrubicina/toxicidade , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Fibroblastos/citologia , Géis , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Fixação de Tecidos
17.
Theranostics ; 11(6): 2876-2891, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33456578

RESUMO

Rationale: Structural remodeling or damage as a result of disease or injury is often not evenly distributed throughout a tissue but strongly depends on localization and extent of damaging stimuli. Skeletal muscle as a mechanically active organ can express signs of local or even systemic myopathic damage, necrosis, or repair. Conventionally, muscle biopsies (patients) or whole muscles (animal models) are mechanically sliced and stained to assess structural alterations histologically. Three-dimensional tissue information can be obtained by applying deep imaging modalities, e.g. multiphoton or light-sheet microscopy. Chemical clearing approaches reduce scattering, e.g. through matching refractive tissue indices, to overcome optical penetration depth limits in thick tissues. Methods: Here, we optimized a range of different clearing protocols. We find aqueous solution-based protocols employing (20-80%) 2,2'-thiodiethanol (TDE) to be advantageous over organic solvents (dibenzyl ether, cinnamate) regarding the preservation of muscle morphology, ease-of-use, hazard level, and costs. Results: Applying TDE clearing to a mouse model of local cardiotoxin (CTX)-induced muscle necrosis, a complete loss of myosin-II signals was observed in necrotic areas with little change in fibrous collagen or autofluorescence (AF) signals. The 3D aspect of myofiber integrity could be assessed, and muscle necrosis in whole muscle was quantified locally via the ratios of detected AF, forward- and backward-scattered Second Harmonic Generation (fSHG, bSHG) signals. Conclusion: TDE optical clearing is a versatile tool to study muscle architecture in conjunction with label-free multiphoton imaging in 3D in injury/myopathy models and might also be useful in studying larger biofabricated constructs in regenerative medicine.


Assuntos
Microscopia Confocal/métodos , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Músculo Esquelético/metabolismo , Necrose/diagnóstico , Animais , Cardiotoxinas/farmacologia , Colágeno/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Imageamento Tridimensional/métodos , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Miofibrilas/metabolismo , Miosina Tipo II/metabolismo , Necrose/induzido quimicamente , Necrose/metabolismo , Compostos de Sulfidrila/farmacologia
18.
Viruses ; 13(1)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467678

RESUMO

While treatment options are available for hepatitis B virus (HBV), there is currently no cure. Anti-HBV nucleoside analogs and interferon-alpha 2b rarely clear HBV covalently closed circular DNA (cccDNA), requiring lifelong treatment. Recently, we identified GLP-26, a glyoxamide derivative which modulates HBV capsid assembly. The impact of GLP-26 on viral replication and integrated DNA was assessed in an HBV nude mouse model bearing HBV transfected AD38 xenografts. At day 45 post-infection, GLP-26 reduced HBV titers by 2.3-3 log10 versus infected placebo-treated mice. Combination therapy with GLP-26 and entecavir reduced HBV log10 titers by 4.6-fold versus placebo. Next, we examined the pharmacokinetics (PK) in cynomolgus monkeys administered GLP-26 via IV (1 mg/kg) or PO (5 mg/kg). GLP-26 was found to have 34% oral bioavailability, with a mean input time of 3.17 h. The oral dose produced a mean peak plasma concentration of 380.7 ng/mL, observed 0.67 h after administration (~30-fold > in vitro EC90 corrected for protein binding), with a mean terminal elimination half-life of 2.4 h and a mean area under the plasma concentration versus time curve of 1660 ng·hr/mL. GLP-26 was 86.7% bound in monkey plasma. Lastly, GLP-26 demonstrated a favorable toxicity profile confirmed in primary human cardiomyocytes. Thus, GLP-26 warrants further preclinical development as an add on to treatment for HBV infection.


