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1.
Nat Commun ; 15(1): 4739, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834613

RESUMO

The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens selective and pan-histone deacetylase inhibitors (HDACis) emerge as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, here we dissect the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstitute the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 (PA2G4) protein. PA2G4 overexpression rescues AML cells from the inhibitory effects of HDACis, while genetic and small molecule inhibition of PA2G4 abrogates EVI1 in 3q26 AML cells, including in patient-derived leukemia xenografts. This study positions PA2G4 at the crosstalk of the EVI1 leukemogenic signal for developing new therapeutics and urges the use of HDACis-based combination therapies in patients with 3q26 AML.


Assuntos
Cromossomos Humanos Par 3 , Inibidores de Histona Desacetilases , Leucemia Mieloide Aguda , Proteína do Locus do Complexo MDS1 e EVI1 , Proteogenômica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteína do Locus do Complexo MDS1 e EVI1/metabolismo , Proteína do Locus do Complexo MDS1 e EVI1/genética , Animais , Inibidores de Histona Desacetilases/farmacologia , Camundongos , Linhagem Celular Tumoral , Cromossomos Humanos Par 3/genética , Proteogenômica/métodos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Feminino , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética
2.
Cell Death Dis ; 15(6): 392, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834617

RESUMO

Keratinocyte proliferation and differentiation in epidermis are well-controlled and essential for reacting to stimuli such as ultraviolet light. Imbalance between proliferation and differentiation is a characteristic feature of major human skin diseases such as psoriasis and squamous cell carcinoma. However, the effect of keratinocyte metabolism on proliferation and differentiation remains largely elusive. We show here that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) promotes differentiation while inhibits proliferation of keratinocyte and suppresses psoriasis development. FBP1 is identified among the most upregulated genes induced by UVB using transcriptome sequencing and is elevated especially in upper epidermis. Fbp1 heterozygous mice exhibit aberrant epidermis phenotypes with local hyperplasia and dedifferentiation. Loss of FBP1 promotes proliferation and inhibits differentiation of keratinocytes in vitro. Mechanistically, FBP1 loss facilitates glycolysis-mediated acetyl-CoA production, which increases histone H3 acetylation at lysine 9, resulting in enhanced transcription of proliferation genes. We further find that the expression of FBP1 is dramatically reduced in human psoriatic lesions and in skin of mouse imiquimod psoriasis model. Fbp1 deficiency in mice facilitates psoriasis-like skin lesions development through glycolysis and acetyl-CoA production. Collectively, our findings reveal a previously unrecognized role of FBP1 in epidermal homeostasis and provide evidence for FBP1 as a metabolic psoriasis suppressor.


Assuntos
Diferenciação Celular , Proliferação de Células , Frutose-Bifosfatase , Histonas , Queratinócitos , Psoríase , Psoríase/patologia , Psoríase/metabolismo , Psoríase/genética , Animais , Queratinócitos/metabolismo , Queratinócitos/patologia , Humanos , Acetilação , Histonas/metabolismo , Frutose-Bifosfatase/metabolismo , Frutose-Bifosfatase/genética , Camundongos , Glicólise , Camundongos Endogâmicos C57BL , Acetilcoenzima A/metabolismo , Modelos Animais de Doenças
3.
Sci Rep ; 14(1): 12868, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834690

RESUMO

Acute myeloid leukemia (AML) is fatal in the majority of adults. Identification of new therapeutic targets and their pharmacologic modulators are needed to improve outcomes. Previous studies had shown that immunization of rabbits with normal peripheral WBCs that had been incubated with fluorodinitrobenzene elicited high titer antibodies that bound to a spectrum of human leukemias. We report that proteomic analyses of immunoaffinity-purified lysates of primary AML cells showed enrichment of scaffolding protein IQGAP1. Immunohistochemistry and gene-expression analyses confirmed IQGAP1 mRNA overexpression in various cytogenetic subtypes of primary human AML compared to normal hematopoietic cells. shRNA knockdown of IQGAP1 blocked proliferation and clonogenicity of human leukemia cell-lines. To develop small molecules targeting IQGAP1 we performed in-silico screening of 212,966 compounds, selected 4 hits targeting the IQGAP1-GRD domain, and conducted SAR of the 'fittest hit' to identify UR778Br, a prototypical agent targeting IQGAP1. UR778Br inhibited proliferation, induced apoptosis, resulted in G2/M arrest, and inhibited colony formation by leukemia cell-lines and primary-AML while sparing normal marrow cells. UR778Br exhibited favorable ADME/T profiles and drug-likeness to treat AML. In summary, AML shows response to IQGAP1 inhibition, and UR778Br, identified through in-silico studies, selectively targeted AML cells while sparing normal marrow.


