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Cetaceans, which are crucial in marine ecosystems, act as sentinels for ecosystem and human-environmental health. However, emerging fungal infections, particularly by Candida spp., pose a growing concern in these marine mammals. This review consolidates current knowledge on the prevalence, clinical manifestations, species distribution, and antifungal resistance of Candida infections in cetaceans. We detail the diverse pathogenic impacts of Candida, including respiratory, dermal, and systemic afflictions, underscoring diagnostic and treatment challenges amid rising antifungal resistance. Our analysis extends beyond health concerns in captive cetaceans, where confinement stress heightens vulnerability, to encompass substantial ecological risks in wild populations. The review emphasizes the One Health perspective, linking cetacean health with broader environmental and human public health issues. We particularly focus on the potential zoonotic transmission of emerging fungal pathogens such as Candida auris and the role of environmental changes in fostering antifungal resistance. The study underscores the need for concerted, interdisciplinary efforts in veterinary, medical, and environmental sciences to enhance understanding and management of Candida infections in cetaceans. We advocate for comprehensive monitoring and collaborative research initiatives to mitigate the rising challenge of these infections. Addressing Candida spp. in cetaceans is not just a conservation priority but a critical step in safeguarding overall marine health and, by extension, human health in the context of evolving infectious diseases.
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Over 60% of emerging infectious diseases in humans are zoonotic, often originating from wild animals. This long-standing ecological phenomenon has accelerated due to human-induced environmental changes. Recent data show a significant increase in fungal infections, with 6.5 million cases annually leading to 3.7 million deaths, indicating their growing impact on global health. Despite the vast diversity of fungal species, only a few are known to infect humans and marine mammals. Fungal zoonoses, especially those involving marine mammals like cetaceans, are of global public health concern. Increased human-cetacean interactions, in both professional and recreational settings, pose risks for zoonotic disease transmission. This review focuses on the epidemiology, clinical manifestations, and zoonotic potential of major fungal pathogens shared in humans and cetaceans, highlighting their interspecies transmission capability and the challenges posed by antifungal resistance and environmental changes. It underscores the need for enhanced awareness and preventative measures in high-risk settings to protect public health and marine ecosystems.
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The emergence and evolutionary path of Candida auris poses an intriguing scientific enigma. Its isolation from a pet dog's oral cavity in Kansas, reported by White et al. (T. C. White, B. D. Esquivel, E. M. Rouse Salcido, A. M. Schweiker, et al., mBio 15:e03080-23, 2024, https://doi.org/10.1128/mbio.03080-23), carries significant implications. This discovery intensifies concerns about its hypothetical capacity for zoonotic transmission, particularly considering the dog's extensive human contact and the absence of secondary animal/human cases in both animals and humans. The findings challenge established notions of C. auris transmissibility and underscore the need for further investigation into the transmission dynamics, especially zooanthroponotic pathways. It raises concerns about its adaptability in different hosts and environments, highlighting potential role of environmental and animal reservoirs in its dissemination. Critical points include the evolving thermal tolerance and the genetic divergence in the isolate. This case exemplifies the necessity for an integrated One Health approach, combining human, animal, and environmental health perspectives, to unravel the complexities of C. auris's emergence and behavior.
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Candida , Candidiasis , Perros , Humanos , Animales , Candida/genética , Candida/aislamiento & purificación , Candidiasis/veterinaria , Candidiasis/microbiología , Candida auris , Kansas , Cambio Climático , Hongos , Zoonosis , BocaRESUMEN
Cetaceans, which are integral to marine ecosystems, face escalating anthropogenic threats, including climate change and pollution, positioning them as critical sentinel species for ocean and human health. This review explores the neglected realm of non-Candida yeasts in cetaceans, addressing the gaps in the understanding of their prevalence, pathogenicity, and environmental impacts. By examining identified species such as Cryptococcus spp., Paracoccidioides spp., and several dimorphic fungi, this review emphasizes global prevalence, epidemiology and ecology, pathogenicity, and potential zoonotic implications. It also discusses the fine line between yeast commensalism and pathogenicity by considering environmental influences such as pollution, climate shifts, and immune suppression. Environmental impact discussions delve into how rising ocean temperatures and pollution can modify yeast mycobiota, potentially affecting marine host health and broader ecosystem dynamics. The cetacean's unique physiology and ecological niches are considered, highlighting potential impacts on behaviors, reproductive success, and survival rates. Identifying crucial knowledge gaps, the review calls for intensified research efforts, employing advanced molecular techniques to unravel the cetacean mycobiome. Systematic studies on yeast diversity, antifungal susceptibility, and their influence on environmental and ecosystem health are proposed, and the balance between commensal and pathogenic species emphasizes the significance of the One Health approach. In conclusion, as marine mammals face unprecedented challenges, unveiling non-Candida yeasts in cetaceans emerges as a critical endeavor with far-reaching implications for the conservation of marine ecosystems and for both animal and human public health.
