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1.
Biomed Res Int ; 2022: 9235837, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36246971

RESUMO

Castration-resistant prostate cancer (CRPC) is still challenging to treat. Dissatisfaction with androgen signal-targeted therapy forces people to look for other treatment strategies. Therefore, this study is aimed at exploring the role of SOX8/Notch signaling in CRPC. The upregulation of SOX8, Notch4, and Hes5 indicated a poor progression-free survival (PFS) in CRPC patients. The expression of these proteins was also upregulated in enzalutamide-resistant LNCaP cells (Enza-R). Moreover, knocking down SOX8 inhibited malignant biological behaviors and decreased the activation of Notch signaling in Enza-R cells. Importantly, knocking down SOX8 obviously reversed the enzalutamide resistance in Enza-R cells, while RO0429097 (a γ secretase inhibitor inactivates Notch signaling) exerted similar effects. At last, we found that both SOX8 knockdown and/or RO0429097 suppressed tumor growth and bone metastasis in vivo. Altogether, our study indicated that the SOX8/Notch signaling is involved in CRPC and that these enzymes are possible targets to develop novel treatment for CRPC.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Fatores de Transcrição SOXE , Androgênios , Benzamidas , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores e Moduladores de Secretases gama , Humanos , Masculino , Nitrilas/farmacologia , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Fatores de Transcrição SOXE/metabolismo , Transdução de Sinais
2.
EMBO J ; 41(21): e111084, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36121025

RESUMO

Alzheimer's disease (AD) pathogenesis has been linked to the accumulation of longer, aggregation-prone amyloid ß (Aß) peptides in the brain. Γ-secretases generate Aß peptides from the amyloid precursor protein (APP). Γ-secretase modulators (GSMs) promote the generation of shorter, less-amyloidogenic Aßs and have therapeutic potential. However, poorly defined drug-target interactions and mechanisms of action have hampered their therapeutic development. Here, we investigate the interactions between the imidazole-based GSM and its target γ-secretase-APP using experimental and in silico approaches. We map the GSM binding site to the enzyme-substrate interface, define a drug-binding mode that is consistent with functional and structural data, and provide molecular insights into the underlying mechanisms of action. In this respect, our analyses show that occupancy of a γ-secretase (sub)pocket, mediating binding of the modulator's imidazole moiety, is sufficient to trigger allosteric rearrangements in γ-secretase as well as stabilize enzyme-substrate interactions. Together, these findings may facilitate the rational design of new modulators of γ-secretase with improved pharmacological properties.


Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Humanos , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Inibidores e Moduladores de Secretases gama , Doença de Alzheimer/metabolismo , Imidazóis/uso terapêutico
3.
Int J Mol Sci ; 23(11)2022 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-35682660

RESUMO

Uterine leiomyosarcoma (uLMS) is a rare and aggressive cancer with few effective therapeutics. The Notch signaling pathway is evolutionarily conserved with oncogenic properties, but it has not been well studied in uLMS. The purpose of our study was to determine expression of Notch family genes and proteins and to investigate the therapeutic effect of γ-secretase inhibitors (GSIs), indirect inhibitors of Notch signaling, in uLMS. We determined expression of Notch genes and proteins in benign uterine smooth muscle tissue, fibroids, and uLMS samples by immunostaining and in two uLMS cell lines, SK-UT-1B (uterine primary) and SK-LMS-1 (vulvar metastasis) by RT-PCR, Western blot and immunostaining. We exposed our cell lines to GSIs, DAPT and MK-0752, and measured expression of HES1, a downstream effector of Notch. Notch proteins were differentially expressed in uLMS. Expression of NOTCH3 and NOTCH4 was higher in uLMS samples than in benign uterine smooth muscle and fibroids. Expression of NOTCH4 was higher in SK-LMS-1 compared to SK-UT-1B. Exposure of SK-UT-1B and SK-LMS-1 to DAPT and MK-0752 decreased expression of HES1 and decreased uLMS cell viability in a dose- and time-dependent manner that was unique to each GSI. Our findings suggest that GSIs are potential therapeutics for uLMS, albeit with limited efficacy.