Assuntos
Proliferação de Células , Leucemia Mieloide Aguda , Proteínas Ativadoras de ras GTPase , Humanos , Proteínas Ativadoras de ras GTPase/metabolismo , Proteínas Ativadoras de ras GTPase/genética , Proteínas Ativadoras de ras GTPase/antagonistas & inibidores , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/genética , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Simulação por Computador , Antineoplásicos/farmacologia , Domínios Proteicos , Animais , Proteômica/métodos
4.
Sci Rep ; 14(1): 12766, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834715

RESUMO

Metabolic reprogramming is widely recognized as a hallmark of malignant tumors, and the targeting of metabolism has emerged as an appealing approach for cancer treatment. Mitochondria, as pivotal organelles, play a crucial role in the metabolic regulation of tumor cells, and their morphological and functional alterations are intricately linked to the biological characteristics of tumors. As a key regulatory subunit of mitochondria, mitochondrial inner membrane protein (IMMT), plays a vital role in degenerative diseases, but its role in tumor is almost unknown. The objective of this research was to investigate the roles that IMMT play in the development and progression of breast cancer (BC), as well as to elucidate the underlying biological mechanisms that drive these effects. In this study, it was confirmed that the expression of IMMT in BC tissues was significantly higher than that in normal tissues. The analysis of The Cancer Genome Atlas (TCGA) database revealed that IMMT can serve as an independent prognostic factor for BC patients. Additionally, verification in clinical specimens of BC demonstrated a positive association between high IMMT expression and larger tumor size (> 2 cm), Ki-67 expression (> 15%), and HER-2 status. Furthermore, in vitro experiments have substantiated that the suppression of IMMT expression resulted in a reduction in cell proliferation and alterations in mitochondrial cristae, concomitant with the liberation of cytochrome c, but it did not elicit mitochondrial apoptosis. Through Gene Set Enrichment Analysis (GSEA) analysis, we have predicted the associated metabolic genes and discovered that IMMT potentially modulates the advancement of BC through its interaction with 16 metabolic-related genes, and the changes in glycolysis related pathways have been validated in BC cell lines after IMMT inhibition. Consequently, this investigation furnishes compelling evidence supporting the classification of IMMT as prognostic marker in BC, and underscoring its prospective utility as a novel target for metabolic therapy.


Assuntos
Neoplasias da Mama , Proliferação de Células , Mitocôndrias , Proteínas Mitocondriais , Humanos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Feminino , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-Idade , Prognóstico , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Células MCF-7 , Proteínas Musculares
5.
Sci Rep ; 14(1): 12833, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834809

RESUMO

Breast Cancer is the most common cancer among women globally. Despite significant improvements in overall survival, many tumours are refractory to therapy and so novel approaches are required to improve patient outcomes. We have evaluated patient-derived explants (PDEs) as a novel preclinical platform for breast cancer (BC) and implemented cutting-edge digital pathology and multi-immunofluorescent approaches for investigating biomarker changes in both tumour and stromal areas at endpoint. Short-term culture of intact fragments of BCs as PDEs retained an intact immune microenvironment, and tumour architecture was augmented by the inclusion of autologous serum in the culture media. Cell death/proliferation responses to FET chemotherapy in BC-PDEs correlated significantly with BC patient progression-free survival (p = 0.012 and p = 0.0041, respectively) and cell death responses to the HER2 antibody therapy trastuzumab correlated significantly with HER2 status (p = 0.018). These studies show that the PDE platform combined with digital pathology is a robust preclinical approach for informing clinical responses to chemotherapy and antibody-directed therapies in breast cancer. Furthermore, since BC-PDEs retain an intact tumour architecture over the short-term, they facilitate the preclinical testing of anti-cancer agents targeting the tumour microenvironment.


Assuntos
Neoplasias da Mama , Trastuzumab , Microambiente Tumoral , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/imunologia , Feminino , Microambiente Tumoral/efeitos dos fármacos , Trastuzumab/uso terapêutico , Trastuzumab/farmacologia , Receptor ErbB-2/metabolismo , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/farmacologia
6.
Sci Rep ; 14(1): 12827, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834834

RESUMO

Gut microbiota plays a crucial role in gastrointestinal tumors. Additionally, gut microbes influence the progression of esophageal cancer. However, the major bacterial genera that affect the invasion and metastasis of esophageal cancer remain unknown, and the underlying mechanisms remain unclear. Here, we investigated the gut flora and metabolites of patients with esophageal squamous cell carcinoma and found abundant Bacteroides and increased secretion and entry of the surface antigen lipopolysaccharide (LPS) into the blood, causing inflammatory changes in the body. We confirmed these results in a mouse model of 4NQO-induced esophageal carcinoma in situ and further identified epithelial-mesenchymal transition (EMT) occurrence and TLR4/Myd88/NF-κB pathway activation in mouse esophageal tumors. Additionally, in vitro experiments revealed that LPS from Bacteroides fragile promoted esophageal cancer cell proliferation, migration, and invasion, and induced EMT by activating the TLR4/Myd88/NF-κB pathway. These results reveal that Bacteroides are closely associated with esophageal cancer progression through a higher inflammatory response level and signaling pathway activation that are both common to inflammation and tumors induced by LPS, providing a new biological target for esophageal cancer prevention or treatment.


