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1.
Int J Mol Sci ; 24(8)2023 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-37108141

RESUMEN

The Saccharomyces cerevisiae Agp2 is a plasma membrane protein initially reported to be an uptake transporter for L-carnitine. Agp2 was later rediscovered, together with three additional proteins, Sky1, Ptk2, and Brp1, to be involved in the uptake of the polyamine analogue bleomycin-A5, an anticancer drug. Mutants lacking either Agp2, Sky1, Ptk2, or Brp1 are extremely resistant to polyamines and bleomycin-A5, suggesting that these four proteins act in the same transport pathway. We previously demonstrated that pretreating cells with the protein synthesis inhibitor cycloheximide (CHX) blocked the uptake of fluorescently labelled bleomycin (F-BLM), raising the possibility that CHX could either compete for F-BLM uptake or alter the transport function of Agp2. Herein, we showed that the agp2Δ mutant displayed striking resistance to CHX as compared to the parent, suggesting that Agp2 is required to mediate the physiological effect of CHX. We examined the fate of Agp2 as a GFP tag protein in response to CHX and observed that the drug triggered the disappearance of Agp2 in a concentration- and time-dependent manner. Immunoprecipitation analysis revealed that Agp2-GFP exists in higher molecular weight forms that were ubiquitinylated, which rapidly disappeared within 10 min of treatment with CHX. CHX did not trigger any significant loss of Agp2-GFP in the absence of the Brp1 protein; however, the role of Brp1 in this process remains elusive. We propose that Agp2 is degraded upon sensing CHX to downregulate further uptake of the drug and discuss the potential function of Brp1 in the degradation process.


Asunto(s)
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Cicloheximida/farmacología , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Bleomicina/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo
2.
Int J Mol Sci ; 23(13)2022 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-35806243

RESUMEN

Cisplatin (cis-diamminedichloroplatinum (II)) is the oldest known chemotherapeutic agent. Since the identification of its anti-tumour activity, it earned a remarkable place as a treatment of choice for several cancer types. It remains effective against testicular, bladder, lung, head and neck, ovarian, and other cancers. Cisplatin treatment triggers different cellular responses. However, it exerts its cytotoxic effects by generating inter-strand and intra-strand crosslinks in DNA. Tumour cells often develop tolerance mechanisms by effectively repairing cisplatin-induced DNA lesions or tolerate the damage by adopting translesion DNA synthesis. Cisplatin-associated nephrotoxicity is also a huge challenge for effective therapy. Several preclinical and clinical studies attempted to understand the major limitations associated with cisplatin therapy, and so far, there is no definitive solution. As such, a more comprehensive molecular and genetic profiling of patients is needed to identify those individuals that can benefit from platinum therapy. Additionally, the treatment regimen can be improved by combining cisplatin with certain molecular targeted therapies to achieve a balance between tumour toxicity and tolerance mechanisms. In this review, we discuss the importance of various biological processes that contribute to the resistance of cisplatin and its derivatives. We aim to highlight the processes that can be modulated to suppress cisplatin resistance and provide an insight into the role of uptake transporters in enhancing drug efficacy.


Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Cisplatino/farmacología , Cisplatino/uso terapéutico , ADN/uso terapéutico , Reparación del ADN , Resistencia a Antineoplásicos , Humanos , Neoplasias/tratamiento farmacológico
3.
Antibiotics (Basel) ; 13(10)2024 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-39452224

RESUMEN

BACKGROUND: The resurgence of colistin has become critical in combating multidrug-resistant Gram-negative bacteria. However, the emergence of mobilized colistin resistance (mcr) genes presents a crucial global challenge, particularly in the Arab world, which includes regions with unique conditions and ongoing conflicts in some parts. METHODS: To address this issue, a systematic review was conducted using multiple databases, including Cochrane, PubMed, Scopus, Web of Science, and Arab World Research Source. RESULTS: A total of 153 studies were included, revealing substantial heterogeneity in the prevalence of mcr genes across 15 Arab countries, with notable findings indicating that Egypt and Lebanon reported the highest number of cases. The analysis indicated that the most prevalent sequence types were ST10, ST101, and ST1011, all of which are Escherichia coli strains linked to significant levels of colistin resistance and multiple antimicrobial resistance profiles. CONCLUSIONS: By analyzing the diverse findings from different Arab countries, this review lays a critical foundation for future research and highlights the necessity for enhanced surveillance and targeted interventions to address the looming threat of colistin resistance in the region. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42024584379.

