Emergence of methicillin resistance predates the clinical use of antibiotics.

The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics1. Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two β-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development

Arrêts du cycle cellulaire et induction d'apoptose pour les lignées de carcinome humain de la tête et du cou HPV-18 positives, après exposition au 5-fluorouracile et aux radiations ionisantes : implication de NF-kB dans la radiosensibilité et l'apoptose spontanée

Non disponible / Not availableDans le cadre de l'étude de la réponse aux traitements anticancéreux, de nombreuses équipes se sont interessées aux comportements cellulaires après exposition aux stress génotoxiques. Les mécanismes cellulaires qu'ils induisent, tels que des blocages dans le cycle ou la mise en place de l'apoptose, ainsi que la sensibilité des cellules, varient selon la nature de ces stress. La protéine P53 occupe un rôle central dans le contrôle du cycle cellulaire ainsi que dans la régulation de l'apoptose. Cependant, dans de nombreux cancers, la fonctionnalité de la protéine P53 est abrogée par des mutations ou des délétions de son gène. D'autres facteurs peuvent entraîner la perte de fonctionnalité de P53. Ainsi, la protéine E6 codée par le virus du papillome humain (HPV), est responsable de la dégradation de P53. Les études portant sur le comportement de cellules HPV positives exposées à des stress génotoxiques comme le 5-fluorouracile (5FU) ou les radiations ionisantes restent rares. La répartition des cellules dans le cycle cellulaire ainsi que l'induction de l'apoptose ont été étudiées après exposition au 5FU ou aux radiations ionisantes, pour les lignées KB et KB3 de carcinome humain de la tête et du cou exprimant une protéine P53 sauvage et infectées par HVP-18. Les deux types de stress induisent une augmentation de l'expression de la protéine P53, en relation avec une diminution de l'expression de la protéine virale E6. Ainsi, malgré le statut HPV des cellules, la protéine P53 reste inductible est fonctionnelle. Le 5FU entraîne un arrêt des cellules en G [exposant 1]/S alors qu'après irradiation les cellules se bloquent en G [exposant2]/M. L'arrêt en G [exposant]1/S apparait avant l'induction de P53, mais celle-ci peut participer au maintien de ce blocage puisqu'elle induit l'expression de P21. Par contre, la mise en place de l'arrêt en G [exposant2]/M est indépendant de P53 mais celle-ci pourrait participer à la levée de ce blocage. Enfin, les deux types de stress peuvent induire de l'apoptose P53-dépendante après exposition au 5FU et P53-indépendante après irradiation. Selon le type de stress génotoxique, le comportement cellulaire peut être différent et l'implication de la protéine P53 sur les mécanismes cellulaires induits, peut se faire à différents niveaux même pour des lignées HVP-positives. Cependant, la protéine P53 n'est pas la seule à posséder un rôle important dans le contrôle du cycle cellulaire et de l'apoptose. En effet, le facteur de transcription NF-KB a été décrit comme étant impliqué dans ces mécanismes cellulaires ainsi que dans la sensibilité des cellules à un stress tel qu'une irradiation. Pour les lignées KB et KB3, une différence d'activité constitutive de NF-KB a été mise en évidence. La modulation de cette activité par exposition des cellules au TNFa. et à la dexaméthasone, a permis de démontrer que l'activité constitutive de NF-KB était en relation avec le phénomène d'apoptose spontanée et le niveau de radiosensibilité. Ainsi, cette activité constitutive serait un paramètre prédictif de la radiosensibilité des cellules et son inhibition avant traitement pourrait être une nouvelle approche de radiopotentialisation

Biomodulation du facteur de transcription NF-κB par les radiations ionisantes

NF-κB (Nuclear Factor -κB) was described for the first time in 1986 as a nuclear protein binding to the kappa immunoglobulin-light chain enhancer. Since then, NF-κB has emerged as an ubiquitous factor involved in the regulation of numerous important processes as diverse as immune and inflammatory responses, apoptosis and cell proliferation. These last two properties explain the implication of NF-κB in the tumorigenic process as well as the promise of a targeted therapeutic intervention. This review focuses on the current knowledge on NF-κB regulation and discusses the therapeutic potential of targeting NF-κB in cancer in particular during radiotherapy. © 2004 Elsevier SAS. Tous droits réservés.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Radiation could induce p53-independent and cell cycle - Unrelated apoptosis in 5-fluorouracil radiosensitized head and neck carcinoma cells

The effect of chemoresistance induction in radiosensitivity and cellular behavior after irradiation remains misunderstood. This study was designed to understand the relationship between radiation-induced cell cycle arrest, apoptosis, and radiosensitivity in KB cell line and KB3 subline selected after 5-fluorouracil (5FU) exposure. Exposure of KB cells to 5FU led to an increase in radiosensitivity. G 2/M cell cycle arrest was observed in the two cell lines after irradiation. The radioresistant KB cell line reached the maximum arrest two hours before KB3. The cellular exit from this arrest was found to be related to the wild type p53 protein expression induction. After irradiation, only KB3 cell line underwent apoptosis. This apoptosis induction seemed to be independent of G 2/M arrest exit, which was carried out later. The difference in radiosensitivity between KB and KB3 subline may result therefore from both a difference in apoptosis induction and a difference in G 2/M arrest maximum duration. Moreover, 5FU exposure has led to an increase in constitutive p53 protein expression, which may be associated with an increase in basal apoptosis cell fraction. Given the existing correlation between radiosensitivity and the percentage of basal apoptosis, the constitutive p53 protein expression may be related to intrinsic radiosensitivity in our cellular model.SCOPUS: cp.jinfo:eu-repo/semantics/publishe

Constitutive NF-κB activity influences basal apoptosis and radiosensitivity of head-and-neck carcinoma cell lines

Purpose: Nuclear factor-κB (NF-κB) has been implicated in anti-apoptotic gene transactivation, according to its transcriptional activity. The present study was designed to investigate whether constitutive NF-κB activity could modulate basal apoptosis and intrinsic radiosensitivity of KB head-and-neck carcinoma cell line and KB3 subline. The KB3 subline was more radiosensitive (SF2 = 0.48, α = 0.064) than the radioresistant KB parental cell line (SF2 = 0.80, α = 0.114). Methods and Materials: Constitutive NF-κB DNA-binding activity was determined using electrophoretic mobility shift assay. Modulation of NF-κB activity was performed by exposing both cell lines to tumor necrosis factor α or dexamethasone. Apoptotic cell population was analyzed using flow cytometry (annexin V/propidium iodide). Radiosensitivity was assessed from determination of the surviving fraction at 2 Gy (SF2), and α and β parameters were determined using the linear-quadratic model. Results: Constitutive NF-κB activity was found to be significantly lower in KB3 than in KB. KB cell line exposure to dexamethasone significantly decreased NF-κB DNA-binding activity and, consequently, enhanced baseline apoptosis and radiosensitivity (α values: 0.114 vs. 0.052). Conversely, exposure of KB3 cells to tumor necrosis factor α increased NF-κB DNA-binding activity and resulted in a significant decrease (50%) in rate of apoptosis and in radiosensitivity (SF2 values: 0.48 vs. 0.63). Conclusions: Modulation of NF-κB DNA-binding activity influences baseline apoptosis and intrinsic radiosensitivity. © 2001 Elsevier Science Inc.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

NF-kappaB modulation and ionizing radiation: mechanisms and future directions for cancer treatment.

NF-kappaB transcription factor regulates important cellular processes ranging from establishment of the immune and inflammatory responses to regulation of cell proliferation or apoptosis, through the induction of a large array of target genes. NF-kappaB is now considered as an important actor in the tumorigenic process mainly because it exerts strong anti-apoptotic functions in cancer cells. NF-kappaB is triggered by chimio- and radio-therapeutic strategies that are intended to eliminate cancerous cells through induction of apoptosis. Numerous studies have demonstrated that inhibition of NF-kappaB by different means increased sensitivity of cancer cells to the apoptotic action of diverses effectors such as TNFalpha or chemo- or radio-therapies. From these studies as emerged the concept that NF-kappaB blockade could be associated to conventional therapies in order to increase their efficiency. This review focuses on the current knowledge on NF-kappaB regulation and discusses the therapeutic potential of targeting NF-kappaB in cancer in particular during radiotherapy.Journal ArticleReviewSCOPUS: sh.jinfo:eu-repo/semantics/publishe