Assuntos
Transição Epitelial-Mesenquimal , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Lipopolissacarídeos , Fator 88 de Diferenciação Mieloide , NF-kappa B , Transdução de Sinais , Receptor 4 Toll-Like , Receptor 4 Toll-Like/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Animais , NF-kappa B/metabolismo , Humanos , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/microbiologia , Camundongos , Carcinoma de Células Escamosas do Esôfago/metabolismo , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/microbiologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Linhagem Celular Tumoral , Invasividade Neoplásica , Inflamação/metabolismo , Inflamação/patologia , Bacteroidetes , Microbioma Gastrointestinal , Movimento Celular/efeitos dos fármacos , Masculino , Metástase Neoplásica , Proliferação de Células , Feminino
7.
Cancer Immunol Immunother ; 73(8): 156, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834869

RESUMO

BACKGROUND: Ubiquitin-specific proteases family is crucial to host immunity against pathogens. However, the correlations between USP21 and immunosurveillance and immunotherapy for colorectal cancer (CRC) have not been reported. METHODS: The differential expression of USP21 between CRC tissues and normal tissues was analyzed using multiple public databases. Validation was carried out in clinical samples through qRT-PCR and IHC. The correlation between USP21 and the prognosis, as well as clinical pathological characteristics of CRC patients, was investigated. Moreover, cell models were established to assess the influence of USP21 on CRC growth and progression, employing CCK-8 assays, colony formation assays, and wound-healing assays. Subsequently, gene set variation analysis (GSVA) was used to explore the potential biological functions of USP21 in CRC. The study also examined the impact of USP21 on cytokine levels and immune cell infiltration in the tumor microenvironment (TME). Finally, the effect of USP21 on the response to immunotherapy and chemotherapy in CRC was analyzed. RESULTS: The expression of USP21 was significantly upregulated in CRC. High USP21 is correlated with poor prognosis in CRC patients and facilitates the proliferation and migration capacities of CRC cells. GSVA indicated an association between low USP21 and immune activation. Moreover, low USP21 was linked to an immune-activated TME, characterized by high immune cell infiltration. Importantly, CRC with low USP21 exhibited higher tumor mutational burden, high PD-L1 expression, and better responsiveness to immunotherapy and chemotherapeutic drugs. CONCLUSION: This study revealed the role of USP21 in TME, response to therapy, and clinical prognosis in CRC, which provided novel insights for the therapeutic application in CRC.


Assuntos
Neoplasias Colorretais , Microambiente Tumoral , Ubiquitina Tiolesterase , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Microambiente Tumoral/imunologia , Prognóstico , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Masculino , Feminino , Proliferação de Células , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-Idade , Imunoterapia/métodos
8.
Mol Med ; 30(1): 75, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834947

RESUMO

BACKGROUND: Liver kinase B1 (LKB1) is frequently mutated in lung adenocarcinoma, and its loss contributes to tumor progression. METHODS: To identify LKB1 downstream genes that promote lung adenocarcinoma aggressiveness, we performed bioinformatical analysis using publicly available datasets. RESULTS: Rab3B was upregulated in LKB1-depleted lung adenocarcinoma cells and suppressed by LKB1 overexpression. CREB protein was enriched at the promoter of Rab3B in lung cancer cells. Silencing of CREB abrogated the upregulation of Rab3B upon LKB1 loss. Immunohistochemistry revealed the elevated expression of Rab3B in lung adenocarcinomas relative to adjacent normal tissues. Upregulation of Rab3B was significantly associated with lymph node metastasis, advanced tumor stage, and reduced overall survival in lung adenocarcinoma patients. Knockdown of Rab3B suppressed and overexpression of Rab3B promoted the proliferation, colony formation, and migration of lung adenocarcinoma cells in vitro. In a mouse xenograft model, Rab3B depletion restrained and Rab3B overexpression augmented the growth of lung adenocarcinoma tumors. Mechanistically, Rab3B interacted with DDX6 and enhanced its protein stability. Ectopic expression of DDX6 significantly promoted the proliferation, colony formation, and migration of lung adenocarcinoma cells. DDX6 knockdown phenocopied the effects of Rab3B depletion on lung adenocarcinoma cells. Additionally, DDX6 overexpression partially rescued the aggressive phenotype of Rab3B-depleted lung adenocarcinoma cells. CONCLUSION: LKB1 deficiency promotes Rab3B upregulation via a CREB-dependent manner. Rab3B interacts with and stabilizes DDX6 protein to accelerate lung adenocarcinoma progression. The Rab3B-DDX6 axis may be potential therapeutic target for lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão , RNA Helicases DEAD-box , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Humanos , Animais , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Linhagem Celular Tumoral , RNA Helicases DEAD-box/metabolismo , RNA Helicases DEAD-box/genética , Proliferação de Células , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Movimento Celular/genética , Estabilidade Proteica , Feminino , Masculino , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Quinases Proteína-Quinases Ativadas por AMP/genética
9.
Mol Cancer ; 23(1): 116, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822351

