RESUMEN
The progress in human disease treatment can be greatly advanced through the implementation of nanomedicine. This approach involves targeted and cell-specific therapy, controlled drug release, personalized dosage forms, wearable drug delivery, and companion diagnostics. By integrating cutting-edge technologies with drug delivery systems, greater precision can be achieved at the tissue and cellular levels through the use of stimuli-responsive nanoparticles, and the development of electrochemical sensor systems. This precision targeting - by virtue of nanotechnology - allows for therapy to be directed specifically to affected tissues while greatly reducing side effects on healthy tissues. As such, nanomedicine has the potential to transform the treatment of conditions such as cancer, genetic diseases, and chronic illnesses by facilitating precise and cell-specific drug delivery. Additionally, personalized dosage forms and wearable devices offer the ability to tailor treatment to the unique needs of each patient, thereby increasing therapeutic effectiveness and compliance. Companion diagnostics further enable efficient monitoring of treatment response, enabling customized adjustments to the treatment plan. The question of whether all the potential therapeutic approaches outlined here are viable alternatives to current treatments is also discussed. In general, the application of nanotechnology in the field of biomedicine may provide a strong alternative to existing treatments for several reasons. In this review, we aim to present evidence that, although in early stages, fully merging advanced technology with innovative drug delivery shows promise for successful implementation across various disease areas, including cancer and genetic or chronic diseases.
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Productos Biológicos , Neoplasias , Humanos , Medicina de Precisión , Sistemas de Liberación de Medicamentos , Nanomedicina , Neoplasias/tratamiento farmacológicoRESUMEN
Hypoxia contributes to the exaggerated yet ineffective airway inflammation that fails to oppose infections in cystic fibrosis (CF). However, the potential for impairment of essential immune functions by HIF-1α (hypoxia-inducible factor 1α) inhibition demands a better comprehension of downstream hypoxia-dependent pathways that are amenable for manipulation. We assessed here whether hypoxia may interfere with the activity of AhR (aryl hydrocarbon receptor), a versatile environmental sensor highly expressed in the lungs, where it plays a homeostatic role. We used murine models of Aspergillus fumigatus infection in vivo and human cells in vitro to define the functional role of AhR in CF, evaluate the impact of hypoxia on AhR expression and activity, and assess whether AhR agonism may antagonize hypoxia-driven inflammation. We demonstrated that there is an important interferential cross-talk between the AhR and HIF-1α signaling pathways in murine and human CF, in that HIF-1α induction squelched the normal AhR response through an impaired formation of the AhR:ARNT (aryl hydrocarbon receptor nuclear translocator)/HIF-1ß heterodimer. However, functional studies and analysis of the AhR genetic variability in patients with CF proved that AhR agonism could prevent hypoxia-driven inflammation, restore immune homeostasis, and improve lung function. This study emphasizes the contribution of environmental factors, such as infections, in CF disease progression and suggests the exploitation of hypoxia:xenobiotic receptor cross-talk for antiinflammatory therapy in CF.
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Fibrosis Quística , Receptores de Hidrocarburo de Aril , Humanos , Ratones , Animales , Receptores de Hidrocarburo de Aril/metabolismo , Hipoxia/metabolismo , Transducción de Señal , Inflamación , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismoRESUMEN
As an appealing alternative to treat and prevent diseases ranging from cancer to COVID-19, mRNA has demonstrated significant clinical effects. Nanotechnology facilitates the successful implementation of the systemic delivery of mRNA for safe human consumption. In this manuscript, we provide an overview of current mRNA therapeutic applications and discuss key biological barriers to delivery and recent advances in the development of nonviral systems. The relevant challenges that LNPs face in achieving cost-effective and widespread clinical implementation when delivering mRNA are likewise discussed.
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COVID-19 , Nanopartículas , Humanos , ARN Mensajero/genética , LiposomasRESUMEN
A large body of evidence, replicated in many mouse models of Alzheimer's disease (AD), supports the therapeutic efficacy of the oral mammalian target of rapamycin inhibitors (mTOR-Is). Our preliminary data show that intracerebroventricular (ICV) administration of everolimus (RAD001) soon after clinical onset greatly diminished cognitive impairment and the intracellular beta amyloid and neurofibrillary tangle load. However, RAD001 shows >90% degradation after 7 days in solution at body temperature, thus hampering the development of proper therapeutic regimens for patients. To overcome such a drawback, we developed a stable, liquid formulation of mTOR-Is by loading RAD001 into distearoylphosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000) micelles using the thin layer evaporation method. The formulation showed efficient encapsulation of RAD001 and a homogeneous colloidal size and stabilised RAD001, with over 95% of activity preserved after 14 days at 37 °C with a total decay only occurring after 98 days. RAD001-loaded DSPE-PEG2000 micelles were unchanged when stored at 4 and 25 °C over the time period investigated. The obtained formulation may represent a suitable platform for expedited clinical translation and effective therapeutic regimens in AD and other neurological diseases.