Assuntos
Leiomioma , Leiomiossarcoma , Neoplasias Pélvicas , Neoplasias Uterinas , Feminino , Inibidores e Moduladores de Secretases gama , Humanos , Leiomiossarcoma/tratamento farmacológico , Leiomiossarcoma/genética , Leiomiossarcoma/metabolismo , Inibidores da Agregação Plaquetária/uso terapêutico , Receptores Notch , Transdução de Sinais , Neoplasias Uterinas/patologia
4.
Neurosci Lett ; 778: 136603, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35364125

RESUMO

During neurodevelopment, differentiation of neural stem/progenitor cells (NSPCs) into neurons are regulated by many factors including Notch signaling pathway. Herein, we report the effect of a Notch signaling blocker, i.e. γ -secretase inhibitor (GSI), on this differentiating process, especially on the morphological development. NSPCs were cultured and induced to differentiate with or without GSI. The neurite outgrowth was impeded by GSI application and the expression of a Notch signaling downstream effector miR-342-5p increased with the downregulated expression of Notch effectors Hes1 and Hes5. Upregulated expression of miR-342-5p in differentiating NSPCs could shorten the neurite length of progeny neurons, which was similar to the effect of GSI. To avoid the possible influence from astrocytes into neurons, we directly applied cultured neurons, on which GSI could shorten the processes and RBP-J knockdown could also reduce the neurite length. Similarly, transfection of miR-342-5p mimics or inhibitors into PC12 cells led to shorter or longer processes of cells compared with control ones. Furthermore, in differentiating NSPCs, GSI-induced shorter neurites could be partially rescued by miR-342-5p inhibitors, and STAT3 was one of the possible targets of miR-342-5p during this differentiating process as indicated by results of Western Blot test, luciferase reporter assay and GFP reporter assay. To further demonstrate the role of STAT3, it was introduced into GSI-treated neurons and the GSI-affected neurites could also be partially rescued. In conclusion, GSI could influence the morphological development of neurons and the possible mechanism involved Notch/miR-342-5p and STAT3. These results would be informative for future therapeutic research.


Assuntos
Inibidores e Moduladores de Secretases gama , MicroRNAs , Células-Tronco Neurais , Receptores Notch , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Inibidores e Moduladores de Secretases gama/farmacologia , MicroRNAs/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Ratos , Receptores Notch/metabolismo , Transdução de Sinais
5.
Scand J Immunol ; 96(2): e13169, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35384009

RESUMO

Rheumatoid arthritis (RA) is a chronic immune disease involving the small joints, which often causes irreversible damage. In recent years, elevated interleukin 20 (IL-20) has been observed in synovial fluid, while IL-20 receptor overexpression has been observed in synovial cells. IL-20 is a pleiotropic cytokine that participates in various immune diseases. Further understanding of the relationship between IL-20 and RA can help to identify a potential clinical treatment for RA. This study demonstrated that IL-20 can regulate osteoclast differentiation and function in a dose-dependent manner, while influencing the expression of Notch signalling. Quantitative reverse transcription polymerase chain reaction and western blotting showed that γ-secretase-inhibiting drugs can reverse the effects of IL-20. The effects of Notch2 on IL-20-induced osteoclastogenesis were investigated by immunofluorescence and Notch2 gene silencing via transfection of small interfering RNA; the results showed that Notch2 obviously affected the expression levels of the key protein NFATc1 and downstream osteoclastic proteins. In conclusion, we found that IL-20 regulated the osteoclastogenesis in a dose-dependent manner via Notch signalling, primarily by means of Notch2 activity. This study may help to find new targets for RA treatment.