RESUMO

BACKGROUND: Elevated evidence suggests that the SENPs family plays an important role in tumor progression. However, the role of SENPs in AML remains unclear. METHODS: We evaluated the expression pattern of SENP1 based on RNA sequencing data obtained from OHSU, TCGA, TARGET, and MILE datasets. Clinical samples were used to verify the expression of SENP1 in the AML cells. Lentiviral vectors shRNA and sgRNA were used to intervene in SENP1 expression in AML cells, and the effects of SENP1 on AML proliferation and anti-apoptosis were detected using in vitro and in vivo models. Chip-qPCR, MERIP-qPCR, CO-IP, RNA pulldown, and dual-luciferase reporter gene assays were used to explore the regulatory mechanisms of SNEP1 in AML. RESULTS: SENP1 was significantly upregulated in high-risk AML patients and closely related to poor prognosis. The AKT/mTOR signaling pathway is a key downstream pathway that mediates SENP1's regulation of AML proliferation and anti-apoptosis. Mechanistically, the CO-IP assay revealed binding between SENP1 and HDAC2. SUMO and Chip-qPCR assays suggested that SENP1 can desumoylate HDAC2, which enhances EGFR transcription and activates the AKT pathway. In addition, we found that IGF2BP3 expression was upregulated in high-risk AML patients and was positively correlated with SENP1 expression. MERIP-qPCR and RIP-qPCR showed that IGF2BP3 binds SENP1 3-UTR in an m6A manner, enhances SENP1 expression, and promotes AKT pathway conduction. CONCLUSIONS: Our findings reveal a distinct mechanism of SENP1-mediated HDAC2-AKT activation and establish the critical role of the IGF2BP3/SENP1signaling axis in AML development.


Assuntos
Adenosina , Proliferação de Células , Cisteína Endopeptidases , Histona Desacetilase 2 , Leucemia Mieloide Aguda , Proteínas Proto-Oncogênicas c-akt , Proteínas de Ligação a RNA , Sumoilação , Animais , Feminino , Humanos , Masculino , Camundongos , Adenosina/análogos & derivados , Adenosina/metabolismo , Apoptose , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Cisteína Endopeptidases/metabolismo , Cisteína Endopeptidases/genética , Progressão da Doença , Regulação Leucêmica da Expressão Gênica , Histona Desacetilase 2/metabolismo , Histona Desacetilase 2/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Exp Clin Cancer Res ; 43(1): 154, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38822363

RESUMO

BACKGROUND: RNA modifications of transfer RNAs (tRNAs) are critical for tRNA function. Growing evidence has revealed that tRNA modifications are related to various disease processes, including malignant tumors. However, the biological functions of methyltransferase-like 1 (METTL1)-regulated m7G tRNA modifications in breast cancer (BC) remain largely obscure. METHODS: The biological role of METTL1 in BC progression were examined by cellular loss- and gain-of-function tests and xenograft models both in vitro and in vivo. To investigate the change of m7G tRNA modification and mRNA translation efficiency in BC, m7G-methylated tRNA immunoprecipitation sequencing (m7G tRNA MeRIP-seq), Ribosome profiling sequencing (Ribo-seq), and polysome-associated mRNA sequencing were performed. Rescue assays were conducted to decipher the underlying molecular mechanisms. RESULTS: The tRNA m7G methyltransferase complex components METTL1 and WD repeat domain 4 (WDR4) were down-regulated in BC tissues at both the mRNA and protein levels. Functionally, METTL1 inhibited BC cell proliferation, and cell cycle progression, relying on its enzymatic activity. Mechanistically, METTL1 increased m7G levels of 19 tRNAs to modulate the translation of growth arrest and DNA damage 45 alpha (GADD45A) and retinoblastoma protein 1 (RB1) in a codon-dependent manner associated with m7G. Furthermore, in vivo experiments showed that overexpression of METTL1 enhanced the anti-tumor effectiveness of abemaciclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor. CONCLUSION: Our study uncovered the crucial tumor-suppressive role of METTL1-mediated tRNA m7G modification in BC by promoting the translation of GADD45A and RB1 mRNAs, selectively blocking the G2/M phase of the cell cycle. These findings also provided a promising strategy for improving the therapeutic benefits of CDK4/6 inhibitors in the treatment of BC patients.