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Enfermedad de Alzheimer , Everolimus , Ratones , Animales , Humanos , Everolimus/farmacología , Everolimus/uso terapéutico , Micelas , Enfermedad de Alzheimer/tratamiento farmacológico , Sirolimus/farmacología , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismo , Línea Celular Tumoral , Mamíferos/metabolismoRESUMEN
The ability to predict invasive fungal infections (IFI) in patients with hematological malignancies is fundamental for successful therapy. Although gut dysbiosis is known to occur in hematological patients, whether airway dysbiosis also contributes to the risk of IFI has not been investigated. Nasal and oropharyngeal swabs were collected for functional microbiota characterization in 173 patients with hematological malignancies recruited in a multicenter, prospective, observational study and stratified according to the risk of developing IFI. A lower microbial richness and evenness were found in the pharyngeal microbiota of high-risk patients that were associated with a distinct taxonomic and metabolic profile. A murine model of IFI provided biologic plausibility for the finding that loss of protective anaerobes, such as Clostridiales and Bacteroidetes, along with an apparent restricted availability of tryptophan, is causally linked to the risk of IFI in hematologic patients and indicates avenues for antimicrobial stewardship and metabolic reequilibrium in IFI.
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Enfermedades Hematológicas/complicaciones , Microbiota , Micosis/etiología , Faringe/microbiología , Neumonía/etiología , Animales , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Modelos Animales de Enfermedad , Neoplasias Hematológicas/complicaciones , Humanos , Metagenoma , Metagenómica/métodos , Ratones , Micosis/diagnóstico , Micosis/tratamiento farmacológico , Neumonía/diagnóstico , Neumonía/tratamiento farmacológico , Medición de Riesgo , Factores de RiesgoRESUMEN
BACKGROUND: This study introduces a newly created strain (Rhodococcus equiEtBr25) by exposing R. equi ATCC 33701 to ethidium bromide (EtBr), a substrate for MDR transporters. Such an approach allowed us to investigate the resulting phenotype and genetic mechanisms underlying the efflux-mediated resistance in R. equi. METHODS: R. equi ATCC 33701 was stimulated with increasing concentrations of EtBr. The antimicrobial susceptibility of the parental strain and R. equiEtBr25 was investigated in the presence/absence of efflux pump inhibitors (EPIs). EtBr efflux was evaluated by EtBr-agar method and flow cytometry. The presence of efflux pump genes was determined by conventional PCR before to quantify the expression of 30 genes coding for membrane transporters by qPCR. The presence of erm(46) and mutations in 23S rRNA, and gyrA/gyrB was assessed by PCR and DNA sequencing to exclude the occurrence of resistance mechanisms other than efflux. RESULTS: R. equi EtBr25 showed an increased EtBr efflux. Against this strain, the activity of EtBr, azithromycin and ciprofloxacin was more affected than that of rifampicin and azithromycin/rifampicin combinations. Resistances were reversed by combining the antimicrobials with EPIs. Gene expression analysis detected a marked up-regulation of REQ_RS13460 encoding for a Major Facilitator Superfamily (MFS) transporter. GâA transition occurred in the transcriptional repressor tetR/acrR adjacent to REQ_RS13460. CONCLUSIONS: Exposure of R. equi to EtBr unmasked an efflux-mediated defence against azithromycin and ciprofloxacin, which seemingly correlates with the overexpression of a specific MFS transporter. This genotype may mirror an insidious low-level resistance of clinically important isolates that could be countered by EPI-based therapies.
