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1.
J Am Chem Soc ; 144(38): 17522-17532, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-36103720

RESUMO

Importins are overexpressed in many cancers and mediate the abnormal nuclear transport of oncogenic factors. The druggable potential of importins still remains unclear, largely because of the lack of potent inhibitors. Herein, the anti-castration-resistant prostate cancer (CRPC) screening of a Euphorbiaceae diterpenoid library followed by target fishing led to the identification of a highly potent importin-ß1 inhibitor, daphnane diterpenoid DD1. DD1 selectively inhibited the growth and survival of CRPC cells at subnanomolar concentrations and completely blocked tumor growth in preclinical models at an extremely low dosage. Mechanistic studies revealed that targeting of importin-ß1 by DD1 significantly reduced the nuclear accumulation of key CRPC drivers, shutting down their downstream oncogenic signaling. Disruption of the predicted binding sites of DD1 on importin-ß1 abolished this anti-CRPC effect. These findings suggest that importin-ß1 is an effective therapeutic target in CRPC and that DD1 as the most potent importin-ß1 inhibitor to date can be developed as therapeutics for treatment of this disease.


Assuntos
Diterpenos , Neoplasias de Próstata Resistentes à Castração , Linhagem Celular Tumoral , Proliferação de Células , Diterpenos/farmacologia , Humanos , Carioferinas/farmacologia , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
2.
Pharmacol Res ; 178: 106160, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35259480

RESUMO

Small cell lung cancer (SCLC) is an aggressive and exceptionally fatal disease. Unlike non- small cell lung cancer (NSCLC), no targetable genetic driver events have been identified in SCLC to date. Here, we investigate the function of RAR-related orphan receptor gamma (RORγ) and identified the anti-cancer activity of its natural inhibitor against SCLC and illustrate the underlying mechanism. We show that RORγ depletion affected cell growth both in 2-D cell proliferation and 3-D organoids formation. Natural marine product N-hydroxyapiosporamide (N-hydap) directly bound to RORγ and inhibited its transcriptional activity, leading to the blocking of transmission process of RORγ signaling. Gene expression profiling analysis revealed that N-hydap reprograms neuroendocrine fate via inhibiting RORγ activity in SCLC. Chromatin immunoprecipitation analysis showed that N-hydap strongly reduced RORγ occupancy and transcriptional activation-linked histone marks H3K27ac on the promoter and/or enhancer sites of neurogenesis markers gene including aurora kinase a (AURKA), delta like canonical Notch ligand 3 (DLL3) and tubulin beta 3 class III (TUBB3). Therapeutically, N-hydap exhibited a strong inhibitory effect on tumor growth and did not show significant toxicity in SCLC mice xenograft models. Taken together, RORγ could be an attractive target for SCLC and thus N-hydap can be a promising therapeutic drug candidate for SCLC by inhibiting the RORγ activation.


Assuntos
Produtos Biológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Animais , Produtos Biológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Camundongos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia
3.
Acta Pharmacol Sin ; 43(4): 1024-1032, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34321613

RESUMO

Androgen receptor (AR) serves as a main therapeutic target for prostate cancer (PCa). However, resistance to anti-androgen therapy (SAT) inevitably occurs. Indomethacin is a nonsteroidal anti-inflammatory drug that exhibits activity against prostate cancer. Recently, we designed and synthesized a series of new indomethacin derivatives (CZ compounds) via Pd (II)-catalyzed synthesis of substituted N-benzoylindole. In this study, we evaluated the antitumor effect of these novel indomethacin derivatives in castration-resistant prostate cancer (CRPC). Upon employing CCK-8 cell viability assays and colony formation assays, we found that these derivatives had high efficacy against CRPC tumor growth in vitro. Among these derivatives, CZ-212-3 exhibited the most potent efficacy against CRPC cell survival and on apoptosis induction. Mechanistically, CZ-212-3 significantly suppressed the expression of AR target gene networks by degrading AR and its variants. Consistently, CZ-212-3 significantly inhibited tumor growth in CRPC cell line-based xenograft and PDX models in vivo. Taken together, the data show that the indomethacin derivative CZ-212-3 significantly inhibited CRPC tumor growth by degrading AR and its variants and could be a promising agent for CRPC therapy.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Linhagem Celular Tumoral , Proliferação de Células , Xenoenxertos , Humanos , Indometacina/farmacologia , Indometacina/uso terapêutico , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Microb Cell Fact ; 17(1): 15, 2018 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-29378572