Assuntos
Neoplasias da Mama , Metiltransferases , RNA de Transferência , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Camundongos , Animais , Metiltransferases/metabolismo , Metiltransferases/genética , RNA de Transferência/genética , RNA de Transferência/metabolismo , Metilação , Linhagem Celular Tumoral , Proliferação de Células , Carcinogênese/genética , Pontos de Checagem do Ciclo Celular , Biossíntese de Proteínas , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus
11.
J Exp Clin Cancer Res ; 43(1): 156, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38822429

RESUMO

BACKGROUND: Platinum-based chemotherapy regimens are a mainstay in the management of ovarian cancer (OC), but emergence of chemoresistance poses a significant clinical challenge. The persistence of ovarian cancer stem cells (OCSCs) at the end of primary treatment contributes to disease recurrence. Here, we hypothesized that the extracellular matrix protects CSCs during chemotherapy and supports their tumorigenic functions by activating integrin-linked kinase (ILK), a key enzyme in drug resistance. METHODS: TCGA datasets and OC models were investigated using an integrated proteomic and gene expression analysis and examined ILK for correlations with chemoresistance pathways and clinical outcomes. Canonical Wnt pathway components, pro-survival signaling, and stemness were examined using OC models. To investigate the role of ILK in the OCSC-phenotype, a novel pharmacological inhibitor of ILK in combination with carboplatin was utilized in vitro and in vivo OC models. RESULTS: In response to increased fibronectin secretion and integrin ß1 clustering, aberrant ILK activation supported the OCSC phenotype, contributing to OC spheroid proliferation and reduced response to platinum treatment. Complexes formed by ILK with the Wnt receptor frizzled 7 (Fzd7) were detected in tumors and correlated with metastatic progression. Moreover, TCGA datasets confirmed that combined expression of ILK and Fzd7 in high grade serous ovarian tumors is correlated with reduced response to chemotherapy and poor patient outcomes. Mechanistically, interaction of ILK with Fzd7 increased the response to Wnt ligands, thereby amplifying the stemness-associated Wnt/ß-catenin signaling. Notably, preclinical studies showed that the novel ILK inhibitor compound 22 (cpd-22) alone disrupted ILK interaction with Fzd7 and CSC proliferation as spheroids. Furthermore, when combined with carboplatin, this disruption led to sustained AKT inhibition, apoptotic damage in OCSCs and reduced tumorigenicity in mice. CONCLUSIONS: This "outside-in" signaling mechanism is potentially actionable, and combined targeting of ILK-Fzd7 may lead to new therapeutic approaches to eradicate OCSCs and improve patient outcomes.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Receptores Frizzled , Células-Tronco Neoplásicas , Neoplasias Ovarianas , Proteínas Serina-Treonina Quinases , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Camundongos , Animais , Receptores Frizzled/metabolismo , Receptores Frizzled/genética , Linhagem Celular Tumoral , Platina/farmacologia , Platina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Proliferação de Células/efeitos dos fármacos
12.
Mol Biol Rep ; 51(1): 703, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38822881

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer morbidity and mortality worldwide, and new diagnostic markers are urgently needed. We aimed to investigate the mechanism by which hsa_circ_0096157 regulates autophagy and cisplatin (DDP) resistance in NSCLC. METHODS: A549 cells were treated with DDP (0 µg/mL or 3 µg/mL). Then, the autophagy activator rapamycin (200 nm) was applied to the A549/DDP cells. Moreover, hsa_circ_0096157 and Nrf2 were knocked down, and Nrf2 was overexpressed in A549/DDP cells. The expression of Hsa_circ_0096157, the Nrf2/ARE pathway-related factors Nrf2, HO-1, and NQO1, and the autophagy-related factors LC3, Beclin-1, and p62 was evaluated by qRT‒PCR or western blotting. Autophagosomes were detected through TEM. An MTS assay was utilized to measure cell proliferation. The associated miRNA levels were also tested by qRT‒PCR. RESULTS: DDP (3 µg/mL) promoted hsa_circ_0096157, LC3 II/I, and Beclin-1 expression and decreased p62 expression. Knocking down hsa_circ_0096157 resulted in the downregulation of LC3 II/I and Beclin-1 expression, upregulation of p62 expression, and decreased proliferation. Rapamycin reversed the effect of interfering with hsa_circ_0096157. Keap1 expression was lower, and Nrf2, HO-1, and NQO1 expression was greater in the A549/DDP group than in the A549 group. HO-1 expression was repressed after Nrf2 interference. In addition, activation of the Nrf2/ARE pathway promoted autophagy in A549/DDP cells. Moreover, hsa_circ_0096157 activated the Nrf2/ARE pathway. The silencing of hsa_circ_0096157 reduced Nrf2 expression by releasing miR-142-5p or miR-548n. Finally, we found that hsa_circ_0096157 promoted A549/DDP cell autophagy by activating the Nrf2/ARE pathway. CONCLUSION: Knockdown of hsa_circ_0096157 inhibits autophagy and DDP resistance in NSCLC cells by downregulating the Nrf2/ARE signaling pathway.