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Rhodococcus equi , Rhodococcus , Antibacterianos/farmacología , Etidio , Humanos , Pruebas de Sensibilidad Microbiana , Rhodococcus equi/genéticaRESUMEN
Amiodarone is a cationic amphiphilic drug used as an antiarrhythmic agent. It induces phospholipidosis, i.e., the accumulation of phospholipids within organelles of the endosomal-lysosomal system. Extracellular vesicles (EVs) are membrane-enclosed structures released by any type of cell and retrieved in every fluid of the body. EVs have been initially identified as a system to dispose cell waste, but they are also considered to be an additional manner to transmit intercellular signals. To understand the role of EVs in drug-induced phospholipidosis, we investigated EVs release in amiodarone-treated HEK-293 cells engineered to produce fluorescently labelled EVs. We observed that amiodarone induces the release of a higher number of EVs, mostly of a large/medium size. EVs released upon amiodarone treatment do not display significant morphological changes or altered size distribution, but they show a dose-dependent increase in autophagy associated markers, indicating a higher release of EVs with an autophagosome-like phenotype. Large/medium EVs also show a higher content of phospholipids. Drugs inducing lysosomal impairment such as chloroquine and bafilomycin A1 similarly prompt a higher release of EVs enriched in autophagy markers. This result suggests a mechanism associated with amiodarone-induced lysosomal impairment more than a connection with the accumulation of specific undigested substrates. Moreover, the implementation of the lysosomal function by overexpressing TFEB, a master gene regulator of lysosomal biogenesis, prevents the amiodarone-induced release of EVs, suggesting that this could be a feasible target to attenuate drug-induced abnormalities.
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Amiodarona/efectos adversos , Antiarrítmicos/efectos adversos , Vesículas Extracelulares/efectos de los fármacos , Lisosomas/efectos de los fármacos , Fosfolípidos/metabolismo , Autofagia , Biomarcadores/metabolismo , Vesículas Extracelulares/metabolismo , Células HEK293 , Humanos , Lisosomas/metabolismoRESUMEN
Inflammasomes are powerful cytosolic sensors of environmental stressors and are critical for triggering interleukin-1 (IL-1)-mediated inflammatory responses. However, dysregulation of inflammasome activation may lead to pathological conditions, and the identification of negative regulators for therapeutic purposes is increasingly being recognized. Anakinra, the recombinant form of the IL-1 receptor antagonist, proved effective by preventing the binding of IL-1 to its receptor, IL-1R1, thus restoring autophagy and dampening NLR family pyrin domain containing 3 (NLRP3) activity. As the generation of mitochondrial reactive oxidative species (ROS) is a critical upstream event in the activation of NLRP3, we investigated whether anakinra would regulate mitochondrial ROS production. By profiling the activation of transcription factors induced in murine alveolar macrophages, we found a mitochondrial antioxidative pathway induced by anakinra involving the manganese-dependent superoxide dismutase (MnSOD) or SOD2. Molecularly, anakinra promotes the binding of SOD2 with the deubiquitinase Ubiquitin Specific Peptidase 36 (USP36) and Constitutive photomorphogenesis 9 (COP9) signalosome, thus increasing SOD2 protein longevity. Functionally, anakinra and SOD2 protects mice from pulmonary oxidative inflammation and infection. On a preclinical level, anakinra upregulates SOD2 in murine models of chronic granulomatous disease (CGD) and cystic fibrosis (CF). These data suggest that protection from mitochondrial oxidative stress may represent an additional mechanism underlying the clinical benefit of anakinra and identifies SOD2 as a potential therapeutic target.
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Inflamasomas/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Proteínas Recombinantes/farmacología , Superóxido Dismutasa/metabolismo , Animales , Células Cultivadas , Fibrosis Quística/etiología , Fibrosis Quística/metabolismo , Fibrosis Quística/patología , Modelos Animales de Enfermedad , Enfermedad Granulomatosa Crónica/etiología , Enfermedad Granulomatosa Crónica/metabolismo , Enfermedad Granulomatosa Crónica/patología , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Oxidación-Reducción , Estrés Oxidativo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Amikacin (Amk) analysis and quantitation, for pharmacokinetics studies and other types of investigations, is conventionally performed after extraction from plasma. No report exists so far regarding drug extraction from whole blood (WB). This can represent an issue since quantification in plasma does not account for drug partitioning to the blood cell compartment, significantly underrating the drug fraction reaching the blood circulation. In the present work, the optimization of an extraction method of Amk from murine WB has been described. The extraction yield was measured by RP-HPLC-UV after derivatization with 1-fluoro-2,4-dinitrobenzene, which produced an appreciably stable derivative with a favorable UV/vis absorption. Several extraction conditions were tested: spiked Amk disulfate solution/acetonitrile/WB ratio; presence of organic acids and/or ammonium hydroxide and/or ammonium acetate in the extraction mixture; re-dissolution of the supernatant in water after a drying process under vacuum; treatment of the supernatant with a solution of inorganic salts. The use of 5% (by volume) of ammonium hydroxide in a hydro-organic solution with acetonitrile, allowed the almost quantitative (95%) extraction of the drug from WB.