RESUMO

BACKGROUND: The CRISPR/dCas9 system is a powerful tool to activate the transcription of target genes in eukaryotic or prokaryotic cells, but lacks assays in complex conditions, such as the biosynthesis of secondary metabolites. RESULTS: In this study, to improve the transcription of the heterologously expressed biosynthetic genes for the production of epothilones, we established the CRISPR/dCas9-mediated activation technique in Myxococcus xanthus and analyzed some key factors involving in the CRISPR/dCas9 activation. We firstly optimized the cas9 codon to fit the M. xanthus cells, mutated the gene to inactivate the nuclease activity, and constructed the dCas9-activator system in an epothilone producer. We compared the improvement efficiency of different sgRNAs on the production of epothilones and the expression of the biosynthetic genes. We also compared the improvement effects of different activator proteins, the ω and α subunits of RNA polymerase, and the sigma factors σ54 and CarQ. By using a copper-inducible promoter, we determined that higher expressions of dCas9-activator improved the activation effects. CONCLUSIONS: Our results showed that the CRISPR/dCas-mediated transcription activation is a simple and broadly applicable technique to improve the transcriptional efficiency for the production of secondary metabolites in microorganisms. This is the first time to construct the CRISPR/dCas9 activation system in myxobacteria and the first time to assay the CRISPR/dCas9 activations for the biosynthesis of microbial secondary metabolites.


Assuntos
Sistemas CRISPR-Cas/genética , Epotilonas/biossíntese , Família Multigênica , Myxococcus xanthus/genética , Proteínas Recombinantes/genética , Transcrição Gênica , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/metabolismo , Epotilonas/genética , Myxococcus xanthus/metabolismo , Regiões Promotoras Genéticas , RNA Guia de Cinetoplastídeos/genética , Metabolismo Secundário , Ativação Transcricional
5.
J Affect Disord ; 346: 42-48, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-37940054

RESUMO

BACKGROUND: It is well established that residence migration can negatively affect the mental health of adolescents. However, the related factors that mediate the association between residence migration and depression are still uncertain. METHODS: The participants were 16,037 adolescents in junior middle schools. A self-administered questionnaire was used for the survey. In addition to collecting general demographic characteristics of the participants, including age, gender, local residence status, only child status, parental marriage status and parent-child relationship, the questionnaire also contained the 9-item Patient Health Questionnaire, the short form of the Childhood Trauma Questionnaire and the Connor-Davidson Resilience Scale. Data analysis was conducted using SPSS software. RESULTS: A total of 14,059 valid questionnaires were collected, resulting in 12,122 local adolescents, defined as being born and raised locally, and 1937 migrant adolescents, defined as being transferred from other regions. Meanwhile, 53.3 % of local adolescents and 58.2 % of migrant adolescents reported depressive symptoms. This result indicated that residence migration might contribute to depression symptoms(OR = 1.136, 95%CI: 1.013-1.273, p < 0.05). Childhood maltreatment and parental divorce are risk factors for depression in migrant adolescents. For all adolescents, resilience and a good parent-child relationship may reduce the risk of depression. Childhood maltreatment completely mediates residence migration-related depression(95 % bootstrap CI = 0.146, 0.323). CONCLUSION: This study revealed that residence migration could contribute to adolescent depression, and childhood maltreatment may largely mediate this process, providing new insight into the relationship between adolescent depressive symptoms and residence migration. Reducing childhood maltreatment may effectively improve the depressive symptoms of migrant adolescents.