Assuntos
Artrite Reumatoide , Inibidores e Moduladores de Secretases gama , Interleucinas , Osteogênese , Receptor Notch2 , Secretases da Proteína Precursora do Amiloide/metabolismo , Células Cultivadas , Inibidores e Moduladores de Secretases gama/farmacologia , Humanos , Interleucinas/metabolismo , Osteoclastos/metabolismo , Receptor Notch2/genética , Receptor Notch2/metabolismo , Membrana Sinovial/metabolismo
6.
Oncotarget ; 13: 373-386, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35186194

RESUMO

Activating variants in the PEST region of NOTCH1 have been associated with aggressive phenotypes in human cancers, including triple-negative breast cancer (TNBC). Previous studies suggested that PEST domain variants in TNBC patients resulted in increased cell proliferation, invasiveness, and decreased overall survival. In this study, we assess the phenotypic transformation of activating NOTCH1 variants and their response to standard of care therapies. AAV-mediated gene targeting was used to isogenically incorporate 3 NOTCH1 variants, including a novel TNBC frameshift variant, in two non-tumorigenic breast epithelial cell lines, MCF10A and hTERT-IMEC. Two different variants at the NOTCH1 A2241 site (A2441fs and A2441T) both demonstrated increased transformative properties when compared to a non-transformative PEST domain variant (S2523L). These phenotypic changes include proliferation, migration, anchorage-independent growth, and MAPK pathway activation. In contrast to previous studies, activating NOTCH1 variants did not display sensitivity to a gamma secretase inhibitor (GSI) or resistance to chemotherapies. This study demonstrates distinct transformative phenotypes are specific to a given variant within NOTCH1 and these phenotypes do not correlate with sensitivities or resistance to chemotherapies or GSIs. Although previous studies have suggested NOTCH1 variants may be prognostic for TNBC, our study does not demonstrate prognostic ability of these variants and suggests further characterization would be required for clinical applications.


Assuntos
Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Proliferação de Células/genética , Inibidores e Moduladores de Secretases gama , Humanos , Receptor Notch1/genética , Receptor Notch1/metabolismo , Transdução de Sinais , Padrão de Cuidado , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/terapia
7.
Microvasc Res ; 140: 104308, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34995552

RESUMO

Intrauterine growth restriction (IUGR) is associated with increased perinatal mortality and morbidity, and plays an important role in the development of adult cardiovascular diseases. This study brings forward a hypothesis that Human umbilical vein endothelial cells (HUVECs) from IUGR newborns present dysfunctions and varying changes of signaling pathways as compared to the Control group. Similar pathways may also be present in pulmonary or systemic vasculatures. HUVECs were derived from newborns. There were three groups according to the different fetal origins: normal newborns (Control), IUGR from poor maternal nutrition (IUGR1), and pregnancy-induced hypertension (IUGR2). We found that IUGR-derived HUVECs showed a proliferative phenotype compared to those from normal subjects. Interestingly, two types IUGR could cause varying degrees of cellular dysfunction. Meanwhile, the Notch1 signaling pathway showed enhanced activation in the two IUGR-induced HUVECs, with subsequent activation of Akt or extracellular signal regulated protein kinases1/2 (ERK1/2). Pharmacological inhibition or gene silencing of Notch1 impeded the proliferative phenotype of IUGR-induced HUVECs and reduced the activation of ERK1/2 and AKT. In summary, elevated Notch1 levels might play a crucial role in IUGR-induced HUVECs disorders through the activation of ERK1/2 and AKT. These pathways could be potential therapeutic targets for prevention of the progression of IUGR associated diseases later in life.