Assuntos
Capsídeo/efeitos dos fármacos , Capsídeo/metabolismo , Cardiotoxinas/farmacocinética , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Compostos de Sulfonilureia/farmacocinética , Montagem de Vírus/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hepatite B/tratamento farmacológico , Hepatite B/virologia , Humanos , Macaca fascicularis , Masculino , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Compostos de Sulfonilureia/efeitos adversos , Compostos de Sulfonilureia/química , Carga Viral
19.
Arterioscler Thromb Vasc Biol ; 41(3): 1019-1031, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472401

RESUMO

Drug-induced cardiotoxicity is a significant clinical issue, with many drugs in the market being labeled with warnings on cardiovascular adverse effects. Treatments are often prematurely halted when cardiotoxicity is observed, which limits their therapeutic potential. Moreover, cardiotoxicity is a major reason for abandonment during drug development, reducing available treatment options for diseases and creating a significant financial burden and disincentive for drug developers. Thus, it is important to minimize the cardiotoxic effects of medications that are in use or in development. To this end, identifying patients at a higher risk of developing cardiovascular adverse effects for the drug of interest may be an effective strategy. The discovery of human induced pluripotent stem cells has enabled researchers to generate relevant cell types that retain a patient's own genome and examine patient-specific disease mechanisms, paving the way for precision medicine. Combined with the rapid development of pharmacogenomic analysis, the ability of induced pluripotent stem cell-derivatives to recapitulate patient-specific drug responses provides a powerful platform to identify subsets of patients who are particularly vulnerable to drug-induced cardiotoxicity. In this review, we will discuss the current use of patient-specific induced pluripotent stem cells in identifying populations who are at risk to drug-induced cardiotoxicity and their potential applications in future precision medicine practice. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Cardiotoxicidade/etiologia , Cardiotoxinas/toxicidade , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Arritmias Cardíacas/induzido quimicamente , Avaliação Pré-Clínica de Medicamentos/métodos , Marcadores Genéticos , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Contração Miocárdica/efeitos dos fármacos , Miocardite/induzido quimicamente , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Testes Farmacogenômicos/métodos , Polimorfismo de Nucleotídeo Único , Medicina de Precisão/métodos , Fatores de Risco
20.
Aging Cell ; 20(2): e13312, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33511781

RESUMO

Recruited immune cells play a critical role in muscle repair, in part by interacting with local stem cell populations to regulate muscle regeneration. How aging affects their communication during myogenesis is unclear. Here, we investigate how aging impacts the cellular function of these two cell types after muscle injury during normal aging or after immune rejuvenation using a young to old (Y-O) or old to old (O-O) bone marrow (BM) transplant model. We found that skeletal muscle from old mice (20 months) exhibited elevated basal inflammation and possessed fewer satellite cells compared with young mice (3 months). After cardiotoxin muscle injury (CTX), old mice exhibited a blunted inflammatory response compared with young mice and enhanced M2 macrophage recruitment and IL-10 expression. Temporal immune and cytokine responses of old mice were partially restored to a young phenotype following reconstitution with young cells (Y-O chimeras). Improved immune responses in Y-O chimeras were associated with greater satellite cell proliferation compared with O-O chimeras. To identify how immune cell aging affects myoblast function, conditioned media (CM) from activated young or old macrophages was applied to cultured C2C12 myoblasts. CM from young macrophages inhibited myogenesis while CM from old macrophages reduced proliferation. These functional differences coincided with age-related differences in macrophage cytokine expression. Together, this study examines the infiltration and proliferation of immune cells and satellite cells after injury in the context of aging and, using BM chimeras, demonstrates that young immune cells retain cell autonomy in an old host to increase satellite cell proliferation.


Assuntos
Senescência Celular/imunologia , Desenvolvimento Muscular/imunologia , Células Satélites de Músculo Esquelético/imunologia , Animais , Cardiotoxinas/farmacologia , Senescência Celular/efeitos dos fármacos , Camundongos , Desenvolvimento Muscular/efeitos dos fármacos , Células Satélites de Músculo Esquelético/efeitos dos fármacos
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