RESUMEN
Cuproptosis is characterized by the aggregation of lipoylated enzymes of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. As dysregulation of copper homeostasis can induce cuproptosis, there is emerging interest in exploiting cuproptosis for cancer therapy. However, the molecular drivers of cancer cell evasion of cuproptosis were previously undefined. Here, we found that cuproptosis activates the Wnt/ß-catenin pathway. Mechanistically, copper binds PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/ß-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/ß-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed the ß-catenin/TCF4 transcriptional complex directly binds the ATP7B promoter, inducing its expression. ATP7B effluxes copper ions, reducing intracellular copper and inhibiting cuproptosis. Knockdown of TCF4 or pharmacological Wnt/ß-catenin blockade increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/ß-catenin pathway and cuproptosis sensitivity, and suggest a precision medicine strategy for cancer treatment through selective cuproptosis induction.
RESUMEN
Transition metal elements, such as copper, play diverse and pivotal roles in oncology. They act as constituents of metalloenzymes involved in cellular metabolism, function as signaling molecules to regulate the proliferation and metastasis of tumors, and are integral components of metal-based anticancer drugs. Notably, recent research reveals that excessive copper can also modulate the occurrence of programmed cell death (PCD), known as cuprotosis, in cancer cells. This modulation occurs through the disruption of tumor cell metabolism and the induction of proteotoxic stress. This discovery uncovers a mode of interaction between transition metals and proteins, emphasizing the intricate link between copper homeostasis and tumor metabolism. Moreover, they provide innovative therapeutic strategies for the precise diagnosis and treatment of malignant tumors. At the crossroads of chemistry and oncology, we undertake a comprehensive review of copper homeostasis in tumors, elucidating the molecular mechanisms underpinning cuproptosis. Additionally, we summarize current nanotherapeutic approaches that target cuproptosis and provide an overview of the available laboratory and clinical methods for monitoring this process. In the context of emerging concepts, challenges, and opportunities, we emphasize the significant potential of nanotechnology in the advancement of this field.
Asunto(s)
Metaloproteínas , Neoplasias , Elementos de Transición , Cobre , Apoptosis , Nanotecnología , Neoplasias/tratamiento farmacológicoRESUMEN
A novel microbial consortium ZY1 capable of degrading tricresyl phosphates (TCPs) was isolated, it could quickly degrade 100% of 1 mg/L tri-o-cresyl phosphate (ToCP), tri-p-cresyl phosphate (TpCP) and tri-m-cresyl phosphate (TmCP) within 36, 24 and 12 h separately and intracellular enzymes occupied the dominated role in TCPs biodegradation. Additionally, triphenyl phosphate (TPHP), 2-ethylhexyl diphenyl phosphate (EHDPP), bisphenol-A bis (diphenyl phosphate) (BDP), tris (2-chloroethyl) phosphate (TCEP) and tris (1-chloro-2-propyl) phosphate (TCPP) could also be degraded by ZY1 and the aryl-phosphates was easier to be degraded. The TCPs reduction observed in freshwater and seawater indicated that high salinity might weak the degradability of ZY1. The detected degradation products suggested that TCPs was mainly metabolized though the hydrolysis and hydroxylation. Sequencing analysis presented that the degradation of TCPs relied on the cooperation between sphingobacterium, variovorax and flavobacterium. The cytochrome P450/NADPH-cytochrome P450 reductase and phosphatase were speculated might involve in TCPs degradation. Finally, toxicity evaluation study found that the toxicity of the diesters products was lower than their parent compound based on the generation of the intracellular reactive oxygen (ROS) and the apoptosis rate of A549 cell. Taken together, this research provided a new insight for the bioremediation of TCPs in actual environment.