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Amicacina/química , Sangre/metabolismo , Plasma/química , Acetonitrilos/química , Hidróxido de Amonio/química , Animales , Cromatografía Líquida de Alta Presión/métodos , Cromatografía de Fase Inversa/métodos , Femenino , RatonesRESUMEN
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in either of two genes, TSC1 or TSC2, resulting in the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1). mTOR inhibitors are now considered the treatment of choice for TSC disease. A major pathological feature of TSC is the development of subependymal giant cell astrocytomas (SEGAs) in the brain. Nowadays, it is thought that SEGAs could be a consequence of aberrant aggregation and migration of neural stem/progenitor cells (NSPCs). Therefore, reactivation of cell migration of NSPCs might be the crucial step for the treatment of patients. In order to identify potential in vitro targets activating migration, we generated Tsc1-deficient NSPCs. These cells summarize most of the biochemical and morphological characteristics of TSC neural cells, such as the mTORC1 activation, the formation of abnormally enlarged astrocytes-like cells, the reduction of autophagy flux and the impairment of cell migration. Moreover, nuclear translocation, namely activation of the transcription factor EB (TFEB) was markedly impaired. Herein, we show that compounds such as everolimus, ionomycin and curcumin, which directly or indirectly stimulate TFEB nuclear translocation, restore Tsc1-deficient NSPC migration. Our data suggest that reduction of TFEB activation, caused by mTORC1 hyperactivation, contributes to the migration deficit characterizing Tsc1-deficient NSPCs. The present work highlights TFEB as a druggable protein target for SEGAs therapy, which can be additionally or alternatively exploited for the mTORC1-directed inhibitory approach.
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Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Células-Madre Neurales/metabolismo , Animales , Astrocitoma/patología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Encéfalo/metabolismo , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones , Mutación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Esclerosis Tuberosa/metabolismo , Esclerosis Tuberosa/patología , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
To take advantage of solid-state properties, the nano spray-drying (NSD) technique was investigated as an innovative one-step method to produce solid lipid nanoparticles (SLN) in the form of a dry powder starting from a lipid/leucine O/W emulsion. Compritol was chosen as wall-forming lipid. Rapamycin (Rp) was employed as a model drug to be loaded into SLN. Based on an initial screening, Lutrol F68 was chosen as surfactant and high-shear homogenization as an emulsification method. A two-level fractional factorial design and an extended factorial design were employed to determine critical factors and best preparation conditions. Compritol concentration, L-leucine/lipid ratio, and Lutrol F68 concentration resulted critical. Best conditions granted 51% yield, 3.2 µm L-leucine/SLN particle size, and a SLN population around 150 nm. All samples showed the presence of lipid aggregates. Material loss in the emulsification step was found responsible for SLN aggregation and low yield. The almost quantitative Rp loading increased SLN population span. Replacing compritol with cetyl palmitate produced aggregation of dry powders and SLN. Overall, NSD was found a fast method to produce SLN dry powders. More insightful assessment of the emulsification step and lipid property effects will be critical to the optimization of the NSD process. Hypotheses account for direct coupling of high-pressure homogenization with NSD for future successful development of this promising manufacturing method.
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Química Farmacéutica/métodos , Invenciones , Nanopartículas/química , Química Farmacéutica/tendencias , Desecación , Composición de Medicamentos/métodos , Invenciones/tendencias , Lípidos , Tamaño de la Partícula , Polvos , Tensoactivos/síntesis químicaRESUMEN
Tryptophan (trp) metabolism is an important regulatory component of gut mucosal homeostasis and the microbiome. Metabolic pathways targeting the trp can lead to a myriad of metabolites, of both host and microbial origins, some of which act as endogenous low-affinity ligands for the aryl hydrocarbon receptor (AhR), a cytosolic, ligand-operated transcription factor that is involved in many biological processes, including development, cellular differentiation and proliferation, xenobiotic metabolism, and the immune response. Low-level activation of AhR by endogenous ligands is beneficial in the maintenance of immune health and intestinal homeostasis. We have defined a functional node whereby certain bacteria species contribute to host/microbial symbiosis and mucosal homeostasis. A microbial trp metabolic pathway leading to the production of indole-3-aldehyde (3-IAld) by lactobacilli provided epithelial protection while inducing antifungal resistance via the AhR/IL-22 axis. In this review, we highlight the role of AhR in inflammatory lung diseases and discuss the possible therapeutic use of AhR ligands in cystic fibrosis.
