Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 8.271
Filtrar
1.
Nat Commun ; 13(1): 4116, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35840573

RESUMO

AMEERA-1 is a Phase 1/2 open-label single-arm study evaluating once-daily (QD) amcenestrant, an orally bioavailable selective estrogen receptor (ER) degrader, in postmenopausal women with ER+/HER2- advanced breast cancer (NCT03284957), who were mostly heavily pretreated (including targeted therapies and fulvestrant). In the dose escalation phase (Part A: n = 16), patients received amcenestrant 20-600 mg QD. Based on absence of dose-limiting toxicities, paired functional 18F-fluoroestradiol positron emission tomography, and pharmacokinetics, 400 mg QD was selected as recommended Phase 2 dose (RP2D) for the dose expansion phase (Part B: n = 49). No Grade ≥3 treatment-related adverse events or clinically significant cardiac/eye toxicities were reported. The Part B primary endpoint, confirmed objective response rate (ORR) was 3/45 at the interim analysis and 5/46 (10.9%) at the final analysis. The overall clinical benefit rate (CBR) was 13/46 (28.3%). CBRs among patients with baseline wild-type and mutated ESR1 were 9/26 (34.6%) and 4/19 (21.1%), respectively. Paired tumor biopsy and cell-free DNA analyses revealed ER inhibition and degradation, and a reduction in detectable ESR1 mutations, including Y537S. In conclusion, amcenestrant at RP2D of 400 mg QD for monotherapy is well-tolerated with no dose-limiting toxicities, and demonstrates preliminary antitumor activity irrespective of baseline ESR1 mutation status.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Antagonistas de Estrogênios/uso terapêutico , Feminino , Fulvestranto , Humanos , Mutação , Pós-Menopausa , Receptor ErbB-2/genética
2.
Breast Cancer Res ; 24(1): 52, 2022 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-35850772

RESUMO

BACKGROUND: Targeting vulnerabilities of cancer cells by inhibiting key regulators of cell proliferation or survival represents a promising way to overcome resistance to current therapies. In breast cancer (BC), resistance to endocrine therapy results from constitutively active or aberrant estrogen receptor alpha (ERα) signaling to the genome. Targeting components of the ERα pathway in these tumors represents, therefore, a rational way toward effective new treatments. Interaction proteomics identified several proteins associated with ERα in BC cells, including epigenetic complexes controlling gene transcription comprising the scaffold protein menin and the histone methyltransferase Dot1L. METHODS: We combined chromatin immunoprecipitation, transcriptome sequencing, siRNA-mediated gene knockdown (kd), pharmacological inhibition coupled to cellular and functional assays and interaction proteomics in antiestrogen (AE)-sensitive and AE-resistant human BC cell models to: map menin and Dot1L chromatin localization, search for their common and specific target genes, measure the effects of single or combinatorial knockdown or pharmacological inhibition of these proteins on cell proliferation and survival, and characterize their nuclear interactomes. RESULTS: Dot1L and menin associate in MCF-7 cells chromatin, where they co-localize in a significant fraction of sites, resulting in co-regulation of genes involved, among others, in estrogen, p53, HIF1α and death receptor signaling, regulation of cell cycle and epithelial-to-mesenchymal transition. Specific inhibitors of the two factors synergize with each other for inhibition of cell proliferation of AE (tamoxifen or fulvestrant)-sensitive and AE-resistant BC cells. Menin and Dot1L interactomes share a sizeable fraction of their nuclear partners, the majority being known BC fitness genes. Interestingly, these include B-WICH and WINAC complexes that share BAZ1B, a bromodomain protein comprising a tyrosine-protein kinase domain playing a central role in chromatin remodeling and transcriptional regulation. BAZ1B kd caused significant inhibition of ERα expression, proliferation and transcriptome changes resulting in inhibition of estrogen, myc, mTOR, PI3K and AKT signaling and metabolic pathways in AE-sensitive and AE-resistant BC cells. CONCLUSIONS: Identification of a functional interplay between ERα, Dot1L, menin and BAZ1B and the significant effects of their co-inhibition on cell proliferation and survival in cell models of endocrine therapy-resistant BC reveal a new therapeutic vulnerability of these aggressive diseases.