Assuntos
Autofagia , Carcinoma Pulmonar de Células não Pequenas , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Fator 2 Relacionado a NF-E2 , Transdução de Sinais , Humanos , Cisplatino/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Autofagia/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Células A549 , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , MicroRNAs/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Linhagem Celular Tumoral , Elementos de Resposta Antioxidante/genética , Antineoplásicos/farmacologia , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo
13.
Chem Biol Drug Des ; 103(6): e14557, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38825578

RESUMO

Recently, natural compounds such as quercetin have gained an increasing amount of attention in treating breast cancer. However, the exact mechanisms responsible for the antiproliferative functions of quercetin are not completely understood. Therefore, we aimed to examine quercetin impacts on breast cancer cell proliferation and survival and the involvement of PI3K/Akt/mTOR pathway. Breast cancer MDA-MB-231 and MCF-7 cells were exposed to quercetin, and cell proliferation was assessed by MTT assay. ELISA was applied to evaluate cell apoptosis. The expression levels of apoptotic mediators such as caspase-3, Bcl-2, Bax and PI3K, Akt, mTOR, and PTEN were assessed via qRT-PCR and western blot. We found that quercetin suppressed dose dependently cell growth capacity in MDA-MB-231 and MCF-7 cells. In addition, quercetin treatment increase apoptosis in both cells lines via modulating the pro- and antiapoptotic markers. Quercetin upregulated PTEN and downregulated PI3K, Akt, and mTOR, hence suppressing this signaling pathway in cells. In conclusion, we showed antiproliferative and pro-apoptotic function of quercetin in breast cancer cell lines, which is mediated by targeting and suppressing PI3K/Akt/mTOR signal transduction.


Assuntos
Apoptose , Neoplasias da Mama , Proliferação de Células , Sobrevivência Celular , PTEN Fosfo-Hidrolase , Proteínas Proto-Oncogênicas c-akt , Quercetina , Transdução de Sinais , Serina-Treonina Quinases TOR , Quercetina/farmacologia , Humanos , Serina-Treonina Quinases TOR/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células MCF-7 , Fosfatidilinositol 3-Quinases/metabolismo
14.
Drug Dev Res ; 85(4): e22218, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38825827

RESUMO

We report herein, the design and synthesis of benzimidazole-oxadiazole derivatives as new inhibitors for vascular endothelial growth factor receptor-2 (VEGFR-2). The designed members were assessed for their in vitro anticancer activity against three cancer cell lines and two normal cell lines; A549, MCF-7, PANC-1, hTERT-HPNE and CCD-19Lu. Compounds 4c and 4d were found to be the most effective compounds against three cancer cell lines. Compounds 4c and 4d were then tested for their in vitro VEGFR-2 inhibitory activity, safety profiles, and selectivity indices using the normal hTERT-HPNE and CCD-19Lu cell lines. It was determined that compound 4c was the most effective and safe member of the produced chemical family. Vascular endothelial growth factor A (VEGFA) immunolocalizations of compounds 4c and 4d were evaluated relative to control by VEGFA immunofluorescence staining. Compounds 4c and 4d inhibited VEGFR-2 enzyme with half-maximal inhibitory concentration values of 0.475 ± 0.021 and 0.618 ± 0.028 µM, respectively. Molecular docking of the target compounds was carried out in the active site of VEGFR-2 (Protein Data Bank: 4ASD).


Assuntos
Antineoplásicos , Benzimidazóis , Simulação de Acoplamento Molecular , Oxidiazóis , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Oxidiazóis/farmacologia , Oxidiazóis/química , Oxidiazóis/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/farmacologia , Benzimidazóis/química , Benzimidazóis/síntese química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos
15.
Zhonghua Bing Li Xue Za Zhi ; 53(6): 592-597, 2024 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-38825905

RESUMO

Objective: To investigate the expression of DARS2 and its clinical significance in colorectal cancer. Methods: In this study, bioinformatics tools, especially gene expression profile interactive analysis 2 (GEPIA2), were used to conduct an in-depth analysis of DARS2 expression in colorectal cancer tissues. Immunohistochemical staining was carried out in 108 colorectal cancer specimens and 30 normal colorectal tissues obtained from the First Affiliated Hospital of Nanchang University, Nanchang, China. Colorectal cancer cell lines (HCT116 and SW480) were transfected with small interfering RNA (siRNA) and DARS2 overexpression plasmid to examine the effects of DARS2 knockdown and overexpression on cell function. To assess the effects on cell function, CCK8 and transwell migration assays were used to assess proliferation and cell motility, respectively. Additionally, protein immunoblotting was employed to scrutinize the expression of proteins associated with the epithelial-mesenchymal transition of colorectal cancer cells. Results: DARS2 exhibited a pronounced upregulation in expression within colorectal cancer tissues compared to their normal epithelial counterparts. Furthermore, DARS2 expression was higher in colorectal cancer of stage Ⅲ-Ⅳ than those of stage Ⅰ-Ⅱ, exhibiting a significant correlation with N staging, M staging, and pathological staging (P<0.05). Kaplan-Meier analyses showed a decreased overall survival rate in colorectal cancer with DARS2 expression compared to those without DARS2 expression (P<0.05). In the siRNA transfection group, there was a significant reduction in cell proliferation and migration (P<0.01 and P<0.05, respectively). Conversely, the transfection of DARS2 overexpression plasmids substantially increased both cell proliferation and migration (P<0.05). Additionally, immunoblotting revealed that DARS2 knockdown led to an upregulation of E-cadherin expression and a downregulation of N-cadherin and vimentin expression. In contrast, DARS2 overexpression resulted in increased N-cadherin and vimentin expression, coupled with reduction in E-cadherin expression. Conclusions: There is a strong association between DARS2 expression and colorectal cancer progression. Silencing DARS2 inhibits cell proliferation and migration, exerting a discernible influence on the epithelial-mesenchymal transition process.