4.
Cells ; 12(23)2023 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-38067110

RESUMEN

Targeting tumour metabolism through glucose transporters is an attractive approach. However, the role these transporters play through interaction with other signalling proteins is not yet defined. The glucose transporter SLC2A3 (GLUT3) is a member of the solute carrier transporter proteins. GLUT3 has a high affinity for D-glucose and regulates glucose uptake in the neurons, as well as other tissues. Herein, we show that GLUT3 is involved in the uptake of arsenite, and its level is regulated by peroxiredoxin 1 (PRDX1). In the absence of PRDX1, GLUT3 mRNA and protein expression levels are low, but they are increased upon arsenite treatment, correlating with an increased uptake of glucose. The downregulation of GLUT3 by siRNA or deletion of the gene by CRISPR cas-9 confers resistance to arsenite. Additionally, the overexpression of GLUT3 sensitises the cells to arsenite. We further show that GLUT3 interacts with PRDX1, and it forms nuclear foci, which are redistributed upon arsenite exposure, as revealed by immunofluorescence analysis. We propose that GLUT3 plays a role in mediating the uptake of arsenite into cells, and its homeostatic and redox states are tightly regulated by PRDX1. As such, GLUT3 and PRDX1 are likely to be novel targets for arsenite-based cancer therapy.


Asunto(s)
Arsenitos , Transportador de Glucosa de Tipo 3 , Arsenitos/toxicidad , Glucosa/metabolismo , Transportador de Glucosa de Tipo 3/genética , Transportador de Glucosa de Tipo 3/metabolismo , Linfocitos Nulos/efectos de los fármacos , Linfocitos Nulos/metabolismo , Peroxirredoxinas/metabolismo , Humanos , Células HEK293
5.
Sci Rep ; 12(1): 10023, 2022 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-35705668

RESUMEN

Rapamycin is an immunosuppressant used for treating many types of diseases such as kidney carcinomas. In yeast, rapamycin inhibits the TORC1 kinase signaling pathway causing rapid alteration in gene expression and ultimately cell cycle arrest in G1 through mechanisms that are not fully understood. Herein, we screened a histone mutant collection and report that one of the mutants, H2B R95A, is strikingly resistant to rapamycin due to a defective cell cycle arrest. We show that the H2B R95A causes defects in the expression of a subset of genes of the pheromone pathway required for α factor-induced G1 arrest. The expression of the STE5 gene and its encoded scaffold protein Ste5, required for the sequential activation of the MAPKs of the pheromone pathway, is greatly reduced in the H2B R95A mutant. Similar to the H2B R95A mutant, cells devoid of Ste5 are also resistant to rapamycin. Rapamycin-induced G1 arrest does not involve detectable phosphorylation of the MAPKs, Kss1, and Fus3, as reported for α factor-induced G1 arrest. However, we observed a sharp induction of the G1 cyclin Cln2 (~ 3- to 4-fold) in the ste5Δ mutant within 30 min of exposure to rapamycin. Our data provide a new insight whereby rapamycin signaling via the Torc1 kinase may exploit the pheromone pathway to arrest cells in the G1 phase.


Asunto(s)
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Ciclinas/metabolismo , Proteínas Fúngicas/genética , Histonas/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Feromonas/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Sirolimus/metabolismo , Sirolimus/farmacología
6.
Microbiol Resour Announc ; 10(2)2021 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-33446591

RESUMEN

Resistance to colistin, a last-resort antibiotic, threatens the treatment of complicated infections, especially in susceptible populations such as Syrian refugees who live in makeshift camps. Two multidrug-resistant Escherichia coli strains with the plasmid-borne colistin resistance gene (mcr-1.1) were isolated from the waters used by refugees and sequenced to analyze antibiotic resistance determinants.

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