Assuntos
Neoplasias da Mama , Receptor alfa de Estrogênio , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Cromatina/genética , Resistencia a Medicamentos Antineoplásicos/genética , Antagonistas de Estrogênios/uso terapêutico , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/metabolismo , Estrogênios , Feminino , Regulação Neoplásica da Expressão Gênica , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/farmacologia , Humanos , Células MCF-7 , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Tirosina Quinases/farmacologia , Fatores de Transcrição
3.
Oncogene ; 41(29): 3705-3718, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35732800

RESUMO

Patients with estrogen receptor-positive (ER+) breast cancer, the most common subtype, remain at risk for lethal metastatic disease years after diagnosis. Recurrence arises partly because tumor cells in bone marrow become resistant to estrogen-targeted therapy. Here, we utilized a co-culture model of bone marrow mesenchymal stem cells (MSCs) and ER+ breast cancer cells to recapitulate interactions of cancer cells in bone marrow niches. ER+ breast cancer cells in direct contact with MSCs acquire cancer stem-like (CSC) phenotypes with increased resistance to standard antiestrogenic drugs. We confirmed that co-culture with MSCs increased labile iron in breast cancer cells, a phenotype associated with CSCs and disease progression. Clinically approved iron chelators and in-house lysosomal iron-targeting compounds restored sensitivity to antiestrogenic therapy. These findings establish iron modulation as a mechanism to reverse MSC-induced drug resistance and suggest iron modulation in combination with estrogen-targeted therapy as a promising, translatable strategy to treat ER+ breast cancer.


Assuntos
Células-Tronco Mesenquimais , Neoplasias , Linhagem Celular Tumoral , Resistência a Medicamentos , Resistencia a Medicamentos Antineoplásicos , Antagonistas de Estrogênios/farmacologia , Estrogênios/farmacologia , Ferro , Receptores de Estrogênio
4.
Elife ; 112022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35575456

RESUMO

Chemical manipulation of estrogen receptor alpha ligand binding domain structural mobility tunes receptor lifetime and influences breast cancer therapeutic activities. Selective estrogen receptor modulators (SERMs) extend estrogen receptor alpha (ERα) cellular lifetime/accumulation. They are antagonists in the breast but agonists in the uterine epithelium and/or in bone. Selective estrogen receptor degraders/downregulators (SERDs) reduce ERα cellular lifetime/accumulation and are pure antagonists. Activating somatic ESR1 mutations Y537S and D538G enable resistance to first-line endocrine therapies. SERDs have shown significant activities in ESR1 mutant setting while few SERMs have been studied. To understand whether chemical manipulation of ERα cellular lifetime and accumulation influences antagonistic activity, we studied a series of methylpyrollidine lasofoxifene (Laso) derivatives that maintained the drug's antagonistic activities while uniquely tuning ERα cellular accumulation. These molecules were examined alongside a panel of antiestrogens in live cell assays of ERα cellular accumulation, lifetime, SUMOylation, and transcriptional antagonism. High-resolution x-ray crystal structures of WT and Y537S ERα ligand binding domain in complex with the methylated Laso derivatives or representative SERMs and SERDs show that molecules that favor a highly buried helix 12 antagonist conformation achieve the greatest transcriptional suppression activities in breast cancer cells harboring WT/Y537S ESR1. Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles.


Assuntos
Neoplasias da Mama , Receptor alfa de Estrogênio/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Ligantes , Mutação , Pirrolidinas , Moduladores Seletivos de Receptor Estrogênico/química , Tetra-Hidronaftalenos
5.
J Med Chem ; 65(7): 5724-5750, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35357160

RESUMO

Endocrine therapies in the treatment of early and metastatic estrogen receptor α positive (ERα+) breast cancer (BC) are greatly limited by de novo and acquired resistance. Selective estrogen receptor degraders (SERDs) like fulvestrant provide new strategies for endocrine therapy combinations due to unique mechanisms. Herein, we disclose our structure-based optimization of LSZ102 by replacing 6-hydroxybenzothiophene with 6H-thieno[2,3-e]indazole. Subsequent acrylic acid degron modifications led us to identify compound 40 as the preferred candidate. In general, compound 40 showed much better pharmacological profiles than the lead LSZ102, exhibiting growth inhibition of wild-type or tamoxifen-resistant MCF-7 cells, potent ERα degradation, together with superior pharmacokinetic properties, directional target tissue distribution including the brain, and robust antitumor efficacy in the mice breast cancer xenograft model. Currently, 40 is being evaluated in preclinical trials.