Asunto(s)
Retardadores de Llama , Tritolilfosfatos , Biodegradación Ambiental , Retardadores de Llama/análisis , Isomerismo , Consorcios Microbianos , Organofosfatos/toxicidad , Fosfatos/análisis , Tritolilfosfatos/análisisRESUMEN
BACKGROUND: N6-methyladenosine (m6A) plays a critical role in various biological processes. However, no study has addressed the role of m6A modification in the statin-induced protection of endothelial cells (ECs). METHODS: Quantitative real-time polymerase chain reaction and Western blotting analyses were used to study the expression of m6A regulatory genes in atorvastatin-treated ECs. Gain- and loss-of-function assays, methylated RNA immunoprecipitation analysis, and dual-luciferase reporter assays were performed to clarify the function of FTO (fat mass and obesity-associated protein) in ECs. RESULTS: Atorvastatin decreased FTO protein expression in ECs. The knockdown of FTO enhanced the mRNA and protein expression of KLF2 (Kruppel-like factor 2) and eNOS (endothelial NO synthase) but attenuated TNFα (tumor necrosis factor alpha)-induced VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) expression, as well as the adhesion of monocytes to ECs. Conversely, FTO overexpression significantly upregulated the mRNA and protein levels of VCAM-1 and ICAM-1, downregulated those of KLF2 and eNOS, and strongly attenuated the atorvastatin-mediated induction of KLF2 and eNOS expression. Subsequent investigations demonstrated that KLF2 and eNOS are functionally critical targets of FTO. Mechanistically, FTO interacted with KLF2 and eNOS transcripts and regulated their expression in an m6A-dependent manner. After FTO silencing, KLF2 and eNOS transcripts with higher levels of m6A modification in their 3' untranslated regions were captured by YTHDF3 (YT521-B homology m6A RNA-binding protein 3), resulting in mRNA stabilization and the induction of KLF2 and eNOS protein expression. CONCLUSIONS: FTO might serve as a novel molecular target to modulate endothelial function in vascular diseases.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacología , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Atorvastatina/farmacología , Células Endoteliales/metabolismo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Molécula 1 de Adhesión Intercelular , Obesidad/genética , ARN Mensajero/genética , Molécula 1 de Adhesión Celular VascularRESUMEN
INTRODUCTION: Previously meta-analysis had different conclusions about the role of breastfeeding in mother-to-child transmission (MTCT) of hepatitis B virus (HBV). We aimed to carry out an updated meta-analysis based on current published evidence to explore that whether breastfeeding increase the risk of HBV infection from mothers carrying HBV after proper immunoprophylaxis in the infants or not. EVIDENCE ACQUISITION: Databases searched from January 1st,2000 to August 1st,2016 included PubMed searching engine, Cochrane Library, Embase database, Chinese National Knowledge Infrastructure, VIP Chinese database, and Wanfang Chinese database. EVIDENCE SYNTHESIS: 17 studies were incorporated into our meta-analysis. Our result showed that there was no significant difference between the breastfeeding group and the non-breastfeeding group (ORs=1.01, 95%CI: 0.75-1.36, I2=0). Further, there was no significant difference between the cases and controls in HBVac group (ORs=1.08, 95%CI: 0.42-2.76, I2=0) and in HBIG combined with HBVac group (ORs=0.97, 95%CI: 0.68-1.37, I2=0). CONCLUSIONS: Our update meta-analysis indicated that breastfeeding would not increase the risk of HBV injection from mothers carrying HBV after proper immunoprophylaxis in the infants. The results suggest that mother carrying HBV can breastfeed their babies after proper immunoprophylaxis in the infants.
Asunto(s)
Lactancia Materna/efectos adversos , Portador Sano/virología , Virus de la Hepatitis B , Hepatitis B/transmisión , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Análisis de Datos , Femenino , Hepatitis B/inmunología , Hepatitis B/prevención & control , Hepatitis B/virología , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/inmunología , Humanos , Inmunización , Lactante , Recién Nacido , Oportunidad Relativa , Sesgo de PublicaciónRESUMEN
In this study, the effects of Rhodopseudomonas capsulata present in wastewater effluent on the biodegradation of carbaryl in soil and improvement of soil fertility were investigated. Compared to control treatment, carbaryl was removed efficiently and soil fertility was remediated with the addition of effluent containing R. capsulata. Molecular analysis revealed that carbaryl induced carbaryl hydrolase gene expression to synthesize carbaryl hydrolase through activating MAPKKKs, MAPKKs, MAPKs genes in MAPK signal transduction pathway. The induction and secretion of carbaryl hydrolase occur after one day in R. capsulata, which can be attributed to its characteristics as an ancient bacteria, which require acclimatization to carbaryl before gene induction. However, lack of organics in soil and control treatment could not maintain R. capsulata growth for over one day. The residual organics in the effluent provided sufficient carbon source and energy for R. capsulata under four effluent treatments. This new method resulted in the remediation of carbaryl pollution and improvement of soil fertility and soybean processing wastewater treatment simultaneously, as well as the reutilization of wastewater and R. capsulata as sludge. Meanwhile, the high-order non-linear mathematical model about carbaryl removal rate was established.