Assuntos
Movimento Celular , Proliferação de Células , Neoplasias Colorretais , Transição Epitelial-Mesenquimal , RNA Interferente Pequeno , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , RNA Interferente Pequeno/genética , Linhagem Celular Tumoral , Vimentina/metabolismo , Vimentina/genética , Caderinas/metabolismo , Caderinas/genética , Taxa de Sobrevida , Células HCT116 , Estadiamento de Neoplasias , Regulação para Cima , Regulação Neoplásica da Expressão Gênica , Relevância Clínica
16.
Reprod Domest Anim ; 59(6): e14628, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38828525

RESUMO

This study aimed to investigate the impact of the epidermal growth factor receptor ligands amphiregulin (AREG) and epiregulin (EREG) on the fundamental functions of feline ovarian granulosa cells. Granulosa cells isolated from feline ovaries were incubated with AREG and EREG (0, 0.1, 1 or 10 ng/mL). The effects of these growth factors on cell viability, proliferation (assessed through BrdU incorporation), nuclear apoptosis (evaluated through nuclear DNA fragmentation) and the release of progesterone and estradiol were determined using Cell Counting Kit-8 assays, BrdU analysis, TUNEL assays and ELISAs, respectively. Both AREG and EREG increased cell viability, proliferation and steroid hormone release and reduced apoptosis. The present findings suggest that these epidermal growth factor receptor ligands may serve as physiological stimulators of feline ovarian cell functions.


Assuntos
Anfirregulina , Apoptose , Proliferação de Células , Sobrevivência Celular , Epirregulina , Células da Granulosa , Animais , Gatos , Feminino , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Anfirregulina/metabolismo , Anfirregulina/genética , Epirregulina/metabolismo , Epirregulina/genética , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progesterona/metabolismo , Progesterona/farmacologia , Estradiol/metabolismo , Estradiol/farmacologia , Células Cultivadas
17.
J Cell Mol Med ; 28(11): e18406, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38822457

RESUMO

Increasing evidence has shown that homologous recombination (HR) and metabolic reprogramming are essential for cellular homeostasis. These two processes are independent as well as closely intertwined. Nevertheless, they have rarely been reported in lung adenocarcinoma (LUAD). We analysed the genomic, immune microenvironment and metabolic microenvironment features under different HR activity states. Using cell cycle, EDU and cell invasion assays, we determined the impacts of si-SHFM1 on the LUAD cell cycle, proliferation and invasion. The levels of isocitrate dehydrogenase (IDH) and α-ketoglutarate dehydrogenase (α-KGDH) were determined by ELISA in the NC and si-SHFM1 groups of A549 cells. Finally, cell samples were used to extract metabolites for HPIC-MS/MS to analyse central carbon metabolism. We found that high HR activity was associated with a poor prognosis in LUAD, and HR was an independent prognostic factor for TCGA-LUAD patients. Moreover, LUAD samples with a high HR activity presented low immune infiltration levels, a high degree of genomic instability, a good response status to immune checkpoint blockade therapy and a high degree of drug sensitivity. The si-SHFM1 group presented a significantly higher proportion of cells in the G0/G1 phase, lower levels of DNA replication, and significantly lower levels of cell migration and both TCA enzymes. Our current results indicated that there is a strong correlation between HR and the TCA cycle in LUAD. The TCA cycle can promote SHFM1-mediated HR in LUAD, raising their activities, which can finally result in a poor prognosis and impair immunotherapeutic efficacy.


Assuntos
Adenocarcinoma de Pulmão , Ciclo do Ácido Cítrico , Recombinação Homóloga , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Prognóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Proliferação de Células , Microambiente Tumoral , Linhagem Celular Tumoral , Ciclo Celular/genética , Reprogramação Celular/genética , Feminino , Células A549 , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Movimento Celular , Complexo Cetoglutarato Desidrogenase/metabolismo , Complexo Cetoglutarato Desidrogenase/genética , Masculino , Regulação Neoplásica da Expressão Gênica , Reprogramação Metabólica
18.
Pak J Pharm Sci ; 37(2(Special)): 443-450, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38822548

RESUMO

Gastric cancer remains a global health concern, driving the exploration of natural products with anticancer potential. This study investigated the antiproliferative activity and chemical composition of a 70% ethanolic extract from Melissa officinalis L. against human gastric cancer cells. The extract was prepared and evaluated for total phenolic content, antioxidant capacity and flavonoid content. The MTT test checked how well it stopped the growth of human gastric adenocarcinoma (AGS) and normal dermal fibroblast (HDF) cells. Data analysis (SPSS Statistics) determined viable cell percentages and performed regression analysis (p<0.05). The extract exhibited significant antiproliferative activity against AGS cells compared to normal cells (p<0.05), with decreasing IC50 values (564.3, 258.0 and 122.5 µg/ml) over 24, 48 and 72 hours. It also displayed antioxidant activity (IC50=16.8±1.41µg/ml) and contained substantial phenolics (225.76±4.1 mg GAE/g) and flavonoids (22.36±2.6 mg RUT/g). This study suggests the 70% ethanolic extract of M. officinalis effectively suppresses AGS cell growth and possesses promising antioxidant properties, highlighting its potential as a natural source of anticancer and antioxidant agents, deserving further investigation.