Assuntos
Maus-Tratos Infantis , Depressão , Humanos , Adolescente , Criança , Depressão/epidemiologia , Depressão/psicologia , Maus-Tratos Infantis/psicologia , Inquéritos e Questionários , Instituições Acadêmicas , Fatores de Risco
6.
Cell Rep Med ; 5(5): 101519, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38692271

RESUMO

Osteosarcoma (OS) is the most common malignant bone tumor with a poor prognosis. Here, we show that the nuclear receptor RORγ may serve as a potential therapeutic target in OS. OS exhibits a hyperactivated oxidative phosphorylation (OXPHOS) program, which fuels the carbon source to promote tumor progression. We found that RORγ is overexpressed in OS tumors and is linked to hyperactivated OXPHOS. RORγ induces the expression of PGC-1ß and physically interacts with it to activate the OXPHOS program by upregulating the expression of respiratory chain component genes. Inhibition of RORγ strongly inhibits OXPHOS activation, downregulates mitochondrial functions, and increases ROS production, which results in OS cell apoptosis and ferroptosis. RORγ inverse agonists strongly suppressed OS tumor growth and progression and sensitized OS tumors to chemotherapy. Taken together, our results indicate that RORγ is a critical regulator of the OXPHOS program in OS and provides an effective therapeutic strategy for this deadly disease.


Assuntos
Neoplasias Ósseas , Mitocôndrias , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Osteossarcoma , Fosforilação Oxidativa , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Osteossarcoma/genética , Humanos , Fosforilação Oxidativa/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Linhagem Celular Tumoral , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/tratamento farmacológico , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Ferroptose/genética , Ferroptose/efeitos dos fármacos , Camundongos Nus , Masculino , Proliferação de Células , Proteínas de Ligação a RNA
7.
J Affect Disord ; 340: 703-710, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37582465

RESUMO

Depressive and anxiety symptoms in adolescents have experienced increase their risk of peripheral mental health and social problems. For adolescents, the role of family environmental factors should be taken into consideration. This study aimed to explore the association between resilience and depressive and anxiety symptoms in adolescents and to extend the findings by examining the moderating effects of family environment. A total of 35,573 adolescents in middle schools were recruited in China. Childhood abuse, resilience, and symptoms of depression and anxiety were evaluated in adolescents. We found a significant association between resilience and symptoms of depression and anxiety [OR = 0.976 (0.975-0.978), P < 0.001; OR = 0.980 (0.978-0.981), P < 0.001]. The adjusted ORs (95 % CIs) for mental health across the categories of resilience were as follows: 1 (reference) for low resilience, 0.660 (0.620-0.703) for medium resilience, 0.309 (0.286-0.333) for high resilience. The relationship between resilience and depressive symptoms was stronger for girls, non-only children, and those without child abuse experience compared to boys, only child, and those with child abuse experience (all p < 0.05). Our findings of a nationally representative sample in China suggest that gender, only child, parent-child relationship and child abuse moderated the relationship between resilience and symptoms of depression and anxiety.


Assuntos
Ansiedade , Depressão , Masculino , Feminino , Humanos , Criança , Adolescente , Depressão/epidemiologia , Depressão/psicologia , Ansiedade/epidemiologia , Ansiedade/psicologia , Transtornos de Ansiedade/epidemiologia , Instituições Acadêmicas , Filho Único
8.
Front Psychiatry ; 13: 870346, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35463512

RESUMO

Background: The Coronavirus Disease-19 (COVID-19) pandemic negatively impacts mental health. Some published studies have investigated the prevalence of depression among children and adolescents in China during the pandemic. However, the results vary widely. We aimed to systematically analyze and estimate the prevalence of depressive symptoms and attempted to reveal the reasons for prevalence variety in previous studies. Methods: Published studies were searched in PubMed, Embase, Cochrane Central, the Chinese Scientific Journal Database (VIP Database), China National Knowledge database (CNKI), and the WanFang database from December 2019 to May 2021. The quality of all included studies was assessed by the Joanna Briggs Institute (JBI) checklist and the American Agency for Health Care Quality and Research's (AHRQ) cross-sectional study quality evaluation items. Meta-analysis was performed using random-effects modeling. Results: Of the 1,708 references screened, 13 related reports that involve 41,729 participants were included. The results suggested that the pooled prevalence of depressive symptoms among Chinese children and adolescents during the COVID-19 epidemic was 28.6%. Subgroup analyses showed that the pooled prevalence was highest among the studies using the Patient Health Questionnaire (PHQ)-9 (46.8%) and lowest among these using Depression Self-Rating Scale for Children (DSRSC) (11.4%). All studies using PHQ-9 set the cutoff at 5 points instead of 10. The pooled prevalence of studies that include primary school students was lower (16.5%) than that of studies excluding primary school students (39.1%). Conclusion: The meta-analysis suggests that depressive symptoms were relatively prevalent among Chinese children and adolescents during COVID-19, especially among the secondary school students. The suitable screening tools and cutoff should be carefully chosen in the survey.