Assuntos
Antineoplásicos , Neoplasias da Mama , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Indazóis/farmacologia , Indazóis/uso terapêutico , Células MCF-7 , Camundongos , Receptores de Estrogênio/metabolismo , Tiofenos
6.
Sci Rep ; 12(1): 1643, 2022 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-35102224

RESUMO

The aim of the study was to compare 3 blood sampling methods, including capillary blood sampling, for determining Tamoxifen (TAM), Z-endoxifen (END), and 4-hydroxytamoxifen (4HT) concentrations. High performance liquid chromatography-mass spectrometry was used to quantify concentrations of TAM, END, and 4HT in plasma, venous blood, and capillary blood samples of 16 participants on TAM therapy for breast cancer. The rhelise kit was used for capillary sampling. Calibration curves using 13C-labeled analogs of TAM, END, and 4HT as internal standards were used for quantifications. A capillary sampling kit was used successfully for all participants. Mean TAM concentrations did not differ significantly in the 3 types of samples. Mean END and 4HT concentrations did differ significantly between capillary and venous blood samples, possibly related to photodegradation in the internal standards prior to use or degradation products with chromatographic retention times similar to the metabolites. TAM, END, and 4HT concentrations were relatively stable when stored for 14 days at 8 °C and 20 °C. Therapeutic drug monitoring of TAM using an innovative kit and capillary blood sampling is feasible. Preliminary data from this study will aid in developing a multicenter, randomized clinical trial of personalized TAM dose monitoring and adjustments, with the goal of enhancing the quality-of-life and outcomes of patients with breast cancer.Clinical Trial Identification: EudraCT No 2017-000641-44.


Assuntos
Neoplasias da Mama/sangue , Monitoramento de Medicamentos/instrumentação , Antagonistas de Estrogênios/sangue , Kit de Reagentes para Diagnóstico , Tamoxifeno/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Capilares , Cromatografia Líquida de Alta Pressão , Antagonistas de Estrogênios/uso terapêutico , Estudos de Viabilidade , Feminino , Humanos , Espectrometria de Massas , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Suécia , Tamoxifeno/sangue , Tamoxifeno/uso terapêutico
7.
Methods Mol Biol ; 2418: 187-201, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35119667

RESUMO

The classical estrogen receptor α (ERα) has been a clinical therapeutic target for decades. ERα-targeted drugs have shown great clinical success, in particular as antagonists for the treatment of ERα-positive breast cancers. However, ERα-targeted agonists have also been clinically useful (e.g., for the treatment of osteoporosis). The breast cancer field is regularly identifying novel ERα-binding compounds with the goal of identifying new potential ERα-targeted therapeutics. To determine whether such newly identified ERα-binding compounds have clinical potential, it is important to characterize the estrogenic activity (i.e., both receptor-mediated agonism and/or antagonism) of these compounds. This chapter focuses on methods that allow determination of whether an ERα-binding compound acts as an agonist or antagonist of the receptor and whether the compound induces degradation of the receptor.


Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Neoplasias da Mama/tratamento farmacológico , Estradiol/farmacologia , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/metabolismo , Estrogênios/farmacologia , Feminino , Humanos , Receptores de Estrogênio/metabolismo
8.
Sci Rep ; 12(1): 77, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34996912

RESUMO

Although the function of the BRCA1 gene has been extensively studied, the relationship between BRCA1 gene expression and tumor aggressiveness remains controversial in sporadic breast cancers. Because the BRCA1 protein is known to regulate estrogen signaling, we selected microarray data of ER+ breast cancers from the GEO public repository to resolve previous conflicting findings. The BRCA1 gene expression level in highly proliferative luminal B tumors was shown to be higher than that in luminal A tumors. Survival analysis using a cure model indicated that patients of early ER+ breast cancers with high BRCA1 expression developed rapid distant metastasis. In addition, the proliferation marker genes MKI67 and PCNA, which are characteristic of aggressive tumors, were also highly expressed in patients with high BRCA1 expression. The associations among high BRCA1 expression, high proliferation marker expression, and high risk of distant metastasis emerged in independent datasets, regardless of tamoxifen treatment. Tamoxifen therapy could improve the metastasis-free fraction of high BRCA1 expression patients. Our findings link BRCA1 expression with proliferation and possibly distant metastasis via the ER signaling pathway. We propose a testable hypothesis based on these consistent results and offer an interpretation for our reported associations.


Assuntos
Proteína BRCA1/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Receptores de Estrogênio/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proliferação de Células , Bases de Dados Genéticas , Antagonistas de Estrogênios/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Neoplásica , Prognóstico , Tamoxifeno/uso terapêutico , Fatores de Tempo , Regulação para Cima
9.
Mol Oncol ; 16(1): 148-165, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34392603

RESUMO

Among others, expression levels of programmed cell death 1 ligand 1 (PD-L1) have been explored as biomarkers of the response to immune checkpoint inhibitors in cancer therapy. Here, we present the results of a chemical screen that interrogated how medically approved drugs influence PD-L1 expression. As expected, corticosteroids and inhibitors of Janus kinases were among the top PD-L1 downregulators. In addition, we identified that PD-L1 expression is induced by antiestrogenic compounds. Transcriptomic analyses indicate that chronic estrogen receptor alpha (ERα) inhibition triggers a broad immunosuppressive program in ER-positive breast cancer cells, which is subsequent to their growth arrest and involves the activation of multiple immune checkpoints together with the silencing of the antigen-presenting machinery. Accordingly, estrogen-deprived MCF7 cells are resistant to T-cell-mediated cell killing, in a manner that is independent of PD-L1, but which is reverted by estradiol. Our study reveals that while antiestrogen therapies efficiently limit the growth of ER-positive breast cancer cells, they concomitantly trigger a transcriptional program that favors their immune evasion.


Assuntos
Antígeno B7-H1 , Neoplasias da Mama , Antígeno B7-H1/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Antagonistas de Estrogênios , Estrogênios/farmacologia , Feminino , Humanos , Fenótipo
10.
Expert Opin Ther Pat ; 32(2): 131-151, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34763600

RESUMO

INTRODUCTION: The estrogen receptor (ER) is a clinically validated oncology target with a pivotal role in hormonally driven breast cancer, the most prevalent form of female cancer. Current treatments that directly modulate ER include antagonists (SERMs), such as tamoxifen, and degraders (SERDs), such as fulvestrant which is administered by intramuscular injection. AREAS COVERED: This review covers patent applications that claim estrogen receptor degraders (SERDs) and covalent antagonists (SERCAs) between the period January 2015 to June 2021. A total of 114 patent applications from 23 different applicants are evaluated with stratification into acidic SERDs, basic SERDs, and SERCAs. EXPERT OPINION: The clinical success of fulvestrant in the treatment of ER+ breast cancer has spurred research over the last decade into the discovery and development of novel SERDs, with a particular focus on the discovery of orally bioavailable drugs. This has resulted in a diverse range of candidates entering clinical trials. Although some have faltered in development, a cohort of oral SERDs has generated encouraging efficacy and safety data that has allowed advancement into late stage clinical trials. Data from these trials is eagerly awaited, with these molecules having the potential to offer significant benefits in the treatment of ER+ breast cancer.


Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/uso terapêutico , Receptor alfa de Estrogênio , Feminino , Humanos , Patentes como Assunto , Receptores de Estrogênio/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico
11.
Breast ; 62 Suppl 1: S34-S42, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34903444

RESUMO

Estrogen receptor (ER+) breast cancer is the most frequently diagnosed breast cancer subtype. Currently, adjuvant treatment for early stage disease consists of endocrine therapy, with or without chemotherapy and bone-targeted therapy, delivered in a risk-adapted manner. Despite this multimodal approach, a significant proportion of high risk patients will develop incurable distant recurrences. There is an ongoing need to develop new treatment strategies that address the biologic causes of treatment failure and to identify the individual patients who can benefit from such interventions. Here we review the clinical investigation of targeted and novel therapies, including inhibitors of the PI3K-AKT-mTOR pathway, oral selective estrogen receptor degraders (SERDs), and PARP-inhibitors for the treatment of early ER+ breast cancer. Furthermore, we highlight opportunities in biomarker development to help guide the delivery of escalated adjuvant strategies.


Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Antagonistas de Estrogênios , Feminino , Humanos , Fosfatidilinositol 3-Quinases , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico
12.
J Hazard Mater ; 423(Pt A): 127108, 2022 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-34523467

RESUMO

Mixture toxicity, including agonistic and antagonistic effects, is an unrevealed environmental problem. Estrogenic endocrine disruptors are known to cause adverse effects for aquatic biota, but causative chemicals and their contributions to the total activity in sewage sludge remain unknown. Therefore, advanced analytical methods, a yeast bioassay and mixture toxicity models were concurrently applied for the characterization of 8 selected sludges with delectable estrogenic activity (and 3 sludges with no activity as blanks) out of 25 samples from wastewater treatment plants (WWTPs). The first applied full logistic model adequately explained total activity by considering the concentrations of the monitored compounds. The results showed that the activity was primarily caused by natural estrogens in municipal WWTP sludge. Nevertheless, activity in a sample originating from a car-wash facility was dominantly caused by partial agonists - nonylphenols - and only a model enabling prediction of all dose-response curve parameters of the final mixture curve explained these results. Antiestrogenic effects were negligible, and effect-directed analysis identified the causative chemicals.


Assuntos
Disruptores Endócrinos , Poluentes Químicos da Água , Disruptores Endócrinos/análise , Disruptores Endócrinos/toxicidade , Antagonistas de Estrogênios , Estrogênios/toxicidade , Esgotos , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
13.
Proc Natl Acad Sci U S A ; 118(49)2021 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-34848535

RESUMO

Antigen-specific peripheral tolerance is crucial to prevent the development of organ-specific autoimmunity. However, its function decoupled from thymic tolerance remains unclear. We used desmoglein 3 (Dsg3), a pemphigus antigen expressed in keratinocytes, to analyze peripheral tolerance under physiological antigen-expression conditions. Dsg3-deficient thymi were transplanted into athymic mice to create a unique condition in which Dsg3 was expressed only in peripheral tissue but not in the thymus. When bone marrow transfer was conducted from high-avidity Dsg3-specific T cell receptor-transgenic mice to thymus-transplanted mice, Dsg3-specific CD4+ T cells developed in the transplanted thymus but subsequently disappeared in the periphery. Additionally, when Dsg3-specific T cells developed in Dsg3 -/- mice were adoptively transferred into Dsg3-sufficient recipients, the T cells disappeared in an antigen-specific manner without inducing autoimmune dermatitis. However, Dsg3-specific T cells overcame this disappearance and thus induced autoimmune dermatitis in Treg-ablated recipients but not in Foxp3-mutant recipients with dysfunctional Tregs. The molecules involved in disappearance were sought by screening the transcriptomes of wild-type and Foxp3-mutant Tregs. OX40 of Tregs was suggested to be responsible. Consistently, when OX40 expression of Tregs was constrained, Dsg3-specific T cells did not disappear. Furthermore, Tregs obtained OX40L from dendritic cells in an OX40-dependent manner in vitro and then suppressed OX40L expression in dendritic cells and Birc5 expression in Dsg3-specific T cells in vivo. Lastly, CRISPR/Cas9-mediated knockout of OX40 signaling in Dsg3-specific T cells restored their disappearance in Treg-ablated recipients. Thus, Treg-mediated peripheral deletion of autoreactive T cells operates as an OX40-dependent regulatory mechanism to avoid undesired autoimmunity besides thymic tolerance.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Desmogleína 3/metabolismo , Pênfigo/imunologia , Abatacepte/farmacologia , Transferência Adotiva , Animais , Técnicas de Cocultura , Proteínas de Ligação a DNA/genética , Desmogleína 3/genética , Antagonistas de Estrogênios/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Masculino , Camundongos , Camundongos Knockout , Linfócitos T Reguladores , Tamoxifeno/farmacologia
14.
Invest Ophthalmol Vis Sci ; 62(14): 23, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34807236