Assuntos
Adenocarcinoma , Antineoplásicos Fitogênicos , Antioxidantes , Proliferação de Células , Melissa , Fenóis , Extratos Vegetais , Neoplasias Gástricas , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Melissa/química , Fenóis/farmacologia , Fenóis/análise , Linhagem Celular Tumoral , Antioxidantes/farmacologia , Antioxidantes/isolamento & purificação , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Flavonoides/farmacologia , Flavonoides/análise , Sobrevivência Celular/efeitos dos fármacos
19.
Mol Biol Rep ; 51(1): 701, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38822973

RESUMO

BACKGROUND: Disabled 2 (DAB2) is a multifunctional protein that has emerged as a critical component in the regulation of tumor growth. Its dysregulation is implicated in various types of cancer, underscoring its importance in understanding the molecular mechanisms underlying tumor development and progression. This review aims to unravel the intricate molecular mechanisms by which DAB2 exerts its tumor-suppressive functions within cancer signaling pathways. METHODS AND RESULTS: We conducted a comprehensive review of the literature focusing on the structure, expression, physiological functions, and tumor-suppressive roles of DAB2. We provide an overview of the structure, expression, and physiological functions of DAB2. Evidence supporting DAB2's role as a tumor suppressor is explored, highlighting its ability to inhibit cell proliferation, induce apoptosis, and modulate key signaling pathways involved in tumor suppression. The interaction between DAB2 and key oncogenes is examined, elucidating the interplay between DAB2 and oncogenic signaling pathways. We discuss the molecular mechanisms underlying DAB2-mediated tumor suppression, including its involvement in DNA damage response and repair, regulation of cell cycle progression and senescence, and modulation of epithelial-mesenchymal transition (EMT). The review explores the regulatory networks involving DAB2, covering post-translational modifications, interactions with other tumor suppressors, and integration within complex signaling networks. We also highlight the prognostic significance of DAB2 and its role in pre-clinical studies of tumor suppression. CONCLUSION: This review provides a comprehensive understanding of the molecular mechanisms by which DAB2 exerts its tumor-suppressive functions. It emphasizes the significance of DAB2 in cancer signaling pathways and its potential as a target for future therapeutic interventions.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas Reguladoras de Apoptose , Neoplasias , Transdução de Sinais , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Animais , Transição Epitelial-Mesenquimal/genética , Progressão da Doença , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Regulação Neoplásica da Expressão Gênica , Proliferação de Células/genética , Carcinogênese/genética , Carcinogênese/metabolismo , Apoptose/genética
20.
Int Heart J ; 65(3): 506-516, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38825495

RESUMO

Hydrogen sulfide (H2S) has been identified as a novel gasotransmitter and a substantial antioxidant that can activate various cellular targets to regulate physiological and pathological processes in mammals. However, under physiological conditions, it remains unclear whether it is involved in regulating cardiomyocyte (CM) proliferation during postnatal development in mice. This study mainly aimed to evaluate the role of H2S in postnatal CM proliferation and its regulating molecular mechanisms. We found that sodium hydrosulfide (NaHS, the most widely used H2S donor, 50-200 µM) increased neonatal mouse primary CM proliferation in a dose-dependent manner in vitro. Consistently, exogenous administration of H2S also promoted CM proliferation and increased the total number of CMs at postnatal 7 and 14 days in vivo. Moreover, we observed that the protein expression of SIRT1 was significantly upregulated after NaHS treatment. Inhibition of SIRT1 with EX-527 or si-SIRT1 decreased CM proliferation, while enhancement of the activation of SIRT1 with SRT1720 promoted CM proliferation. Meanwhile, pharmacological and genetic blocking of SIRT1 repressed the effect of NaHS on CM proliferation. Taken together, these results reveal that H2S plays a promotional role in proliferation of CMs in vivo and in vitro and SIRT1 is required for H2S-mediated CM proliferation, which indicates that H2S may be a potential modulator for heart development in postnatal time window.


Assuntos
Proliferação de Células , Sulfeto de Hidrogênio , Miócitos Cardíacos , Transdução de Sinais , Sirtuína 1 , Regulação para Cima , Animais , Sirtuína 1/metabolismo , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Proliferação de Células/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Camundongos , Transdução de Sinais/efeitos dos fármacos , Animais Recém-Nascidos , Células Cultivadas , Camundongos Endogâmicos C57BL , Sulfetos
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