Assuntos
Retardo do Crescimento Fetal/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Neovascularização Patológica , Receptor Notch1/metabolismo , Adulto , Apoptose , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Diaminas/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Retardo do Crescimento Fetal/patologia , Inibidores e Moduladores de Secretases gama/farmacologia , Inativação Gênica , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Recém-Nascido , Fenótipo , Fosforilação , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/genética , Transdução de Sinais , Tiazóis/farmacologia
8.
Hepatology ; 75(3): 584-599, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34687050

RESUMO

BACKGROUND AND AIMS: The mechanisms involved in liver regeneration after partial hepatectomy (pHx) are complicated. Cellular senescence, once linked to aging, plays a pivotal role in wound repair. However, the regulatory effects of cellular senescence on liver regeneration have not been fully elucidated. APPROACH AND RESULTS: Mice subjected to pHx were analyzed 14 days after surgery. The incomplete remodeling of liver sinusoids affected shear stress-induced endothelial nitric oxide synthase (eNOS) signaling on day 14, resulting in the accumulation of senescent LSECs. Removing macrophages to augment LSEC senescence led to a malfunction of the regenerating liver. A dynamic fluctuation in Notch activity accompanied senescent LSEC accumulation during liver regeneration. Endothelial Notch activation by using Cdh5-CreERT NICeCA mice triggered LSEC senescence and senescence-associated secretory phenotype, which disrupted liver regeneration. Blocking the Notch by γ-secretase inhibitor (GSI) diminished senescence and promoted LSEC expansion. Mechanically, Notch-hairy and enhancer of split 1 signaling inhibited sirtuin 1 (Sirt1) transcription by binding to its promoter region. Activation of Sirt1 by SRT1720 neutralized the up-regulation of P53, P21, and P16 caused by Notch activation and eliminated Notch-driven LSEC senescence. Finally, Sirt1 activator promoted liver regeneration by abrogating LSEC senescence and improving sinusoid remodeling. CONCLUSIONS: Shear stress-induced LSEC senescence driven by Notch interferes with liver regeneration after pHx. Sirt1 inhibition accelerates liver regeneration by abrogating Notch-driven senescence, providing a potential opportunity to target senescent cells and facilitate liver repair after injury.


Assuntos
Senescência Celular , Regeneração Hepática , Receptores Notch , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Animais , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Inibidores e Moduladores de Secretases gama/farmacologia , Hepatectomia/métodos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Regeneração Hepática/efeitos dos fármacos , Regeneração Hepática/fisiologia , Camundongos , Óxido Nítrico Sintase Tipo III/metabolismo , Receptores Notch/antagonistas & inibidores , Receptores Notch/metabolismo , Fenótipo Secretor Associado à Senescência/genética
9.
J Org Chem ; 86(21): 15481-15487, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34641679

RESUMO

A desymmetrization-based approach for the synthesis of piperidinyl acetic acid γ-secretase modulators has been developed. The synthetic sequence features the use of N-tert-butanesulfinyl imine reduction and a diastereoselective lactam formation to set up the chiral centers. The synthetic utility is demonstrated by the concise asymmetric synthesis of γ-secretase modulator GSM-1.


Assuntos
Ácido Acético , Secretases da Proteína Precursora do Amiloide , Inibidores e Moduladores de Secretases gama
10.
Int J Med Sci ; 18(12): 2551-2560, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34104086