RESUMO

Purpose: Cytoplasmic dynein-1 (henceforth dynein) moves cargo in conjunction with dynactin toward the minus end of microtubules. The dynein heavy chain, DYNC1H1, comprises the backbone of dynein, a retrograde motor. Deletion of Dync1h1 abrogates dynein function. The purpose of this communication is to demonstrate effects of photoreceptor dynein inactivation during late postnatal development and in adult retina. Methods: We mated Dync1h1F/F mice with iCre75 and Prom1-CreERT2 mice to generate conditional rod and tamoxifen-induced knockout in rods and cones, respectively. We documented retina degeneration with confocal microscopy at postnatal day (P) 10 to P30 for the iCre75 line and 1 to 4 weeks post tamoxifen induction (wPTI) for the Prom1-CreERT2 line. We performed scotopic and photopic electroretinography (ERG) at P16 to P30 in the iCre75 line and at 1-week increments in the Prom1-CreERT2 line. Results were evaluated statistically using Student's t-test, two-factor ANOVA, and Welch's ANOVA. Results: Cre-induced homologous recombination of Dync1h1F/F mice truncated DYNC1H1 after exon 23. rodDync1h1-/- photoreceptors degenerated after P14, reducing outer nuclear layer (ONL) thickness and combined inner segment/outer segment (IS/OS) length significantly by P18. Scotopic ERG a-wave amplitudes decreased by P16 and were extinguished at P30. Cones were stable under rod-knockout conditions until P21 but inactive at P30. In tamDync1h1-/- photoreceptors, the IS/OS began shortening by 3wPTI and were nearly eliminated by 4wPTI. The ONL shrank significantly over this interval, indicating rapid photoreceptor degeneration following the loss of dynein. Conclusions: Our results demonstrate dynein is essential for the secretory pathway, formation of outer segments, and photoreceptor maintenance.


Assuntos
Dineínas do Citoplasma/genética , Deleção de Genes , Células Fotorreceptoras de Vertebrados/metabolismo , Degeneração Retiniana/genética , Oxirredutases do Álcool/metabolismo , Animais , Animais Recém-Nascidos , Proteínas Correpressoras/metabolismo , Visão de Cores/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo , Eletrorretinografia , Antagonistas de Estrogênios/toxicidade , Proteínas do Olho/metabolismo , Feminino , Técnicas de Genotipagem , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Visão Noturna/fisiologia , Estimulação Luminosa , Tamoxifeno/toxicidade
15.
Dermatol Online J ; 27(8)2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34755968

RESUMO

Oral pigmented lesions can be physiological or pathological, exogenous or endogenous, as well as focal, multifocal, or diffuse. Among them, the oral melanotic macule (OMM) is a small, well-delimited brown-to-black macule, often affecting the lip and gingiva. Amalgam tattoo (AT) is a grey or black area of discoloration on the oral mucosa as a result of entry of dental amalgam into the soft tissues, commonly gingiva and alveolar ridge. Herein, we present a patient with gingival pigmentation with features of both OMM and AT in the same location.