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Fibrosis Quística/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Humanos , Indoles/metabolismo , Lactobacillus/metabolismoRESUMEN
Not all of the issues impacting the success of tuberculosis (TB) treatment arise from pathogen-related disease characteristics. Nowadays, there is an increasing awareness that antibiotic treatment is not the only answer to the TB problem, promoting the search for alternative administration strategies and host-directed therapies. Among all the administration routes, being the lungs the main TB focus, inhalation is conceptually a logical solution to enhance treatment effectiveness and compliance. Nevertheless, research efforts and funding are almost entirely conveyed to conventional approaches. This review will critically evaluate the reasons constraining research in this field, providing some future perspectives. The most recent advances in inhalation approaches for TB will be discussed, either at the preclinical or clinical phase, illustrating the risk of failure and chances of success.
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Antituberculosos/administración & dosificación , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Administración por Inhalación , Animales , Antituberculosos/metabolismo , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/microbiología , Mycobacterium tuberculosis/metabolismo , Tuberculosis/metabolismoRESUMEN
Although human amniotic fluid does contain different populations of foetal-derived stem cells, scanty information is available on the stemness and the potential immunomodulatory activity of in vitro expanded, amniotic fluid stem cells. By means of a methodology unrequiring immune selection, we isolated and characterized different stem cell types from second-trimester human amniotic fluid samples (human amniotic fluid stem cells, HASCs). Of those populations, one was characterized by a fast doubling time, and cells were thus designated as fHASCs. Cells maintained their original phenotype under prolonged in vitro passaging, and they were able to originate embryoid bodies. Moreover, fHASCs exhibited regulatory properties when treated with interferon (IFN)-γ, including induction of the immunomodulatory enzyme indoleamine 2,3-dioxygenase 1 (IDO1). On coculture with human peripheral blood mononuclear cells, IFN-γ-treated fHASCs caused significantly decreased T-cell proliferation and increased frequency in CD4(+) CD25(+) FOXP3(+) regulatory T cells. Both effects required an intact IDO1 function and were cell contact-independent. An unprecedented finding in our study was that purified vesicles from IFN-γ-treated fHASCs abundantly expressed the functional IDO1 protein, and those vesicles were endowed with an fHASC-like regulatory function. In vivo, fHASCs were capable of immunoregulatory function, promoting allograft survival in a mouse model of allogeneic skin transplantation. This was concurrent with the expansion of CD4(+) CD25(+) Foxp3(+) T cells in graft-draining lymph nodes from recipient mice. Thus fHASCs, or vesicles thereof, may represent a novel opportunity for immunoregulatory maneuvers both in vitro and in vivo.
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Líquido Amniótico/citología , Inmunomodulación , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Células Madre/inmunología , Células Madre/metabolismo , Adulto , Aloinjertos/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Comunicación Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Separación Celular , Forma de la Célula/efectos de los fármacos , Células Clonales , Cuerpos Embrioides/citología , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunomodulación/efectos de los fármacos , Interferón gamma/farmacología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones SCID , Fenotipo , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Células Madre/citología , Células Madre/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunologíaRESUMEN
BACKGROUND: Porcine Sertoli cells (pSCs) have been employed for cell therapy in pre-clinical studies for several chronic/immune diseases as they deliver molecules associated with trophic and anti-inflammatory effects. To be employed for human xenografts, pSCs products need to comply with safety and stability. To fulfill such requirements, we employed a microencapsulation technology to increase pre-transplant storage stability of specific pathogen-free pSCs (SPF-pSCs) and evaluated the in vivo long-term viability and safety of grafts. METHODS: Specific pathogen free neonatal pigs underwent testis excision under sterility. pSCs were isolated, characterized by immunofluorescence (IF) and cytofluorimetric analysis (CA) and examined in terms of viability and function [namely, production of anti-müllerian hormone (AMH), inhibin B, and transforming growth factor beta-1 (TFGß-1)]. After microencapsulation in barium alginate microcapsules (Ba-MC), long-term SPF-pSCs (Ba-MCpSCs) viability and barium concentrations were evaluated at 1, 24 throughout 40 h to establish pre-transplant storage conditions. RESULTS: The purity of isolated pSCs was about 95% with negligible contaminating cells. Cultured pSCs monolayers, both prior to and after microencapsulation, maintained high function and full viability up to 24 h of storage. At 40 h post-encapsulation, pSCs viability decreased to 80%. Barium concentration in Ba-MCpSCs lagged below the normal maximum daily allowance and was stable for 4 months in mice with no evident side effects. CONCLUSIONS: Such results suggest that this protocol for the isolation and microencapsulation of pSCs is compatible with long-haul transportation and that Ba-MCpSCs could be potentially employable for xenotransplantation.
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Células de Sertoli/trasplante , Trasplante Heterólogo/métodos , Alginatos , Animales , Animales Recién Nacidos , Separación Celular , Trasplante de Células/métodos , