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1.
Chem Biol Interact ; 311: 108794, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31421115

RESUMO

Acanthoic acid (AA) is a pimaradiene diterpene isolated from Acanthopanax koreanum Nakai (Araliaceae), with anti-inflammatory and hepatic-protective effects. The present study intended to reveal the effect and mechanism of AA on nonalcoholic fatty liver disease (NAFLD) associated with lipid accumulation by activating Farnesoid X receptor (FXR) and liver X receptors (LXRs) signaling. C57BL/6 mice were received a modified Lieber-DeCarli diet with 71% high-fat (L-D) and treated with AA (20 and 40 mg/kg) or equal volume of saline for 12 weeks. The regulation of AA on lipid accumulation was also detected in pro-steatotic stimulated AML12 cells with palmitic acid (PA). When L-D diet-fed mice were treated with AA, loss in body weight, liver index, and liver lipid droplet were observed along with reduced triglyceride (TG) and serum transaminase. Furthermore, AA decreased sterol regulatory element binding protein 1 (SREBP-1) and target genes expression, regulated PPARα and PPARγ expressions, ameliorated hepatic fibrosis markers, enhanced hepatic FXR and LXR, and regulated AMPK-LKB1 and SIRT1 signaling pathway. Moreover, AA attenuated lipid accumulation via FXR and LXR activation in steatotic AML-12 cells, which was confirmed by guggulsterones (FXR antagonist) or GW3965 (LXR agonist). Activation of FXR and LXR signaling caused by AA might increase AMPK-SIRT1 signaling and then contribute to modulating lipid accumulation and fatty acid synthesis, which suggested that activated FXR-LXR axis by AA represented an effective strategy for relieving NAFLD.


Assuntos
Diterpenos/farmacologia , Lipogênese/efeitos dos fármacos , Receptores X do Fígado/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Dieta Hiperlipídica , Diterpenos/química , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores X do Fígado/agonistas , Receptores X do Fígado/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/genética , PPAR alfa/metabolismo , Ácido Palmítico/farmacologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/sangue
2.
N Engl J Med ; 381(8): 727-738, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31433920

RESUMO

BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options. METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point. RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients. CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Hidrazinas/administração & dosagem , Carioferinas/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Triazóis/administração & dosagem , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/sangue , Dexametasona/efeitos adversos , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Hidrazinas/efeitos adversos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Trombocitopenia/induzido quimicamente , Triazóis/efeitos adversos , Adulto Jovem
3.
Handb Exp Pharmacol ; 256: 325-357, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31201553

RESUMO

Nonalcoholic steatohepatitis (NASH) is within the spectrum of nonalcoholic fatty liver disease (NAFLD) and can progress to fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). The prevalence of NASH is rising and has become a large burden to the medical system worldwide. Unfortunately, despite its high prevalence and severe health consequences, there is currently no therapeutic agent approved to treat NASH. Therefore, the development of efficacious therapies is of utmost urgency and importance. Many molecular targets are currently under investigation for their ability to halt NASH progression. One of the most promising and well-studied targets is the bile acid (BA)-activated nuclear receptor, farnesoid X receptor (FXR). In this chapter, the characteristics, etiology, and prevalence of NASH will be discussed. A brief introduction to FXR regulation of BA homeostasis will be described. However, for more details regarding FXR in BA homeostasis, please refer to previous chapters. In this chapter, the mechanisms by which tissue and cell type-specific FXR regulates NASH development will be discussed in detail. Several FXR agonists have reached later phase clinical trials for treatment of NASH. The progress of these compounds and summary of released data will be provided. Lastly, this chapter will address safety liabilities specific to the development of FXR agonists.


Assuntos
Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Ácidos e Sais Biliares , Humanos
4.
Handb Exp Pharmacol ; 256: 137-165, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31201554

RESUMO

In the recent years, bile acid receptors FXR and GPBAR1 have attracted the interest of scientific community and companies, as they proved promising targets for the treatment of several diseases, ranging from liver cholestatic disorders to metabolic syndrome, inflammatory states, nonalcoholic steatohepatitis (NASH), and diabetes.Consequently, the development of dual FXR/GPBAR1 agonists, as well as selective targeting of one of these receptors, is considered a hopeful possibility in the treatment of these disorders. Because endogenous bile acids and steroidal ligands, which cover the same chemical space of bile acids, often target both receptor families, speculation on nonsteroidal ligands represents a promising and innovative strategy to selectively target GPBAR1 or FXR.In this review, we summarize the most recent acquisition on natural, semisynthetic, and synthetic steroidal and nonsteroidal ligands, able to interact with FXR and GPBAR1.