Assuntos
Amálgama Dentário/efeitos adversos , Antagonistas de Estrogênios/efeitos adversos , Doenças da Gengiva/etiologia , Transtornos da Pigmentação/etiologia , Tamoxifeno/efeitos adversos , Adulto , Feminino , Gengiva/patologia , Doenças da Gengiva/patologia , Humanos , Doenças da Boca/etiologia , Mucosa Bucal/patologia , Transtornos da Pigmentação/patologia
16.
Biol Pharm Bull ; 44(11): 1594-1597, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34719637

RESUMO

Estrogen is essential for the growth and development of mammary glands and its signaling is associated with breast cancer growth. Estrogen can exert physiological actions via estrogen receptors α/ß (ERα/ß). There is experimental evidence suggesting that in ERα/ß-positive breast cancer, ERα promotes tumor cell proliferation and ERß inhibits ERα-mediated transcriptional activity, resulting in abrogation of cell growth. Therefore, ERß is attracting attention as a potential tumor suppressor, and as a biomarker and therapeutic target in the ERα/ß-positive breast cancer. Based on this information, we have hypothesized that some endocrine-disrupting chemicals (EDCs) that can perturb the balance between ERα and ERß expression levels in breast cancer cells might have effects on the breast cancer proliferation (i.e., down-regulation of the α-type of ER). We have recently reported that 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), an active metabolite of bisphenol A, in ERα/ß-positive human breast cancer significantly down-regulates ERα expression, yet stimulates cell proliferation through the activation of ERß-mediated transcription. These results support our hypothesis by demonstrating that exposure to MBP altered the functional role of ERß in breast cancer cells from suppressor to promoter. In contrast, some EDCs, such as Δ9-tetrahydrocannabinol and bisphenol AF, can exhibit anti-estrogenic effects through up-regulation of ERß expression without affecting the ERα expression levels. However, there is no consensus on the correlation between ERß expression levels and clinical prognosis, which might be due to differences in exposed chemicals. Therefore, elucidating the exposure effects of EDCs can reveal the reason for inconsistent functional role of ERß in ERα/ß-positive breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Disruptores Endócrinos/toxicidade , Receptor beta de Estrogênio/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/induzido quimicamente , Antagonistas de Estrogênios/uso terapêutico , Receptor beta de Estrogênio/metabolismo , Receptor beta de Estrogênio/fisiologia , Feminino , Humanos
17.
Oxid Med Cell Longev ; 2021: 1210675, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804359

RESUMO

Fibrosis is the final common pathology of most chronic diseases as seen in the heart, liver, lung, kidney, and skin and contributes to nearly half of death in the developed countries. Fibrosis, or scarring, is mainly characterized by the transdifferentiation of fibroblasts into myofibroblasts and the excessive accumulation of extracellular matrix (ECM) secreted by myofibroblasts. Despite immense efforts made in the field of organ fibrosis over the past decades and considerable understanding of the occurrence and development of fibrosis gained, there is still lack of an effective treatment for fibrotic diseases. Therefore, identifying a new therapeutic strategy against organ fibrosis is an unmet clinical need. Naringenin, a flavonoid that occurs naturally in citrus fruits, has been found to confer a wide range of pharmacological effects including antioxidant, anti-inflammatory, and anticancer benefits and thus potentially exerting preventive and curative effects on numerous diseases. In addition, emerging evidence has revealed that naringenin can prevent the pathogenesis of fibrosis in vivo and in vitro via the regulation of various pathways that involved signaling molecules such as transforming growth factor-ß1/small mother against decapentaplegic protein 3 (TGF-ß1/Smad3), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), sirtuin1 (SIRT1), nuclear factor-kappa B (NF-κB), or reactive oxygen species (ROS). Targeting these profibrotic pathways by naringenin could potentially become a novel therapeutic approach for the management of fibrotic disorders. In this review, we present a comprehensive summary of the antifibrotic roles of naringenin in vivo and in vitro and their underlying mechanisms of action. As a food derived compound, naringenin may serve as a promising drug candidate for the treatment of fibrotic disorders.