RESUMO

Malignant gliomas are a type of central nervous system cancer with extremely high mortality rates in humans. γ-secretase has been becoming a potential target for cancer therapy, including glioma, because of the involvement of its enzymatic activity in regulating the proliferation and metastasis of cancer cells. In this study, we attempted to determine whether γ-secretase activity regulates E-cadherin to affect glioma cell migration. The human glioma cell lines, including LN18 and LN229, and the γ-secretase inhibitors, including N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) and RO4929097, were used in this study. It was shown that γ-secretase activity inhibition by DAPT and RO4929097 could promote LN18 and LN229 glioma cell migration via downregulating E-cadherin mRNA and protein expressions, but not via affecting E-cadherin protein processing. In addition, γ-secretase activity inhibition was regulated by bone morphogenetic proteins-independent Smad5 activation in glioma cells. Moreover, endogenous Smad1 in glioma cells was found to play an important role in regulating E-cadherin expression and subsequent cell migration but did not affect DAPT-stimulated effects. These results help further elucidate the molecular mechanisms of γ-secretase activity regulation involved in controlling glioma cell malignancy. Information about a potential role for Smad1/5 activity upregulation and subsequent E-cadherin downregulation during inhibition of γ-secretase activity in the development of gliomas is therefore relevant for future research.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Inibidores e Moduladores de Secretases gama/farmacologia , Glioma/tratamento farmacológico , Antígenos CD/genética , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Neoplasias Encefálicas/patologia , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Diaminas/farmacologia , Diaminas/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Inibidores e Moduladores de Secretases gama/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/patologia , Humanos , Proteína Smad5/metabolismo , Tiazóis/farmacologia , Tiazóis/uso terapêutico
12.
Molecules ; 27(1)2021 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-35011410

RESUMO

γ-Secretase is an intramembrane aspartyl protease that is important in regulating normal cell physiology via cleavage of over 100 transmembrane proteins, including Amyloid Precursor Protein (APP) and Notch family receptors. However, aberrant proteolysis of substrates has implications in the progression of disease pathologies, including Alzheimer's disease (AD), cancers, and skin disorders. While several γ-secretase inhibitors have been identified, there has been toxicity observed in clinical trials associated with non-selective enzyme inhibition. To address this, γ-secretase modulators have been identified and pursued as more selective agents. Recent structural evidence has provided an insight into how γ-secretase inhibitors and modulators are recognized by γ-secretase, providing a platform for rational drug design targeting this protease. In this study, docking- and pharmacophore-based screening approaches were evaluated for their ability to identify, from libraries of known inhibitors and modulators with decoys with similar physicochemical properties, γ-secretase inhibitors and modulators. Using these libraries, we defined strategies for identifying both γ-secretase inhibitors and modulators incorporating an initial pharmacophore-based screen followed by a docking-based screen, with each strategy employing distinct γ-secretase structures. Furthermore, known γ-secretase inhibitors and modulators were able to be identified from an external set of bioactive molecules following application of the derived screening strategies. The approaches described herein will inform the discovery of novel small molecules targeting γ-secretase.


Assuntos
Secretases da Proteína Precursora do Amiloide/química , Descoberta de Drogas/métodos , Inibidores e Moduladores de Secretases gama/química , Modelos Moleculares , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores e Moduladores de Secretases gama/farmacologia , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Reprodutibilidade dos Testes , Relação Estrutura-Atividade
13.
J Med Chem ; 64(19): 14426-14447, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34550687

RESUMO

The recent approval of aducanumab for Alzheimer's disease has heightened the interest in therapies targeting the amyloid hypothesis. Our research has focused on identification of novel compounds to improve amyloid processing by modulating gamma secretase activity, thereby addressing a significant biological deficit known to plague the familial form of the disease. Herein, we describe the design, synthesis, and optimization of new gamma secretase modulators (GSMs) based on previously reported oxadiazine 1. Potency improvements with a focus on predicted and measured properties afforded high-quality compounds further differentiated via robust Aß42 reductions in both rodents and nonhuman primates. Extensive preclinical profiling, efficacy studies, and safety studies resulted in the nomination of FRM-024, (+)-cis-5-(4-chlorophenyl)-6-cyclopropyl-3-(6-methoxy-5-(4-methyl-1H-imidazole-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine, as a GSM preclinical candidate for familial Alzheimer's disease.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Encéfalo/metabolismo , Descoberta de Drogas , Inibidores e Moduladores de Secretases gama/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Área Sob a Curva , Cães , Inibidores e Moduladores de Secretases gama/farmacocinética , Meia-Vida , Haplorrinos , Humanos , Camundongos , Fragmentos de Peptídeos/metabolismo , Ratos
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