Assuntos
Ácidos e Sais Biliares/química , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Ácidos e Sais Biliares/farmacologia , Humanos , Ligantes
5.
Handb Exp Pharmacol ; 256: 299-324, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31201556

RESUMO

The farnesoid X receptor (FXR, NR1H4) is a bile acid (BA)-activated transcription factor, which is essential for BA homeostasis. FXR and its hepatic and intestinal target genes, small heterodimer partner (SHP, NR0B2) and fibroblast growth factor 15/19 (Fgf15 in mice, FGF19 in humans), transcriptionally regulate BA synthesis, detoxification, secretion, and absorption in the enterohepatic circulation. Furthermore, FXR modulates a large variety of physiological processes, such as lipid and glucose homeostasis as well as the inflammatory response. Targeted deletion of FXR renders mice highly susceptible to cholic acid feeding resulting in cholestatic liver injury, weight loss, and increased mortality. Combined deletion of FXR and SHP spontaneously triggers early-onset intrahepatic cholestasis in mice resembling human progressive familial intrahepatic cholestasis (PFIC). Reduced expression levels and activity of FXR have been reported in human cholestatic conditions, such as PFIC type 1 and intrahepatic cholestasis of pregnancy. Recently, two pairs of siblings with homozygous FXR truncation or deletion variants were identified. All four children suffered from severe, early-onset PFIC and liver failure leading to death or need for liver transplantation before the age of 2. These findings underscore the central role of FXR as regulator of systemic and hepatic BA levels. Therefore, targeting FXR has been exploited in different animal models of both intrahepatic and obstructive cholestasis, and the first FXR agonist obeticholic acid (OCA) has been approved for the treatment of primary biliary cholangitis (PBC). Further FXR agonists as well as a FGF19 analogue are currently tested in clinical trials for different cholestatic liver diseases. This chapter will summarize the current knowledge on the role of FXR in cholestasis both in rodent models and in human diseases.


Assuntos
Colestase Intra-Hepática/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Animais , Ácidos e Sais Biliares , Modelos Animais de Doenças , Homeostase , Humanos , Fígado , Camundongos
6.
Handb Exp Pharmacol ; 256: 359-378, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31144046

RESUMO

Bariatric surgical procedures, including Roux-en-Y gastric bypass and vertical sleeve gastrectomy, are currently the most effective clinical approaches to achieve a significant and sustainable weight loss. Bariatric surgery also concomitantly improves type 2 diabetes and other metabolic diseases such as nonalcoholic steatohepatitis, cardiovascular diseases, and hyperlipidemia. However, despite the recent exciting progress in the understanding how bariatric surgery works, the underlying molecular mechanisms of bariatric surgery remain largely unknown. Interestingly, bile acids are emerging as potential signaling molecules to mediate the beneficial effects of bariatric surgery. In this review, we summarize the recent findings on bile acids and their activated receptors in mediating the beneficial metabolic effects of bariatric surgery. We also discuss the potential to target bile acid-activated receptors in order to treat obesity and other metabolic diseases.


Assuntos
Cirurgia Bariátrica , Ácidos e Sais Biliares , Derivação Gástrica , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Diabetes Mellitus Tipo 2 , Humanos , Perda de Peso
7.
MBio ; 10(3)2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088931