Asunto(s)
Rhodobacter capsulatus , Aguas Residuales , Biodegradación Ambiental , Carbaril , SueloRESUMEN
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of Editors-in-Chief and first Author. The article duplicates significant parts of a paper that had already appeared in Fish & Shellfish Immunology, Volume 93 (2019) 726-731, https://doi.org/10.1016/j.fsi.2019.06.052. One of the conditions of submission of a paper for publication is that authors declare explicitly that the paper has not been previously published and is not under consideration for publication elsewhere. As such this article represents a misuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. The first author informed the journal that the article was published without the knowledge of the co-authors.
Asunto(s)
Burkholderiales/metabolismo , Carpas/fisiología , Eliminación de Residuos Líquidos , Aguas Residuales/microbiología , Calidad del Agua , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Acuicultura , Carpas/crecimiento & desarrollo , Carpas/microbiología , Digestión , Resistencia a la Enfermedad , Microbioma Gastrointestinal , Transducción de SeñalRESUMEN
Simultaneous (SPW and propyzamide) wastewater treatment and the production of biochemicals by Rhodopseudomonas capsulata (R. capsulata) were investigated with supplement of soybean processing wastewater (SPW). Compared to control group, propyzamide was removed and biochemicals production were enhanced with the supplement of SPW. Propyzamide induced camH gene expression through activating MAPKKKs gene in MAPK signal transduction pathway. The induction of camH gene and CamH occurs after 1 day for R. capsulata. However, lack of organics in original wastewater did not maintain R. capsulata growth for over 1 day. The supplement of SPW provided sufficient carbon source for R. capsulata under three addition dosages. This new method resulted in the mixed (SPW and propyzamide) wastewater treatment and improvement of biochemicals simultaneously, as well as the realization of reutilization of wastewater and R. capsulata as sludge. Meanwhile, high-order nonlinear mathematical model of the relationship between propyzamide removal rate, Xt and Xt/r, was established.
Asunto(s)
Benzamidas , Glycine max/química , Rhodopseudomonas/crecimiento & desarrollo , Eliminación de Residuos Líquidos , Aguas Residuales/microbiología , Benzamidas/química , Benzamidas/metabolismoRESUMEN
The biorestoration of cyhalofop-butyl and fertility in soil using Rhodopseudanonas palustris (R. palustris) in the treated wastewater were investigated in this research. Cyhalofop-butyl was not degraded under control group. The treated wastewater containing R. palustris degraded cyhalofop-butyl and remediated fertility. Interestingly, the cyhalofop-butyl-hydrolyzing carboxylesterase gene was expressed after inoculation 24â¯h. Subsequently, the cyhalofop-butyl-hydrolyzing carboxylesterase were synthesized to degrade cyhalofop-butyl. The cyhalofop-butyl started to be degraded after inoculation 24â¯h. The cyhalofop-butyl as stimulus signal induced cyhalofop-butyl-hydrolyzing carboxylesterase gene expression through signal transduction pathway. This process took 24â¯h for R. palustris as they were ancient bacteria. The residual organics in the wastewater provided sufficient carbon sources and energy for R. palustris under three dosage groups. The new method completed the remediation of cyhalofop-butyl pollution, the improvement of soil fertility and soybean processing wastewater treatment simultaneously, and realized the resource reutilization of wastewater and R. palustris as sludge.