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Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the accumulation of ß-amyloid (Aß), C99, and Tau in vulnerable areas of the brain. Despite extensive research, current strategies to lower Aß levels have shown limited efficacy in slowing the cognitive decline associated with AD. Recent findings suggest that C99 may also play a crucial role in the pathogenesis of AD. Our laboratory has discovered that CK1γ2 phosphorylates Presenilin 1 at the γ-secretase complex, leading to decreased C99 and Aß levels. Thus, CK1γ2 activation appears as a promising therapeutic target to lower both C99 and Aß levels. In this study, we demonstrate that CK1γ2 is inhibited by intramolecular autophosphorylation and describe a high-throughput screen designed to identify inhibitors of CK1γ2 autophosphorylation. We hypothesize that these inhibitors could lead to CK1γ2 activation and increased PS1-Ser367 phosphorylation, ultimately reducing C99 and Aß levels. Using cultured cells, we investigated the impact of these compounds on C99 and Aß concentrations and confirmed that CK1γ2 activation effectively reduced their levels. Our results provide proof of concept that CK1γ2 is an attractive therapeutic target for AD. Future studies should focus on the identification of specific compounds that can inhibit CK1γ2 autophosphorylation and evaluate their efficacy in preclinical models of AD. These studies will pave the way for the development of novel therapeutics for the treatment of AD.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Humanos , Precursor de Proteína beta-Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Encéfalo/metabolismoRESUMEN
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by decreased immunoglobulins and recurrent infections. Its aetiology remains unknown, and some patients present with severe non-infectious autoimmune or inflammatory complications with elevated associated morbimortality. Recently, intestinal dysbiosis has been proposed as a driver of immune dysregulation. In this study, we assessed the oral, respiratory, and gastrointestinal microbiota of 41 CVID patients (24 with dysimmune and 17 with infection complications) and 15 healthy volunteers using 16S rRNA gene sequencing to explore associations between microbiome profiles and CVID phenotypes. Profound differences in the composition of the microbiota in saliva, sputum, and stool were detected between dysimmune CVID patients and healthy individuals. Globally, respiratory species diversity and faecal bacterial richness were lower in CVID individuals with immune complications. Although a single species could not be identified as a robust predictor of dysimmunity, a combination of around 5-7 bacterial species in each type of sample could predict this severe phenotype with an accuracy of around 90% in the study population. Our study provides new insights into these previously unexplored but highly interrelated ecological niches among themselves and with patient profiles. Our data suggest that this disease-related systemic dysbiosis could be implicated in the immune dysregulation associated with severe cases of CVID.
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Inmunodeficiencia Variable Común , Microbioma Gastrointestinal , Humanos , Disbiosis , ARN Ribosómico 16S/genética , Bacterias/genéticaRESUMEN
Candida auris is an emerging yeast of worldwide interest due to its antifungal resistance and mortality rates. The aim of this study was to analyse the in vitro and in vivo antifungal activity of a nanoemulsion loaded with amphotericin B (NEA) against planktonic cells and biofilm of C. auris clinical isolates belonging to four different clades. In vivo assays were performed using the Galleria mellonella model to analyse antifungal activity and histopathological changes. The in vitro results showed that NEA exhibited better antifungal activity than free amphotericin B (AmB) in both planktonic and sessile cells, with >31% inhibition of mature biofilm. In the in vivo assays, NEA demonstrated superior antifungal activity in both haemolymph and tissue. NEA reduced the fungal load in the haemolymph more rapidly and with more activity in the first 24 h after infection. The histological analysis of infected larvae revealed clusters of yeast, immune cells, melanisation, and granulomas. In conclusion, NEA significantly improved the in vitro and in vivo antifungal activity of AmB and could be considered a promising therapy for C. auris infections.
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BACKGROUND: One of the most puzzling traits of Candida auris is the recent simultaneous and independent emergence of five genetically distinct clades on three continents. Global warming has been proposed as a contributing factor for this emergence owing to high thermotolerance of C. auris compared with phylogenetically close Candida species. This hypothesis postulates that climate change induced an environmental ancestor to become pathogenic through thermal adaptation and was then globally disseminated by an intermediate host. OBJECTIVES: The aim of this review is to compile the current knowledge on the emergence and ecological environmental niches of C. auris and highlight the potential role of animals in transmission. SOURCES: A literature search was conducted using PubMed, MEDLINE, Google Scholar, and Web of Science from May 2022 to January 2023. CONTENT: We discuss the up-to-date data on the ecological niches of this fungus and its mechanisms of emergence, transmission cycle in nature, and worldwide dissemination. We highlight the possibility of an originally intermediate host possibly related to marine or freshwater ecosystems on the basis of recent molecular and microbiological evidence from a One Health perspective. The consequences of harmful human impact on the environment in the rise of new fungal pathogenic species, such as C. auris, are also analysed and compared with other animal precedents. IMPLICATIONS: The present knowledge can prompt the generation of new evidence on the ecological reservoirs of C. auris and its original mechanisms of environmental or interspecies transmission. Further research on the highlighted gaps will help understand the importance of the relationships between human, animal, and ecosystem health as factors involved in the rise and spread of emerging fungal pathogenic species.
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Candidiasis , Salud Única , Animales , Humanos , Candidiasis/epidemiología , Candidiasis/microbiología , Candida auris , Ecosistema , Cambio ClimáticoRESUMEN
Chimeric antigen receptor (CAR) T cell therapy relies on T cells that are guided by synthetic receptors to target and lyse cancer cells. CARs bind to cell surface antigens through an scFv (binder), the affinity of which is central to determining CAR T cell function and therapeutic success. CAR T cells targeting CD19 were the first to achieve marked clinical responses in patients with relapsed/refractory B cell malignancies and to be approved by the U.S. Food and Drug Administration (FDA). We report cryo-EM structures of CD19 antigen with the binder FMC63, which is used in four FDA-approved CAR T cell therapies (Kymriah, Yescarta, Tecartus, and Breyanzi), and the binder SJ25C1, which has also been used extensively in multiple clinical trials. We used these structures for molecular dynamics simulations, which guided creation of lower- or higher-affinity binders, and ultimately produced CAR T cells endowed with distinct tumor recognition sensitivities. The CAR T cells exhibited different antigen density requirements to trigger cytolysis and differed in their propensity to prompt trogocytosis upon contacting tumor cells. Our work shows how structural information can be applied to tune CAR T cell performance to specific target antigen densities.
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Proteínas Adaptadoras Transductoras de Señales , Antígenos CD19 , Estados Unidos , Humanos , Antígenos de Superficie , Linfocitos B , Muerte CelularRESUMEN
Introduction:Candida auris is a major threat to public health. Rapid detection is essential for early treatment and transmission control. The use of chromogenic media allows the presumptive identification of this new species. The aim of this study is to describe the morphological characteristics of C. auris colonies on three commercial chromogenic media. Methods: Nineteen C. auris isolates from different countries/clades and 18 isolates of other species were cultivated in CHROMagarTM Candida Plus, HiCromeTM Candida, CHROMagar-Candida, and fluconazole-supplemented (32 mg/L) CHROMagar-Candida media. Results: On CHROMagarTM Candida Plus and HiCromeTM Candida, C. auris isolates from Colombia, Venezuela, India, Korea, and Japan displayed blue-shaded colonies, while isolates from Spain and Germany exhibited light pink shades with a bluish halo. All isolates showed white to pink colonies on CHROMagar-Candida. On CHROMagar Candida supplemented with fluconazole, whilst C. auris, C. glabrata, or C. krusei showed a similar pink color at 48 h incubation, phenotypic differentiation was possible by the rough, paraffin-like texture or the intense purple color acquired by C. krusei and C. glabrata, respectively. Moreover, in this medium, the presence of C. auris in combination with other species of similar color was not limiting for its early identification, due to this medium selecting only strains resistant to this antifungal. Conclusions: The use of chromogenic media such as CHROMagarTM Candida Plus facilitates a presumptive identification of C. auris. However, this identification can be difficult in the presence of mixed cultures. In these cases, the use of CHROMagarTM Candida medium with 32 mg/L fluconazole offers better performance for the identification of C. auris by inhibiting fluconazole-susceptible strains and selecting rare or high fluconazole MIC (>32 mg/L) isolates.
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Common variable immunodeficiency (CVID) constitutes a heterogenic group of primary immunodeficiency disorders with a wide-ranging clinical spectrum. CVID-associated non-infectious morbidity constitutes a major challenge requiring a full understanding of its pathophysiology and its clinical importance and global variability, especially considering the broad clinical, genetic, and regional heterogeneity of CVID disorders. This work aimed to develop a nationwide, multicenter, retrospective study over a 3-year period describing epidemiological, clinical, laboratory, therapeutic, and prognostic features of 250 CVID patients in Spain. The mean diagnostic delay was around 10 years and most patients initially presented with infectious complications followed by non-infectious immune disorders. However, infectious diseases were not the main cause of morbimortality. Non-infectious lung disease was extraordinarily frequent in our registry affecting approximately 60% of the patients. More than one-third of the patients in our cohort showed lymphadenopathies and splenomegaly in their follow-up, and more than 33% presented immune cytopenias, especially Evans' syndrome. Gastrointestinal disease was observed in more than 40% of the patients. Among biopsied organs in our cohort, benign lymphoproliferation was the principal histopathological alteration. Reaching 15.26%, the global prevalence of cancer in our registry was one of the highest reported to date, with non-Hodgkin B lymphoma being the most frequent. These data emphasize the importance of basic and translational research delving into the pathophysiological pathways involved in immune dysregulation and diffuse lymphocytic infiltration. This would reveal new tailored strategies to reduce immune complications, and the associated healthcare burden, and ensure a better quality of life for CVID patients.
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Inmunodeficiencia Variable Común , Linfoma no Hodgkin , Humanos , Inmunodeficiencia Variable Común/epidemiología , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/complicaciones , España/epidemiología , Estudios Retrospectivos , Calidad de Vida , Diagnóstico Tardío , Sistema de Registros , Linfoma no Hodgkin/complicacionesRESUMEN
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency (PID) in general population. PID are genetic diseases that share a dysfunction in the immune system entailing a greater risk of both chronic and recurrent infections. These patients can also develop chronic gastrointestinal infections caused by norovirus with persistent viral dissemination, which can be detect ed months after primoinfection. Additionally, a proportion of CVID patients show a typical severe enteropathy presenting with recurrent diarrhoea, intestinal malabsorption, inflammatory lesions, and villous atrophy. Some studies have related this enteropathy with chronic intestinal infection caused by norovirus. (AU)
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Humanos , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/patología , Infecciones por Caliciviridae , Diarrea , Enfermedades GastrointestinalesRESUMEN
Little evidence is available regarding the incidence of CMV disease in patients with solid cancers. Latest data show that approximately 50 % of these patients with CMV PCR positivity developed clinically relevant CMV-viremia, and would require specific therapy. In the clinical arena, CMV reactivation is an important differential diagnosis in the infectological work up of these patients, but guidelines of management on this subject are not yet available. CMV reactivation should be considered during differential diagnosis for patients with a severe decline in lymphocyte counts when receiving chemoradiotherapy or immunochemotherapy with lymphocyte-depleting or blocking agents. Monitoring of CMV reactivation followed by the implementation of preemptive strategies or the establishment of early antiviral treatment improves the prognosis and reduces the morbidity and mortality of these patients. (AU)
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Humanos , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/terapia , Neoplasias , Viremia , LinfopeniaRESUMEN
The indiscriminate and massive antibiotic use in the clinical practice and in agriculture or cattle during the past few decades has produced a serious world health problem that entails high morbidity and mortality: the antibiotic multi-drug resistance. In 2017 and 2019, the World Health Organization published a list of urgent threats and priorities in the context of drug resistance, which only included Gram-negative bacteria and specially focused on carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, as well as carbapenem and third generation cephalosporin-resistant Enterobacteriaceae. This scenario emphasizes the need of developing and testing new antibiotics from different families, such as new beta-lactams, highlighting cefiderocol and its original mechanism of action; new beta-lactamase inhibitors, with vaborbactam or relebactam among others; new quinolones such as delafloxacin, and also omadacycline or eravacycline, as members of the tetracycline family. The present work reviews the importance and impact of Gram-negative bacterial infections and their resistance mechanisms, and analyzes the current therapeutic paradigm as well as the role of new antibiotics with a promising future in the era of multi and pan-drug resistance. (AU)
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Humanos , Historia del Siglo XXI , Resistencia betalactámica , Antibacterianos , Infecciones por Bacterias Gramnegativas , Acinetobacter baumannii , Pseudomonas aeruginosa , Organización Mundial de la SaludRESUMEN
Patients with a compromised immune system suffer awide variety of insults. Pulmonary complications remain amajor cause of both morbidity and mortality in immunocompromised patients. When such individuals present with radiographic infiltrates, the clinician faces a diagnostic challenge.The differential diagnosis in this setting is broad and includesboth infectious and non-infectious conditions. Evaluation ofthe immunocompromised host with diffuse pulmonary infiltrates can be difficult, frustrating, and time-consuming. Thiscommon and serious problem results in significant morbidityand mortality, approaching 90%. Infections are the most common causes of both acute and chronic lung diseases leading torespiratory failure. Non-invasive diagnostic methods for evaluation are often of little value, and an invasive procedure (suchas bronchoalveolar lavage, transbronchial biopsy or even openlung biopsy) is therefore performed to obtain a microbiologicand histologic diagnosis. Bronchoscopy allows certain identification of some aetiologies, and often allows the exclusion ofinfectious agents. Early use of computed tomography scanning is able to demonstrate lesions missed by conventionalchest X-ray. However, even when a specific diagnosis is made,it might not impact patients overall survival and outcomes (AU)
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Humanos , Animales , Neumonía/diagnóstico , Neumonía/tratamiento farmacológico , Neumonía/etiología , Huésped Inmunocomprometido , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/microbiología , Enfermedades Pulmonares/mortalidadRESUMEN
Background: Granulomatous-lymphocytic interstitial lung disease (GLILD) is a distinct clinic-radio-pathological interstitial lung disease (ILD) that develops in 9% to 30% of patients with common variable immunodeficiency (CVID). Often related to extrapulmonary dysimmune disorders, it is associated with long-term lung damage and poorer clinical outcomes. The aim of this study was to explore the potential use of the integration between clinical parameters, laboratory variables, and developed CT scan scoring systems to improve the diagnostic accuracy of non-invasive tools. Methods: A retrospective cross-sectional study of 50 CVID patients was conducted in a referral unit of primary immune deficiencies. Clinical variables including demographics and comorbidities; analytical parameters including immunoglobulin levels, lipid metabolism, and lymphocyte subpopulations; and radiological and lung function test parameters were collected. Baumann's GLILD score system was externally validated by two observers in high-resolution CT (HRCT) scans. We developed an exploratory predictive model by elastic net and Bayesian regression, assessed its discriminative capacity, and internally validated it using bootstrap resampling. Results: Lymphadenopathies (adjusted OR 9.42), splenomegaly (adjusted OR 6.25), Baumann's GLILD score (adjusted OR 1.56), and CD8+ cell count (adjusted OR 0.9) were included in the model. The larger range of values of the validated Baumann's GLILD HRCT scoring system gives it greater predictability. Cohen's κ statistic was 0.832 (95% CI 0.70-0.90), showing high concordance between both observers. The combined model showed a very good discrimination capacity with an internally validated area under the curve (AUC) of 0.969. Conclusion: Models integrating clinics, laboratory, and CT scan scoring methods may improve the accuracy of non-invasive diagnosis of GLILD and might even preclude aggressive diagnostic tools such as lung biopsy in selected patients.
