RESUMO
Due to the emerging global epidemic of obesity, developing safe and effective agents for anti-obesity is urgently needed. Our previous study found that 2-pyrimidinylindole derivative Wd3d exhibited potential anti-obesity activity. Herein, to further optimize the potential moiety, structural modifications were proceeded for two rounds in this study. Firstly, we designed, synthesized, and evaluated 36 new derivatives of 2-pyrimidinylindole scaffold with different substituents on the indole ring and pyrimidine ring to investigate their structure-activity relationship (SAR). Then, analogs with potent activity had the aldehyde group replaced with the acylhydrazone group to reduce cytotoxicity and improve metabolic stability. Detailed SAR studies and animal evaluation experiments led to the discovery of the compound 9ga, which significantly reduced TG accumulation with an EC50 value of 0.07 µM and showed relatively low cytotoxicity with an IC50 value of around 24 µM. Oral administration of 9ga effectively prevented the excessive growth of body weight and lessened fat mass as well as liver mass, decreased lipid accumulation in the liver and blood, and improved the heart injury parameter in the diet-induced obesity mouse model significantly better than Wd3d. A mechanism study showed that 9ga regulated the lipid metabolism during early adipogenesis by inhibiting PPARγ pathway. In conclusion, our study further highlights the anti-obesity potential of 2-pyrimidinylindole derivatives in diet-induced obesity.
RESUMO
The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound 14d, featuring an 8a-N-acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound 14d shares a similar lipid-lowering mechanism with our lead compound 3, but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of 14d significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify 14d as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an N-acylhydrazone to enhance drug-like properties.
Assuntos
Aldeídos , Fármacos Antiobesidade , Hidrazonas , Obesidade , Animais , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/uso terapêutico , Fármacos Antiobesidade/química , Hidrazonas/farmacologia , Hidrazonas/química , Hidrazonas/síntese química , Hidrazonas/farmacocinética , Hidrazonas/uso terapêutico , Camundongos , Relação Estrutura-Atividade , Aldeídos/química , Masculino , Obesidade/tratamento farmacológico , Camundongos Endogâmicos C57BL , Dieta Hiperlipídica/efeitos adversos , Humanos , Camundongos Obesos , Estrutura MolecularRESUMO
Obesity, a global pandemic posing a growing threat to human health, necessitates the development of effective and safe anti-obesity agents. Our previous studies highlighted the lipid-lowering effects of indolylquinazoline Bouchardatine and its derivatives. In this study, we employed scaffold hopping and simplification strategies to design and synthesize two new series derivatives by modifying the D ring. Extensive discussions have been conducted regarding the structure-activity relationship between lipid-lowering activity and the new compounds. These discussions have resulted in the discovery of 2-pyrimidinylindole derivatives as a promising scaffold for anti-obesity treatment. The new 2-pyrimidinylindole derivatives exhibited comparable lipid-lowering activity to the previously reported indolylquinazoline derivatives, including SYSU-3d and R17, with reduced toxicity. The most potent compound, 5a, demonstrated a larger therapeutic index, improved aqueous solubility and oral bioavailability compared to the previous lead compounds. In vivo evaluation indicated that 5a effectively reduced lipid accumulation in adipose tissue, improved glucose tolerance, and mitigated insulin resistance and liver function damage caused by a high-fat and high-cholesterol diet. Mechanism studies indicated that 5a may regulate lipid metabolism through the modulation of the PPARγ signaling pathway. Overall, our study has identified a highly active compound 5a, and provided the basis for further development of 2-pyrimidinylindole as a promising scaffold for obesity treatment.
Assuntos
Fármacos Antiobesidade , Hipercolesterolemia , Humanos , Metabolismo dos Lipídeos , Fármacos Antiobesidade/farmacologia , Disponibilidade Biológica , Obesidade/tratamento farmacológico , LipídeosRESUMO
Metabolic reprogramming is a crucial hallmark of tumorigenesis. Modulating the reprogrammed energy metabolism is an attractive anticancer therapeutic strategy. We previously found a natural product, bouchardatine, modulated aerobic metabolism and inhibited proliferation in the colorectal cancer cell (CRC). Herein, we designed and synthesized a new series of bouchardatine derivatives to discover more potential modulators. We applied the dual-parametric high-content screening (HCS) to evaluate their AMP-activated protein kinase (AMPK) modulation and CRC proliferation inhibition effect simultaneously. And we found their antiproliferation activities were highly correlated to AMPK activation. Among them, 18a was identified with nanomole-level antiproliferation activities against several CRCs. Interestingly, the evaluation found that 18a selectively upregulated oxidative phosphorylation (OXPHOS) and inhibited proliferation by modulating energy metabolism. Additionally, this compound effectively inhibited the RKO xenograft growth along with AMPK activation. In conclusion, our study identified 18a as a promising candidate for CRC treatment and suggested a novel anti-CRC strategy by AMPK activating and OXPHOS upregulating.
Assuntos
Proteínas Quinases Ativadas por AMP , Neoplasias Colorretais , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Alcaloides Indólicos/farmacologia , Metabolismo Energético , Proliferação de Células , Linhagem Celular TumoralRESUMO
The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (1). Among the new compounds, a6 with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA and 1 in TNBC cells. Remarkably, a6 caused more G4-related DNA damage and G4-related differentially expressed genes, consistent with its effect on disrupting the cell cycle, invasion, and glycolysis. Furthermore, a6 significantly suppresses the proliferation of various TNBC cells and the MDA-MB-231 xenograft model without evident toxicity. Our study suggests a novel strategy for TNBC therapeutics through dual-targeting HDAC and G4.
Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , DNA/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Zinco/farmacologiaRESUMO
Active crosstalk between the nervous system and breast cancer cells has been experimentally demonstrated in vitro and in animal models. However, low frequencies of peripheral nerve presence in human breast cancers reported in previous studies (~30% of cases) potentially negate a major role of the nervous system in breast cancer development and progression. This study aimed to clarify the incidence of nerves within human breast cancers and to delineate associations with clinicopathological features. Immunohistochemical staining was conducted in formalin-fixed paraffin-embedded breast cancer tissue sections using antibodies against the pan-neuronal markers protein gene product 9.5 and growth-associated protein 43, and the sympathetic nerve-specific marker tyrosine hydroxylase. Nerve trunks and isolated nerve fibers were quantitated. The chi-squared test was used to determine the associations between nerve counts and clinicopathological parameters. The log-rank test was used to compare differences in patient progression-free survival (PFS) and overall survival (OS). The overall frequency of peripheral nerves in breast cancers was 85%, a markedly higher proportion than reported previously. Of note, most nerves present in breast cancers were of the sympathetic origin. While high density of nerve trunks or isolated nerve fibers was associated with poor PFS and OS of patients, high nerve trunk density appeared also to predict poor patient PFS independently of lymph node metastasis. Innervation of breast cancers is a common event correlated with poor patient outcomes. These findings support the notion that the nervous system plays an active role in breast cancer pathogenesis.
RESUMO
Genomic amplification of the distal portion of chromosome 3q, which encodes a number of oncogenic proteins, is one of the most frequent chromosomal abnormalities in malignancy. Here we functionally characterise a non-protein product of the 3q region, the long noncoding RNA (lncRNA) PLANE, which is upregulated in diverse cancer types through copy number gain as well as E2F1-mediated transcriptional activation. PLANE forms an RNA-RNA duplex with the nuclear receptor co-repressor 2 (NCOR2) pre-mRNA at intron 45, binds to heterogeneous ribonucleoprotein M (hnRNPM) and facilitates the association of hnRNPM with the intron, thus leading to repression of the alternative splicing (AS) event generating NCOR2-202, a major protein-coding NCOR2 AS variant. This is, at least in part, responsible for PLANE-mediated promotion of cancer cell proliferation and tumorigenicity. These results uncover the function and regulation of PLANE and suggest that PLANE may constitute a therapeutic target in the pan-cancer context.
Assuntos
Processamento Alternativo/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias/genética , RNA Longo não Codificante/genética , Células A549 , Linhagem Celular Tumoral , Proliferação de Células/genética , Cromossomos Humanos Par 3/genética , Variações do Número de Cópias de DNA/genética , Fator de Transcrição E2F1/metabolismo , Células HCT116 , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/genética , Humanos , Células MCF-7 , Neoplasias/patologia , Correpressor 2 de Receptor Nuclear/genética , Interferência de RNA , RNA Interferente Pequeno/genéticaRESUMO
Based on our previous research, thirty new 5-amino-1H-1,2,4-triazoles possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities. Among them, compounds IIa, IIIh, and IIIm demonstrated significant antiproliferative activities against a panel of tumor cell lines, and the promising compound IIIm dose-dependently caused G2/M phase arrest in HeLa cells. Furthermore, analogue IIa exhibited the most potent tubulinpolymerization inhibitory activity with an IC50 value of 9.4 µM, and molecular modeling studies revealed that IIa formed stable interactions in the colchicine-binding site of tubulin, suggesting that 5-amino-1H-1,2,4-triazole scaffold has potential for further investigation to develop novel tubulin polymerization inhibitors with anticancer activity.
Assuntos
Antineoplásicos/farmacologia , Triazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Estrutura Molecular , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
PURPOSE: Ulcerative colitis (UC) patients have an increased risk of colorectal cancer (CRC), and compared with sporadic CRC, ulcerative colitis-associated colorectal cancer (CAC) is more aggressive with a worse prognosis. This study aimed to identify a gene signature to predict the risk of CAC for patients with UC in remission. PATIENTS AND METHODS: Series of quiescent UC-related transcriptome data obtained from the Gene Expression Omnibus (GEO) data set were divided into a training set and a validation set. Gene Set Variation Analysis (GSVA), Gene Set Enrichment Analysis (GSEA), and \Weighted Correlation Network Analysis (WGCNA) combined with protein-protein interaction (PPI) analysis were used to identify the pathways and gene signatures related to tumorigenesis among quiescent UC patients. A generalized linear model (GLM) of Poisson regression based on the training set was applied to estimate the diagnostic power of the gene signature in our validation set. RESULTS: The tumor necrosis factor (TNF) signaling via NF-κB pathway was significantly augmented with the highest normalized enrichment score (NES). The genes in the brown module from WGCNA have shown a significant correlation with CAC (Pearson coefficient = 0.83, p = 6e-06). A subset of NF-κB related genes (FOS, CCL4, CXCL1, MYC, CEBPB, ATF3, and JUNB) were identified with a relatively higher expression level in CAC samples. The diagnostic value of this 7-gene biomarker was estimated by the receiver operating characteristic (ROC) curve with an area under the ROC curve (AUC) at 0.82 (p<0.0001, 95% CI: 0.7098-0.9400) in the validation cohort. CONCLUSION: In summary, the increased expression of this seven-NF-κB-related gene signature may act as a powerful index for tumorigenesis prediction among patients with UC in remission.
RESUMO
PURPOSE: Pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) is associated with favourable outcomes of patients with triple-negative breast cancer (TNBC). However, a proportion of TNBC patients with the residual disease do not relapse and achieve long-term survival. The aim of this study was to identify biomarkers that predict clinical outcomes in these patients. PATIENTS AND METHODS: A retrospective series of 10 TNBC patients who displayed non-pCR to NACT were included in the discovery cohort. Total RNA from pre-NACT core biopsies and paired surgical specimens were subjected to the Affymetrix Human Transcriptome Array. Gene set enrichment analysis (GSEA) was used to identify signal pathways and gene signatures associated with metastasis. The Cox proportional hazard model and Kaplan-Meier survival curves were employed to assess the prognostic value of the identified signature in two independent TNBC datasets included in Gene Expression Omnibus (GEO). RESULTS: The epithelial-mesenchymal transition (EMT) pathway was markedly more enriched in pre- (NES = 1.92; p.adjust = 0.019) and post-NACT samples (NES = 2.02; p.adjust = 0.010) from patients who developed metastasis after NACT. A subset of 6 EMT genes including LUM, SFRP4, COL6A3, MMP2, CXCL12, and HTRA1 were expressed constantly at higher levels in samples from patients who progressed to metastatic disease. The potential of the 6-EMT gene signature to predict TNBC metastasis after NACT was validated with a GEO dataset (HR=0.36, p=0.0008, 95% CI: 0.200-0.658). Moreover, the signature appeared of predictive value in another GEO dataset of TNBC patients who received surgery followed by adjuvant chemotherapy (HR = 0.46, 95% CI: 0.225-0.937). CONCLUSION: Expression analysis of the 6-EMT gene signature at diagnosis may be of predictive value for metastasis in TNCB patients who did not achieve pCR to NACT and for patients treated with surgery in combination with adjuvant therapy.
RESUMO
Metastatic breast involvement from extra-mammary neoplasms is unusual with a low incidence of 0.5% to 1.2% in clinical practice, 2.7% in cytological series, and 1.7% to 6.6% in autopsy series of all breast malignancies. Nearly 500 cases have been reported in small series and case reports. Gastric carcinoma rarely metastasizes to the breast. There are only 38 cases reported in PubMed. In this study, we present a case report of a 49-year-old woman who was diagnosed with right breast metastasis from a gastric carcinoma and undertake a literature review to pay attention to the diagnosis, treatment, and the prognosis of the disease.
Assuntos
Neoplasias da Mama/secundário , Carcinoma de Células em Anel de Sinete/secundário , Neoplasias Gástricas/patologia , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Carcinoma de Células em Anel de Sinete/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Neoplasias Gástricas/diagnósticoRESUMO
PM2.5 and PM10 samples were collected on campus of Xinjiang Agricultural University during Dec. 14-28, 2009, and the speciation of Cd in PM10 and PM2.5 and its health risk index was analyzed. The results showed that the pollution caused by PM10 and PM2.5 was severe here during the heating period; Cd in PM10 and PM2.5 was of concentration 3.642 and 1.964 ng x m(-3) respectively, mainly in the form of residue; however, Cd in PM2.5 had a higher bioavailability than that in PM10. The carcinogenic risk of Cd in PM10 and PM2.5 was 6.56 x 10(-6) and 3.46 x 10(-6) respectively, which were both acceptable.
Assuntos
Poluentes Atmosféricos/análise , Cádmio/análise , Monitoramento Ambiental , China , Tamanho da PartículaRESUMO
<p><b>INTRODUCTION</b>The primary and secondary objectives of this study were to identify and assess the risks associated with the occurrence of drug-drug interactions (DDIs) and to determine the value of pharmacists' interventions in the management of clinically significant DDIs, respectively.</p><p><b>METHODS</b>A prospective, case-control study was carried out on patients admitted to the intensive care unit (ICU), and involved a review of patients' medication chart daily by the pharmacist and the clinical parameters. All identified DDIs were carefully analysed in order to provide recommendations on the management of clinically significant DDIs.</p><p><b>RESULTS</b>The majority of DDIs were categorised as Type-C severity level (n = 305, 75.9%). 'Substitution' was recommended in 34 cases of clinically significant DDIs, 'dosage adjustment' in 17 (4.2%) and 'stop or avoid' in 13 (3.2%). The number of drugs prescribed (p = 0.001, rS = 0.539) and length of ICU stay (p = 0.001, rS = 0.364) were significantly associated and positively correlated with the occurrence of DDIs. Patients with DDIs had a longer length of ICU stay than those without DDIs (9.5 days vs. 2.4 days, p = 0.001). No significant difference was found between patients aged below 50 years and those above 50 years (odds ratio 0.488, 95% confidence interval 0.166-1.434) in terms of the risk of DDIs.</p><p><b>CONCLUSION</b>A large number of DDIs were identified in this study, but only a small number were clinically significant. Pharmacists' participation in daily ward rounds could play an important role in the detection and management of clinically significant DDIs.</p>
Assuntos
Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Estudos de Casos e Controles , Interações Medicamentosas , Unidades de Terapia Intensiva , Farmacêuticos , Estudos Prospectivos , Medição de Risco , Métodos , Fatores de RiscoRESUMO
<p><b>OBJECTIVE</b>To investigate the clinical effect of electrochemical therapy (ECT) combined with pingyangmycin (PYM) injection for the treatment of high-return flow venous malformation.</p><p><b>METHODS</b>A total of 68 cases of the high-return flow venous malformation were retrospectively analyzed, in which 32 cases received simplely ECT,and 36 cases received ECT combined with PYM injection. The patients were followed up from 6 to 30 months.</p><p><b>RESULTS</b>The effectiveness of ECT was 78% (25/32), and of ECT combined with PYM injection was 97% (35/36). The effectiveness of ECT combined with PYM injection was higher than that of ECT (P < 0.05). No serious adverse effects were encountered.</p><p><b>CONCLUSIONS</b>ECT combined with PYM injection is an effective method for the treatment of high-return flow venous malformation.</p>
Assuntos
Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Bleomicina , Usos Terapêuticos , Velocidade do Fluxo Sanguíneo , Terapia Combinada , Técnicas Eletroquímicas , Métodos , Seguimentos , Injeções , Estudos Retrospectivos , Malformações Vasculares , Tratamento Farmacológico , Terapêutica , Veias , Anormalidades CongênitasRESUMO
<p><b>OBJECTIVE</b>To investigate the expression and correlation of mast cell, Clusterin/apoJ and transforming growth factor-beta (TGF-beta) in the different stages of human dermal hemangioma.</p><p><b>METHODS</b>Immunohistochemical stain technique (SABC) and toluidine blue (TB) stain technique were respectively used to detect the expression level of Clusterin/apoJ and TGF-beta and the number of mast cells in the different stages of human dermal hemangioma.</p><p><b>RESULTS</b>There was remarkable statistical difference between the advanced stage of proliferative hemangioma and the other stages of proliferative hemangioma in the number of mast cell(P<0.01). There was also remarkable statistical difference between the early stage of involutional hemangioma and the other stages of involutional hemangioma in the number of mast cell (P<0.01). The expression of Clusterin/apoJ and TGF-beta in the advanced stage of proliferative hemangioma was significantly higher than the other stages in proliferative hemangioma (P<0.01). The expression of Clusterin/apoJ and TGF-beta in the early stage of involutional hemangioma was significantly higher than the other stages in involutional hemangioma (P<0.01). There was a significantly positive correlation between Clusterin/apoJ and TGF-beta in the different stages of human dermal hemangioma (P<0.01). The expression level of Clusterin/apoJ and TGF-beta was positively correlated with the number of mast cell in the different stages of human dermal hemangioma (P<0.01).</p><p><b>CONCLUSION</b>Mast cell may play a promotive role of apoptosis during the spontaneous regulate the expression of Clusterin/apoJ and promote the spontaneous involution of human dermal hemangioma.</p>