RESUMO
Proteolysis-targeting chimeras (PROTACs) selectively eliminate detrimental proteins by exploiting the ubiquitin-proteasome system (UPS), representing a promising therapeutic strategy against various diseases. Effective adaptations of degradation signal sequences and E3 ligases for PROTACs remain limited. Here, we employed three amino acidsâGly, Pro, and Lysâas the ligand to recruit the corresponding E3 ligases: CRL2ZYG11B/ZER1, GID4, and UBRs, to degrade EML4-ALK and mutant EGFR, two oncogenic drivers in NSCLC. We found that the extent of EML4-ALK and EGFR reduction can be easily fine-tuned by using different degradation signals. These amino acid-based PROTACs, termed AATacs, hindered proliferation and induced cell cycle arrest and apoptosis of NSCLC cells in vitro. Compared to other PROTACs, AATacs are small, interchangeable but with different degradation efficiency. Our study further expands the repertoire of E3 ligases and their ligands for PROTAC application, improving the versatility and utility of targeted protein degradation for therapeutic purposes.
Assuntos
Aminoácidos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteólise , Ubiquitina-Proteína Ligases , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteólise/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Aminoácidos/farmacologia , Aminoácidos/metabolismo , Aminoácidos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Quimera de Direcionamento de ProteóliseRESUMO
Reverse osmosis (RO) plays a pivotal role in shale gas wastewater resource utilization. However, managing the reverse osmosis concentrate (ROC) characterized by high salinity and increased concentrations of organic matter is challenging. In this study, we aimed to elucidate the enhancement effects and mechanisms of pre-ozonation on organic matter removal efficacy in ROC using a biological activated carbon (BAC) system. Our findings revealed that during the stable operation phase, the ozonation (O3 and O3/granular activated carbon)-BAC system removes 43.6-72.2 % of dissolved organic carbon, achieving a 4-7 fold increase in efficiency compared with that in the BAC system alone. Through dynamic analysis of influent and effluent water quality, biofilm performance, and microbial community structure, succession, and function prediction, we elucidated the following primary enhancement mechanisms: 1) pre-ozonation significantly enhances the biodegradability of ROC by 4.5-6 times and diminishes the organic load on the BAC system; 2) pre-ozonation facilitates the selective enrichment of microbes capable of degrading organic compounds in the BAC system, thereby enhancing the biodegradation capacity and stability of the microbial community; and 3) pre-ozonation accelerates the regeneration rate of the granular activated carbon adsorption sites. Collectively, our findings provide valuable insights into treating ROC through pre-oxidation combined with biotreatment.
Assuntos
Carvão Vegetal , Osmose , Ozônio , Eliminação de Resíduos Líquidos , Águas Residuárias , Eliminação de Resíduos Líquidos/métodos , Águas Residuárias/química , Carvão Vegetal/química , Biodegradação Ambiental , Poluentes Químicos da Água/análise , Gás NaturalRESUMO
BACKGROUND: The intestine of young ruminants is in the developmental stage and has weaker resistance to the changes of external environment. Improving intestinal health is vital to promoting growth of young ruminants. This study investigated effects of guanidino acetic acid (GAA) and rumen-protected betaine (RPB) supplementation on growth, dietary nutrient digestion and GAA metabolism in the small intestine of sheep. METHODS: Eighteen healthy Kazakh rams (27.46 ± 0.10 kg of body weight and 3-month old) were categorized into control, test group I and test group II, which were fed a basal diet, 1500 mg/kg GAA and 1500 mg/kg GAA + 600 mg/kg RPB, respectively. RESULTS: Compared with control group, test group II had increased (p < 0.05) average daily gain, plasma creatine level, ether extract (EE) and phosphorus digestibility on day 30. On day 60, the EE apparent digestibility, jugular venous plasma GAA, GAA content in the duodenal mucosa and GAA content in the jejunal and ileal mucosa of test group II were higher (p < 0.05) than other groups. Transcriptome analysis revealed that the differentially expressed genes (DEGs) involved in the duodenal pathways of oxidative phosphorylation and non-alcoholic fatty liver disease were significantly altered in test group II versus test group I (p < 0.05). Moreover, in the jejunum, the MAPK signalling pathway, complement and coagulation cascade and B-cell receptor signalling pathway were significantly enriched, with ATPase, solute carrier transporter protein, DHFR, SI, GCK, ACACA and FASN being the significantly DEGs (p < 0.05). CONCLUSION: Dietary supplementation of RPB on top of GAA in sheep diets may promote sheep growth and development by improving the body's energy, amino acid, glucose and lipid metabolism capacity.
Assuntos
Ração Animal , Betaína , Creatina , Dieta , Suplementos Nutricionais , Digestão , Glicina , Animais , Suplementos Nutricionais/análise , Betaína/metabolismo , Betaína/administração & dosagem , Ração Animal/análise , Dieta/veterinária , Masculino , Digestão/efeitos dos fármacos , Creatina/metabolismo , Glicina/análogos & derivados , Glicina/administração & dosagem , Glicina/metabolismo , Ovinos/fisiologia , Ovinos/metabolismo , Carneiro Doméstico/fisiologia , Carneiro Doméstico/metabolismo , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Distribuição Aleatória , Nutrientes/metabolismoRESUMO
BACKGROUND: Cytoplasmic epidermal growth factor receptor (EGFR) is overexpressed in both nasopharyngeal carcinoma (NPC) and triple-negative breast cancer (TNBC), while clinical outcome and prognosis vary greatly among patients treated with gefitinib, and all patients eventually develop resistance to this agent. Therefore, we propose a new concept for synthesizing multitarget compounds and reveal new therapeutic strategies for NPC and TNBC expressing EGFR. METHODS: Compound H was synthesized in our previous study. Molecular docking, and cell thermal shift assays (CETSAs) and drug affinity responsive target stability(DARTS) were used to confirm the binding of compound H to EGFR and GLUT1. Methylthiazolyldiphenyl-tetrazolium bromide(MTT), annexin V-PE assays, mitochondrial membrane potential (MMP) assays, and animal models were used to evaluate the inhibitory effect of compound H on TNBC cell lines. Energy metabolism tests, Western blotting, and immunofluorescence staining were performed to evaluate the synergistic effects on EGFR- and glucose transporter type 1(GLUT1)-mediated energy metabolism. RESULTS: Compound H can simultaneously act on the EGFR tyrosine kinase ATP-binding site and inhibit GLUT1-mediated energy metabolism, resulting in reductions in ATP, MMP, intra-cellular lactic acid, and EGFR nuclear transfer. The anti-tumor activity of compound H is significantly superior to the combination of GLUT1 inhibitor BAY876 and EGFR inhibitor gefitinib. Compound H has remarkable anti-proliferative effects on TNBC MDA-MB231 cells, and importantly, no obvious toxicity effects of compound H were found in vivo. CONCLUSIONS: Synergistic effects of inhibition of EGFR- and GLUT1-mediated energy metabolism by compound H may present a new strategy for the treatment of TNBC and NPC.
Assuntos
Antineoplásicos , Receptores ErbB , Transportador de Glucose Tipo 1 , Carcinoma Nasofaríngeo , Neoplasias de Mama Triplo Negativas , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Humanos , Animais , Linhagem Celular Tumoral , Feminino , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Simulação de Acoplamento Molecular , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Camundongos Nus , Camundongos Endogâmicos BALB C , Gefitinibe/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , CamundongosRESUMO
Lysosomes are essential components for managing tumor microenvironment and regulating tumor growth. Moreover, recent studies have also demonstrated that long non-coding RNAs could be used as a clinical biomarker for diagnosis and treatment of colorectal cancer. However, the influence of lysosome-related lncRNA (LRLs) on the progression of colon cancer is still unclear. This study aimed to identify a prognostic LRL signature in colon cancer and elucidated potential biological function. Herein, 10 differential expressed lysosome-related genes were obtained by the TCGA database and ultimately 4 prognostic LRLs for conducting a risk model were identified by the co-expression, univariate cox, least absolute shrinkage and selection operator analyses. Kaplan-Meier analysis, principal-component analysis, functional enrichment annotation, and nomogram were used to verify the risk model. Besides, the association between the prognostic model and immune infiltration, chemotherapeutic drugs sensitivity were also discussed in this study. This risk model based on the LRLs may be promising for potential clinical prognosis and immunotherapeutic responses related indicator in colon cancer patients.
Assuntos
Neoplasias do Colo , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Prognóstico , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Nomogramas , Lisossomos/genética , Microambiente Tumoral/genéticaRESUMO
Background: Endoplasmic reticulum (ER) stress is a therapeutic target in cancer given its regulation of bioenergetics and cell death. Methodology & results: We synthesized 14 ER stress-triggered anthraquinone derivatives by introducing an amino group at the 3-position side chain of the lead compound obtained previously. Most of the anthraquinone derivatives exhibited good antitumor activity due to their ability to induce ER damage through cytoplasmic vacuoles. The mechanisms of ER stress caused by compound KA-4c were related to increasing the expression levels of the ATF6 and Bip proteins and upregulating CHOP and cleaved PARP. Conclusion: Compound KA-4c triggers ER stress response and induces apoptosis via the ATF6-CHOP signaling pathway.