Assuntos
Antagonistas de Estrogênios/farmacologia , Fibroblastos/efeitos dos fármacos , Fibrose/tratamento farmacológico , Flavanonas/farmacologia , Animais , Fibrose/patologia , Humanos
18.
Oxid Med Cell Longev ; 2021: 4053276, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34840667

RESUMO

Dry age-related macular degeneration (dAMD) is a chronic degenerative ophthalmopathy that leads to serious burden of visual impairment. Antioxidation in retinal pigment epithelium (RPE) cells is considered as a potential treatment for dAMD. Our previous studies have showed that naringenin (NAR) protects RPE cells from oxidative damage partly through SIRT1-mediated antioxidation. In this study, we tested the hypothesis that the Nrf2 signaling is another protective mechanism of NAR on dAMD. NaIO3-induced mouse retinopathy and ARPE-19 cell injury models were established. Immunochemical staining, immunofluorescence, and western blotting were performed to detect the protein expressions of Nrf2 and HO-1. In addition, ML385 (activity inhibitor of Nrf2) and zinc protoporphyrin (ZnPP, activity inhibitor of HO-1) were applied to explore the effect of NaIO3 or NAR. The results showed that NAR increased the protein expressions of Nrf2 and HO-1 in the retinas in mice exposed to NaIO3 at the early stage. NAR treatment also resulted in a stronger activation of Nrf2 at the early stage in NaIO3-treated ARPE-19 cells. Moreover, inhibition of HO-1 by ZnPP weakened the cytoprotective effect of NAR. The constitutive accumulation and activation of Nrf2 induced by NaIO3 led to the death of RPE cells. However, NAR decreased the protein expressions of Nrf2 and HO-1 towards normal level in the mouse retinas and ARPE-19 cells exposed to NaIO3 at the late stage. Our findings indicate that NAR protects RPE cells from oxidative damage via activating the Nrf2 signaling pathway.


Assuntos
Flavanonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Substâncias Protetoras/farmacologia , Doenças Retinianas/tratamento farmacológico , Epitélio Pigmentado da Retina/efeitos dos fármacos , Animais , Antagonistas de Estrogênios/farmacologia , Feminino , Iodatos/toxicidade , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , Espécies Reativas de Oxigênio/metabolismo , Doenças Retinianas/induzido quimicamente , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Regulação para Cima
19.
Int J Mol Sci ; 22(22)2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34830456

RESUMO

Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ERα) agonists or antagonists depending on the target issue. Tamoxifen (TAM) (a non-steroidal triphenylethylene derivative) was the first SERM approved as anti-estrogen for the treatment of metastatic breast cancer. On the hunt for novel SERMs with potential growth inhibitory activity on breast cancer cell lines yet no potential to induce endometrial carcinoma, we designed and synthesized 28 novel TAM analogs. The novel analogs bear a triphenylethylene scaffold. Modifications on rings A, B, and C aim to attenuate estrogenic/anti-estrogenic activities of the novel compounds so they can potentially inhibit breast cancer and provide positive, beneficial estrogenic effects on other tissues with no risk of developing endometrial hyperplasia. Compound 12 (E/Z-1-(2-{4-[1-(4-Chloro-phenyl)-2-(4-methoxy-phenyl)-propenyl]-phenoxy}-ethyl)-piperidine) showed an appreciable relative ERα agonistic activity in a yeast estrogen screen (YES) assay. It successfully inhibited the growth of the MCF-7 cell line with GI50 = 0.6 µM, and it was approximately three times more potent than TAM. It showed no potential estrogenicity on Ishikawa endometrial adenocarcinoma cell line via assaying alkaline phosphatase (AlkP) activity. Compound 12 was tested in vivo to assess its estrogenic properties in an uterotrophic assay in an ovariectomized rat model. Compared to TAM, it induced less increase in wet uterine wet weight and showed no uterotrophic effect. Compound 12 is a promising candidate for further development due to its inhibition activity on MCF-7 proliferation with moderate AlkP activity and no potential uterotrophic effects. The in vitro estrogenic activity encourages further investigations toward potential beneficial properties in cardiovascular, bone, and brain tissues.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Receptor alfa de Estrogênio/genética , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Tamoxifeno/farmacologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Antagonistas de Estrogênios/síntese química , Antagonistas de Estrogênios/farmacologia , Feminino , Humanos , Células MCF-7 , Ratos , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/genética , Moduladores Seletivos de Receptor Estrogênico/síntese química , Estilbenos/síntese química , Estilbenos/farmacologia , Tamoxifeno/análogos & derivados
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...