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Inmunodeficiencia Variable Común , Enfermedades Pulmonares Intersticiales , Teorema de Bayes , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/diagnóstico por imagen , Estudios Transversales , Humanos , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/etiología , Estudios RetrospectivosRESUMEN
Candida auris has globally emerged as a multidrug-resistant fungus linked to healthcare-associated outbreaks. There is still limited evidence on its virulence, pathogenicity determinants, and complex host-pathogen interactions. This study analyzes the in vivo fungal behaviour, immune response, and host-pathogen interactions upon C. auris infection compared to C. albicans and C. parapsilosis in G. mellonella. This was performed by immunolabelling fungal structures and larval plasmatocytes and using a quantitative approach incorporating bioinformatic morphometric techniques into the study of microbial pathogenesis. C. auris presents a remarkably higher immunogenic activity than expected at its moderate degree of tissue invasion. It induces a greater inflammatory response than C. albicans and C. parapsilosis at the expense of plasmatocyte nodule formation, especially in non-aggregative strains. It specifically invades the larval respiratory system, in a pattern not previously observed in other Candida species, and presents inter-phenotypic tissue tropism differences. C. auris filaments in vivo less frequently than C. albicans or C. parapsilosis mostly through pseudohyphal growth. Filamentation might not be a major pathogenic determinant in C. auris, as less virulent aggregative phenotypes form pseudohyphae to a greater extent. C. auris has important both interspecific and intraspecific virulence and phenotype heterogeneity, with aggregative phenotypes of C. auris sharing characteristics with low pathogenic species such as C. parapsilosis. Our work suggests that C. auris owns an important morphogenetic plasticity that distinguishes it from other yeasts of the genus. Routine phenotypic identification of aggregative or non-aggregative phenotypes should be performed in the clinical setting as it may impact patient management.
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Candida auris/fisiología , Interacciones Huésped-Patógeno , Mariposas Nocturnas/inmunología , Mariposas Nocturnas/microbiología , Animales , Candida albicans/inmunología , Candida albicans/patogenicidad , Candida albicans/fisiología , Candida auris/citología , Candida auris/inmunología , Candida auris/patogenicidad , Candida parapsilosis/inmunología , Candida parapsilosis/patogenicidad , Candida parapsilosis/fisiología , Hemocitos/inmunología , Hemocitos/fisiología , Hemolinfa/microbiología , Inmunidad , Larva/microbiología , Mariposas Nocturnas/fisiología , Sistema Respiratorio/inmunología , Sistema Respiratorio/microbiología , VirulenciaRESUMEN
Several chemical compounds including natural products have been suggested as being effective against age-related diseases or as beneficial for a healthy life. On the other hand, forkhead box O (FOXO) proteins are emerging as key cellular components associated with extreme human longevity. FOXO proteins are mainly regulated by posttranslational modifications and as these modifications are reversible, activation and inactivation of FOXO are attainable through pharmacological treatment. Here, we questioned whether a panel of compounds with known health-beneficial properties has the capacity to induce the activity of FOXO factors. We show that resveratrol, a phytoalexin present in grapes and other food products, the amide alkaloid piperlongumine found in the fruit of the long pepper, and the plant-derived ß-carboline compound harmine induced nuclear translocation of FOXO3. We also show that piperlongumine and harmine but not resveratrol activate FOXO-dependent transcription. We determined the half maximal effective concentration (EC50) values for resveratrol, piperlongumine, and harmine for FOXO translocation, and analyzed their inhibitory impact on chromosomal maintenance 1 (CRM1)-mediated nuclear export and the production of reactive oxygen species (ROS). We also used chemical biology approach and Western blot analysis to explore the underlying molecular mechanisms. We show that harmine, piperlongumine, and resveratrol activate FOXO3 independently of phosphoinositide 3-kinase (PI3K)/AKT signaling and the CRM1-mediated nuclear export. The effect of harmine on FOXO3 activity is at least partially mediated through the inhibition of dual-specificity tyrosine (Y) phosphorylationregulated kinase 1A (DYRK1A) and can be reverted by the inhibition of sirtuins (SIRTs).