9.
J Med Chem ; 64(18): 13918-13932, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34516133

RESUMO

Human dihydroorotate dehydrogenase (hDHODH) is an attractive tumor target essential to de novo pyrimidine biosynthesis. Novel potent hDHODH inhibitors with low toxicity are urgently needed. Herein, we demonstrate the isolation of 25 ascochlorin (ASC) derivatives, including 13 new ones, from the coral-derived fungus Acremonium sclerotigenum, and several of them showed pronounced inhibitions against hDHODH and triple-negative breast cancer (TNBC) cell lines, MDA-MB-231/-468. Interestingly, we found that hDHODH is required for proliferation and survival of TNBC cells, and several ASCs significantly inhibited TNBC cell growth and induced their apoptosis via hDHODH inhibition. Furthermore, the novel and potent hDHODH inhibitors (1 and 21) efficiently suppressed tumor growth in patient-derived TNBC xenograft models without obvious body weight loss or overt toxicity in mice. Collectively, our findings offered a novel lead scaffold as the hDHODH inhibitor for further development of potent anticancer agents and a potential therapeutic strategy for TNBC.


Assuntos
Alcenos/uso terapêutico , Antineoplásicos/uso terapêutico , Di-Hidro-Orotato Desidrogenase/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Fenóis/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Acremonium/química , Alcenos/química , Alcenos/isolamento & purificação , Alcenos/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Di-Hidro-Orotato Desidrogenase/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/metabolismo , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Estrutura Molecular , Fenóis/química , Fenóis/isolamento & purificação , Fenóis/metabolismo , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Acta Pharm Sin B ; 10(12): 2313-2322, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33354503

RESUMO

Prostate cancer (PCa) patients who progress to metastatic castration-resistant PCa (mCRPC) mostly have poor outcomes due to the lack of effective therapies. Our recent study established the orphan nuclear receptor RORγ as a novel therapeutic target for CRPC. Here, we reveal that elaiophylin (Elai), an antibiotic from Actinomycete streptomyces, is a novel RORγ antagonist and showed potent antitumor activity against CRPC in vitro and in vivo. We demonstrated that Elai selectively binded to RORγ protein and potently blocked RORγ transcriptional regulation activities. Structure-activity relationship studies showed that Elai occupied the binding pocket with several key interactions. Furthermore, Elai markedly reduced the recruitment of RORγ to its genomic DNA response element (RORE), suppressed the expression of RORγ target genes AR and AR variants, and significantly inhibited PCa cell growth. Importantly, Elai strongly suppressed tumor growth in both cell line based and patient-derived PCa xenograft models. Taken together, these results suggest that Elai is novel therapeutic RORγ inhibitor that can be used as a drug candidate for the treatment of human CRPC.

11.
Front Microbiol ; 8: 122, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28203231

RESUMO

dnaE is an alpha subunit of the tripartite protein complex of DNA polymerase III that is responsible for the replication of bacterial genome. The dnaE gene is often duplicated in many bacteria, and the duplicated dnaE gene was reported dispensable for cell survivals and error-prone in DNA replication in a mystery. In this study, we found that all sequenced myxobacterial genomes possessed two dnaE genes. The duplicate dnaE genes were both highly conserved but evolved divergently, suggesting their importance in myxobacteria. Using Myxococcus xanthus DK1622 as a model, we confirmed that dnaE1 (MXAN_5844) was essential for cell survival, while dnaE2 (MXAN_3982) was dispensable and encoded an error-prone enzyme for replication. The deletion of dnaE2 had small effects on cellular growth and social motility, but significantly decreased the development and sporulation abilities, which could be recovered by the complementation of dnaE2. The expression of dnaE1 was always greatly higher than that of dnaE2 in either the growth or developmental stage. However, overexpression of dnaE2 could not make dnaE1 deletable, probably due to their protein structural and functional divergences. The dnaE2 overexpression not only improved the growth, development and sporulation abilities, but also raised the genome mutation rate of M. xanthus. We argued that the low-expressed error-prone DnaE2 played as a balancer for the genome mutation rates, ensuring low mutation rates for cell adaptation in new environments but avoiding damages from high mutation rates to cells.

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