RESUMO

The abnormal proliferation of cancer cells is driven by deregulated oncogenes or tumor suppressors, among which the cancer-vulnerable genes are attractive therapeutic targets. Targeting mislocalization of oncogenes and tumor suppressors resulting from aberrant nuclear export is effective for inhibiting growth transformation of cancer cells. We performed a clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) screening in a unique model of matched primary and oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV)-transformed cells and identified genes that were growth promoting and growth suppressive for both types of cells, among which exportin XPO1 was demonstrated to be critical for the survival of transformed cells. Using XPO1 inhibitor KPT-8602 and by small interfering RNA (siRNA) knockdown, we confirmed the essential role of XPO1 in cell proliferation and growth transformation of KSHV-transformed cells and in cell lines of other cancers, including gastric cancer and liver cancer. XPO1 inhibition induced cell cycle arrest through p53 activation, but the mechanisms of p53 activation differed among the different types of cancer cells. p53 activation depended on the formation of promyelocytic leukemia (PML) nuclear bodies in gastric cancer and liver cancer cells. Mechanistically, XPO1 inhibition induced relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. Taken the data together, we have identified novel growth-promoting and growth-suppressive genes of primary and cancer cells and have demonstrated that XPO1 is a vulnerable target of cancer cells. XPO1 inhibition induces cell arrest through a novel PML- and p62-dependent mechanism of p53 activation in some types of cancer cells.IMPORTANCE Using a model of oncogenic virus KSHV-driven cellular transformation of primary cells, we have performed a genome-wide CRISPR-Cas9 screening to identify vulnerable genes of cancer cells. This screening is unique in that this virus-induced oncogenesis model does not depend on any cellular genetic alterations and has matched primary and KSHV-transformed cells, which are not available for similar screenings in other types of cancer. We have identified genes that are both growth promoting and growth suppressive in primary and transformed cells, some of which could represent novel proto-oncogenes and tumor suppressors. In particular, we have demonstrated that the exportin XPO1 is a critical factor for the survival of transformed cells. Using a XPO1 inhibitor (KPT-8602) and siRNA-mediated knockdown, we have confirmed the essential role of XPO1 in cell proliferation and in growth transformation of KSHV-transformed cells, as well as of gastric and liver cancer cells. XPO1 inhibition induces cell cycle arrest by activating p53, but the mechanisms of p53 activation differed among different types of cancer cells. p53 activation is dependent on the formation of PML nuclear bodies in gastric and liver cancer cells. Mechanistically, XPO1 inhibition induces relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. These results illustrate that XPO1 is a vulnerable target of cancer cells and reveal a novel mechanism for blocking cancer cell proliferation by XPO1 inhibition as well as a novel PML- and p62-mediated mechanism of p53 activation in some types of cancer cells.


Assuntos
Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Herpesvirus Humano 8/patogenicidade , Carioferinas/genética , Receptores Citoplasmáticos e Nucleares/genética , Sistemas CRISPR-Cas , Pontos de Checagem do Ciclo Celular , Detecção Precoce de Câncer , Genes p53 , Humanos , Carioferinas/antagonistas & inibidores , Leucemia Promielocítica Aguda , Neoplasias Hepáticas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Proteína Sequestossoma-1/genética , Neoplasias Gástricas , Células Tumorais Cultivadas
8.
Cell Physiol Biochem ; 52(4): 802-821, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30946556

RESUMO

BACKGROUND/AIMS: The rapid nuclear translocation of signaling proteins upon stimulation is important for the regulation of de-novo gene expression. However, the molecular mechanisms of this translocation is not well understood, although some studies suggest that much of this translocation may be mediated by beta-like importins (Imps). Here we undertook to study the stimulated nuclear shuttling of JNK and p38 MAPKs. METHODS: For this purpose, we used coimmunoprecipitation, proximity ligation assay, gel filtration and immunostaining to examine the mechanism of nuclear translocation of these proteins. RESULTS: We found that JNK and p38 MAPKs translocate into the nucleus in a Ran dependent, but NLS- or NTS-independent manner, unrelated to their catalytic activity. We show that this translocation involves three ß-like Imps, 3, 7 and 9. Knockdown of these Imps inhibits the nuclear translocation of the MAPKs, and thereby, phosphorylation of their transcription factor targets. We further demonstrate that the translocation requires the stimulated formation of heterotrimers composed of Imp3/Imp7/MAPK or Imp3/Imp9/MAPK. JNK1/2 and p38α/ß bind to either Imp7 or Imp9 upon stimulated post-translational modifications of the two Imps, while Imp3 joins the complex after its stimulation-induced phosphorylation. Once formed, these heterotrimers move to the nuclear envelope where Imp3 remains, while Imp7 or Imp9 escort the MAPKs into the nucleus. CONCLUSION: These results suggest that ß-like Imps are central mediators of stimulated nuclear translocation of signaling proteins, providing a central level of regulation of the induction of cellular processes such as transcription upon stimulation.


Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Sequência de Aminoácidos , Anisomicina/farmacologia , Núcleo Celular/metabolismo , Células HeLa , Humanos , Células MCF-7 , Microscopia de Fluorescência , Fosforilação , Ligação Proteica , Transporte Proteico/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/genética , Alinhamento de Sequência
9.
Mol Cancer ; 18(1): 51, 2019 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-30925918

RESUMO

The tumor microenvironment is a complex and dynamic cellular community comprising the tumor epithelium and various tumor-supporting cells such as immune cells, fibroblasts, immunosuppressive cells, adipose cells, endothelial cells, and pericytes. The interplay between the tumor microenvironment and tumor cells represents a key contributor to immune evasiveness, physiological hardiness and the local and systemic invasiveness of malignant cells. Nuclear receptors are master regulators of physiological processes and are known to play pro-/anti-oncogenic activities in tumor cells. However, the actions of nuclear receptors in tumor-supporting cells have not been widely studied. Given the excellent druggability and extensive regulatory effects of nuclear receptors, understanding their biological functionality in the tumor microenvironment is of utmost importance. Therefore, the present review aims to summarize recent evidence about the roles of nuclear receptors in tumor-supporting cells and their implications for malignant processes such as tumor proliferation, evasion of immune surveillance, angiogenesis, chemotherapeutic resistance, and metastasis. Based on findings derived mostly from cell culture studies and a few in vivo animal cancer models, the functions of VDR, PPARs, AR, ER and GR in tumor-supporting cells are relatively well-characterized. Evidence for other receptors, such as RARß, RORγ, and FXR, is limited yet promising. Hence, the nuclear receptor signature in the tumor microenvironment may harbor prognostic value. The clinical prospects of a tumor microenvironment-oriented cancer therapy exploiting the nuclear receptors in different tumor-supporting cells are also encouraging. The major challenge, however, lies in the ability to develop a highly specific drug delivery system to facilitate precision medicine in cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Células Estromais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Animais , Humanos , Neoplasias/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais , Células Estromais/metabolismo
10.
Ecotoxicol Environ Saf ; 175: 208-214, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30901638

RESUMO

The widely used surfactant nonylphenol ethoxylate (NPEO) and its raw material 4-n-nonylphenol (4-n-NP), as well as its degradation products, are recognized as endocrine disrupting chemicals. The USA Environmental Protection Agency (EPA) released an assessment that looked for safe alternatives to NPEO. Vanillin ethoxylate (VAEO) is a novel substitute for NPEO and is quite similar to NPEO in structure; there is a risk that it has similar endocrine disrupting effects to NPEO. However, their effects on various nuclear hormone receptors have not been thoroughly examined. In this study, the effects of NPEO, VAEO, 4-n-NP and Vanillin on the estrogen receptor α (ERα), androgen receptor (AR), thyroid hormone receptor (TR), retinoic X receptor ß (RXRß) and estrogen-related receptor γ (ERRγ) were determined and compared using a battery of recombined yeast strains expressing ß-galactosidase. The results showed that NPEO and 4-n-NP acted as significant antagonists of ER, AR, TR and ERRγ. In addition, 4-n-NP also had antagonistic activity toward RXRß. Moreover, VAEO was shown to be a very weak antagonist of TR and ERRγ, and Vanillin had no interaction with any nuclear receptors. For the first time, it was found that NPEO had AR, TR and ERRγ antagonistic effects and that 4-n-NP was an antagonist of RXRß. The in vitro data indicated that NPEO, 4-n-NP and VAEO have the potential to act as endocrine disruptors involving more than one nuclear hormone receptor, but VAEO has much lower endocrine disrupting potential than NPEO. Thus, it is critical to find safe substitutes for NPEO and a substitute of NPEO with structural analogues should be carried out with caution. Furthermore, to look for preferable alternatives for NPEO, more in vivo and in vitro studies of the alternatives concerning endocrine disruption are needed, especially in vitro studies need to involve various target points, not only focus on their effects on ER but also take other nuclear hormone receptor pathways into consideration.


Assuntos
Benzaldeídos/toxicidade , Disruptores Endócrinos/toxicidade , Etilenoglicóis/toxicidade , Fenóis/toxicidade , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Benzaldeídos/química , Relação Dose-Resposta a Droga , Disruptores Endócrinos/química , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/genética , Etilenoglicóis/química , Estrutura Molecular , Fenóis/química , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores dos Hormônios Tireóideos/antagonistas & inibidores , Receptores dos Hormônios Tireóideos/genética , Receptor X Retinoide beta/antagonistas & inibidores , Receptor X Retinoide beta/genética , Técnicas do Sistema de Duplo-Híbrido
11.
Neurochem Res ; 44(4): 735-750, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30610652

RESUMO

The central nervous system (CNS) is the most injury-prone part of the mammalian body. Any acute or chronic, central or peripheral neurological disorder is related to abnormal biochemical and electrical signals in the brain cells. As a result, ion channels and receptors that are abundant in the nervous system and control the electrical and biochemical environment of the CNS play a vital role in neurological disease. The N-methyl-D-aspartate receptor, 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid receptor, kainate receptor, acetylcholine receptor, serotonin receptor, α2-adrenoreceptor, and acid-sensing ion channels are among the major channels and receptors known to be key components of pathophysiological events in the CNS. The primary amine agmatine, a neuromodulator synthesized in the brain by decarboxylation of L-arginine, can regulate ion channel cascades and receptors that are related to the major CNS disorders. In our previous studies, we established that agmatine was related to the regulation of cell differentiation, nitric oxide synthesis, and murine brain endothelial cell migration, relief of chronic pain, cerebral edema, and apoptotic cell death in experimental CNS disorders. In this review, we will focus on the pathophysiological aspects of the neurological disorders regulated by these ion channels and receptors, and their interaction with agmatine in CNS injury.


Assuntos
Agmatina/uso terapêutico , Canais Iônicos/metabolismo , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Agmatina/farmacologia , Animais , Humanos , Canais Iônicos/antagonistas & inibidores , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de Serotonina/metabolismo , Resultado do Tratamento
12.
Oncol Rep ; 41(1): 143-153, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30320362

RESUMO

Hepatoblastoma is the most common malignant liver tumor in children. Since it is often unresectable and exhibits drug resistance, the treatment of advanced hepatoblastoma is challenging. The orphan nuclear receptor liver receptor homolog­1 (LRH­1) serves prominent roles in malignancy; however, to the best of our knowledge, the role of LRH­1 in hepatoblastoma remains unknown. In the present study, human hepatoblastoma cell lines were analyzed; the mRNA and protein expression levels of LRH­1 were significantly higher in HepG2 and HuH6 cells compared with those in HepT1 cells and control THLE­2 cells. Knockdown of LRH­1 resulted in decreased HepG2 and HuH6 cell proliferation via downregulation of cyclin D1 (CCND1) and c­Myc. Furthermore, treatment with an LRH­1 antagonist (LRA) inhibited the proliferation and colony formation of cell lines in a dose­dependent manner, and induced cell cycle arrest at G1 phase through inhibition of CCND1 expression. Finally, LRA treatment enhanced the cytotoxic effects of doxorubicin on hepatoblastoma cells. Collectively, these findings suggested that LRH­1 may have an important role in the progression of hepatoblastoma and implicated LRA as a novel, potential therapeutic agent for the treatment of hepatoblastoma.


Assuntos
Hepatoblastoma/metabolismo , Neoplasias Hepáticas/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Regulação para Cima/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Pré-Escolar , Ciclina D1/metabolismo , Doxorrubicina/farmacologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células Hep G2 , Hepatoblastoma/genética , Humanos , Neoplasias Hepáticas/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores
13.
J Steroid Biochem Mol Biol ; 185: 7-16, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29981820

RESUMO

Chromosome region maintenance 1 (CRM-1) and calreticulin (CALR) are two proteins that act as exportins for some nuclear receptors, in addition to other critical functions for cellular homeostasis. In several cancer types, CRM-1 and CALR are upregulated suggesting an imbalance in their functions. However, the regulation of CRM-1 and CALR, and their biological implications, are not completely known. Here, we evaluated the interplay between the levels of CRM-1 and CALR, and estrogen receptor alpha (ERα) status, in breast cancer cells. CRM-1 and CALR were upregulated in mammary tumors relative to normal mammary tissue. Furthermore, the mRNA and protein levels of CRM-1 and CALR were higher in breast cancer cells lacking ERα, in comparison with those that express ERα. Additionally, both proteins were distributed in the nucleus and cytoplasm in the two cell types. Importantly, we identified novel interactions for these exportins. First, we showed an interaction between CRM-1 and CALR, and then we identified that SUN1 and SUN2, two proteins localized in the nuclear envelop, were able to interact specifically with CRM-1, but not CALR. Interestingly, SUN1 and SUN2 expression seemed to be decreased in breast cancer, thereby affecting the interactions of these proteins with CRM-1, and possibly its actions as an exportin. Thus, our data suggest that expression levels for CRM-1 and CALR, the interaction between these exportins, and specific interactions of SUN1 and SUN2 with CRM-1 but not CALR, may be central elements in nucleo-cytoplasmic transport. Furthermore, deregulation of these elements may have serious implications in the progression of breast and other types of cancer.


Assuntos
Neoplasias da Mama/patologia , Calreticulina/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Carioferinas/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Calreticulina/genética , Linhagem Celular Tumoral , Receptor alfa de Estrogênio/metabolismo , Ácidos Graxos Insaturados/farmacologia , Feminino , Humanos , Carioferinas/antagonistas & inibidores , Carioferinas/genética , Células MCF-7 , RNA Mensageiro/genética , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/genética
14.
Chin J Nat Med ; 16(8): 572-579, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30197122

RESUMO

Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. As a metabolic regulator, FXR plays key roles in bile acid and cholesterol metabolism and lipid and glucose homeostasis. Therefore, FXR is a potential drug target for several metabolic syndromes, especially those related to lipidemia disorders. In the present study, we identified small molecule SIPI-7623, a derivative of an extract from Oriental wormwood (Artemisia capillaris), and found that it specifically upregulated the expression of cholesterol-7-alpha-hydroxylase (CYP7A1), downregulated the expression of sterol-regulatory element-binding protein 1c (SREBP-1c) in the liver, and inhibited the expression of ileal bile acid binding-protein (IBABP) in the ileum of rats. We found that inhibition of FXR by SIPI-7623 decreased the level of cholesterol and triglyceride. SIPI-7623 reduced the levels of cholesterol and triglyceride in in vitro HepG2 cell models, ameliorated diet-induced atherosclerosis, and decreased the serum lipid content on rats and rabbits model of atherosclerosis in vivo. Furthermore, SIPI-7623 decreased the extent of atherosclerotic lesions. Our resutls demonstrated that antagonism of the FXR pathway can be employed as a therapeutic strategy to treat metabolic diseases such as hyperlipidemia and atherosclerosis. In conclusion, SIPI-7623 could be a promising lead compound for development of drugs to treat hyperlipidemia and atherosclerosis.


Assuntos
Artemisia/química , Aterosclerose/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Humanos , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Coelhos , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
15.
Int J Mol Sci ; 19(8)2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30104471

RESUMO

BACKGROUND: Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). Immunoneutralization of heightened MBG by Digibind, a digoxin antibody, reduces blood pressure (BP) in patients with PE, and anti-MBG monoclonal antibody lessens BP in a rat model of PE. Recently, we demonstrated that MBG induces fibrosis in cardiovascular tissues via a mechanism involving inhibition of Fli-1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. OBJECTIVES AND METHODS: We hypothesized that in PE, elevated placental MBG levels are associated with development of fibrosis in umbilical arteries. Eleven patients with PE (mean BP 124 ± 4 mmHg; age 29 ± 2 years; 39 weeks gest. age) and 10 gestational age-matched normal pregnant subjects (mean BP 92 ± 2 mmHg; controls) were enrolled in the clinical study. RESULTS: PE was associated with a higher placental (0.04 ± 0.01 vs. 0.49 ± 0.11 pmol/g; p < 0.01) and plasma MBG (0.5 ± 0.1 vs. 1.6 ± 0.5 nmol/L; p < 0.01), lower Na/K-ATPase activity in erythrocytes (2.7 ± 0.2 vs. 1.5 ± 0.2 µmol Pi/mL/hr; p < 0.01), 9-fold decrease of Fli-1 level and 2.5-fold increase of collagen-1 in placentae (p < 0.01) vs. control. Incubation of umbilical arteries from control patients with 1 nmol/L MBG was associated with four-fold decrease in Fli-1 level and two-fold increase in collagen-1 level vs. those incubated with placebo (p < 0.01), i.e., physiological concentration of MBG mimicked effect of PE in vitro. Collagen-1 abundance in umbilical arteries from PE patients was 4-fold higher than in control arteries, and this PE-associated fibrosis was reversed by monoclonal anti-MBG antibody ex vivo. CONCLUSION: These results demonstrate that elevated placental MBG level is implicated in the development of fibrosis of the placenta and umbilical arteries in PE.


Assuntos
Anticorpos/uso terapêutico , Bufanolídeos/imunologia , Placenta/metabolismo , Pré-Eclâmpsia/tratamento farmacológico , Artérias Umbilicais/metabolismo , Adulto , Animais , Anticorpos/imunologia , Pressão Sanguínea , Bufanolídeos/sangue , Estudos de Casos e Controles , Colágeno Tipo I/metabolismo , Eritrócitos/enzimologia , Feminino , Fibrose , Idade Gestacional , Humanos , Imunoterapia , Proteínas dos Microfilamentos/antagonistas & inibidores , Proteínas dos Microfilamentos/metabolismo , Pré-Eclâmpsia/imunologia , Pré-Eclâmpsia/patologia , Gravidez , Ratos , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Artérias Umbilicais/patologia
16.
Diabetes ; 67(9): 1720-1728, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30135133

RESUMO

Bariatric surgery procedures, such as Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), are the most effective interventions available for sustained weight loss and improved glucose metabolism. Bariatric surgery alters the enterohepatic bile acid circulation, resulting in increased plasma bile levels as well as altered bile acid composition. While it remains unclear why both VSG and RYGB can alter bile acids, it is possible that these changes are important mediators of the effects of surgery. Moreover, a molecular target of bile acid synthesis, the bile acid-activated transcription factor FXR, is essential for the positive effects of VSG on weight loss and glycemic control. This Perspective examines the relationship and sequence of events between altered bile acid levels and composition, FXR signaling, and gut microbiota after bariatric surgery. We hypothesize that although bile acids and FXR signaling are potent mediators of metabolic function, unidentified downstream targets are the main mediators behind the benefits of weight-loss surgery. One of these targets, the gut-derived peptide FGF15/19, is a potential molecular and therapeutic marker to explain the positive metabolic effects of bariatric surgery. Focusing research efforts on identifying these complex molecular mechanisms will provide new opportunities for therapeutic strategies to treat obesity and metabolic dysfunction.


Assuntos
Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Hipoglicemiantes/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Modelos Biológicos , Obesidade Mórbida/fisiopatologia , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Cirurgia Bariátrica/efeitos adversos , Ácidos e Sais Biliares/metabolismo , Terapia Combinada/efeitos adversos , Circulação Êntero-Hepática/efeitos dos fármacos , Fatores de Crescimento de Fibroblastos/agonistas , Fatores de Crescimento de Fibroblastos/metabolismo , Microbioma Gastrointestinal , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/microbiologia , Terapia de Alvo Molecular/efeitos adversos , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Obesidade Mórbida/terapia , Especificidade de Órgãos , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo
17.
Vitam Horm ; 108: 29-73, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30029731

RESUMO

Dehydroepiandrosterone (3ß-hydroxy-5-androsten-17-one, DHEA) and its sulfated metabolite DHEA-S are the most abundant steroids in circulation and decline with age. Rodent studies have shown that DHEA has a wide variety of effects on liver, kidney, adipose, reproductive tissues, and central nervous system/neuronal function. The mechanisms by which DHEA and DHEA-S impart their physiological effects may be direct actions on plasma membrane receptors, including a DHEA-specific, G-protein-coupled receptor in endothelial cells; various neuroreceptors, e.g., aminobutyric-acid-type A, N-methyl-d-aspartate (NMDA), and sigma-1 (S1R) receptors; by binding steroid receptors: androgen and estrogen receptors (ARs, ERα, or ERß); or by their metabolism to more potent sex steroid hormones, e.g., testosterone, dihydrotestosterone, and estradiol, which bind with higher affinity to ARs and ERs. DHEA inhibits voltage-gated T-type calcium channels. DHEA activates peroxisome proliferator-activated receptor (PPARα) and CAR by a mechanism apparently involving PP2A, a protein phosphatase dephosphorylating PPARα and CAR to activate their transcriptional activity. We review our recent study showing DHEA activated GPER1 (G-protein-coupled estrogen receptor 1) in HepG2 cells to stimulate miR-21 transcription. This chapter reviews some of the physiological, biochemical, and molecular mechanisms of DHEA and DHEA-S activity.


Assuntos
Desidroepiandrosterona/farmacologia , Receptores Citoplasmáticos e Nucleares , Receptores de Esteroides , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores de Esteroides/agonistas , Receptores de Esteroides/antagonistas & inibidores
18.
Int J Mol Sci ; 19(7)2018 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-29958417

RESUMO

Farnesoid X receptor (FXR) is a receptor for bile acids and plays an important role in the regulation of bile acid metabolism in the liver. Although FXR has been shown to affect hepatocarcinogenesis through both direct and indirect mechanisms, potential roles of FXR in epithelial⁻mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) remain unclear. We examined the effect of several FXR ligands on EMT-related morphological changes in HCC cell lines, such as HuH-7 and Hep3B cells. FXR agonists (chenodeoxycholic acid, GW4064, and obeticholic acid)—but not an antagonist (guggulsterone)—induced actin polymerization and expression of N-cadherin and phosphorylated focal adhesion kinase, although they were less effective than transforming growth factor β (TGF-β). FXR agonist treatment enhanced TGF-β-induced EMT morphologic changes and FXR antagonist inhibited the effect of TGF-β. Thus, FXR activation enhances EMT in HCC and FXR antagonists may be EMT-suppressing drug candidates.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Receptores Citoplasmáticos e Nucleares/genética , Fator de Crescimento Transformador beta1/genética , Ácidos e Sais Biliares/metabolismo , Caderinas/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Isoxazóis/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores
19.
Cell Physiol Biochem ; 48(1): 158-172, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30001540

RESUMO

BACKGROUND/AIMS: Intrahepatic cholangiocarcinoma (ICC) is a complicated condition, with difficult diagnosis and poor prognosis. The expression and clinical significance of the farnesoid X receptor (FXR), an endogenous receptor of bile acids, in ICC is not well understood. METHODS: Western blotting and immunochemical analyses were used to determine the levels of FXR in 4 cholangiocarcinoma cell lines, a human intrahepatic biliary epithelial cell line (HIBEpic) and 322 ICC specimens, respectively, while quantitative reverse transcription polymerase chain reaction was used to detect the mRNA levels of FXR in cholangiocarcinoma cell lines. We evaluated the prognostic value of FXR expression and its association with clinical parameters. We determined the biological significance of FXR in ICC cell lines by agonist-mediated activation and lentivirus-mediated silence. IL-6 expression was tested by an enzyme-linked immunosorbent assay and flow cytometry. In vitro, cell proliferation was examined by Cell Counting Kit-8, migration and invasion were examined by wound healing and transwell assays; in vivo, tumor migration and invasion were explored in NOD-SCID mice. RESULTS: FXR was downregulated in ICC cell lines and clinical ICC specimens. Loss of FXR was markedly correlated with aggressive tumor phenotypes and poor prognosis in patients with ICC. Moreover, FXR expression also had significant prognostic value in carbohydrate antigen 19-9 (CA19-9) negative patients. The expression of FXR was negatively correlated with IL-6 levels in clinical ICC tissues. FXR inhibited the proliferation, migration, invasion and epithelial mesenchymal transition (EMT) of ICC cells via suppression of IL-6 in vitro. Obeticholic acid, an agonist of FXR, inhibited IL-6 production, tumor growth and lung metastasis of ICC in vivo. CONCLUSIONS: FXR could be a promising ICC prognostic biomarker, especially in CA19-9 negative patients with ICC. FXR inhibits the tumor growth and metastasis of ICC via IL-6 suppression.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Transição Epitelial-Mesenquimal , Interleucina-6/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/mortalidade , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/genética
20.
PLoS One ; 13(5): e0196787, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29723273

RESUMO

The nuclear receptors REV-ERBα and REV-ERBß have been demonstrated to be core members of the circadian clock and participate in the regulation of a diverse set of metabolic functions. Due to their overlapping tissue expression patterns and gene expression profiles, REV-ERBß is thought to be redundant to REV-ERBα. Recent work has highlighted REV-ERBα's role in the regulation of skeletal muscle oxidative capacity and mitochondrial biogenesis. Considering the similarity between the REV-ERBs and the hypothesized overlap in function, we sought to determine whether REV-ERBß-deficiency presented with a similar skeletal muscle phenotype as REV-ERBα-deficiency. Ectopic overexpression in C2C12 cells demonstrated that REV-ERBß drives mitochondrial biogenesis and the expression of genes involved in fatty acid oxidation. Intriguingly, knock down of REV-ERBß in C2C12 cultures also resulted in mitochondrial biogenesis and increased expression of genes involved in fatty acid ß-oxidation. To determine whether these effects occurred in vivo, we examined REV-ERBß-deficient mice and observed a similar increase in expression of genes involved in mitochondrial biogenesis and fatty acid ß-oxidation. Consistent with these results, REV-ERBß-deficient mice exhibited an altered metabolic phenotype compared to wild-type littermate controls when measured by indirect calorimetry. This likely compensated for the increased food consumption that occurred, possibly aiding in the maintenance of their weight over time. Since feeding behaviors are a direct circadian output, this study suggests that REV-ERBß may have more subtle effects on circadian behaviors than originally identified. Furthermore, these data implicate REV-ERBß in the control of skeletal muscle metabolism and energy expenditure and suggest that development of REV-ERBα versus REV-ERBß selective ligands may have therapeutic utility in the treatment of metabolic syndrome.


Assuntos
Ritmo Circadiano/fisiologia , Metabolismo Energético/fisiologia , Mitocôndrias Musculares/fisiologia , Músculo Esquelético/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/fisiologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Proteínas Repressoras/fisiologia , Animais , Peso Corporal , Calorimetria Indireta , Linhagem Celular , Ritmo Circadiano/genética , Metabolismo Energético/genética , Ácidos Graxos/metabolismo , Comportamento Alimentar/fisiologia , Feminino , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Knockout , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/deficiência , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Biogênese de Organelas , Oxirredução , Fosforilação Oxidativa , Interferência de RNA , RNA Interferente Pequeno/genética , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/deficiência , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/deficiência , Proteínas Repressoras/genética
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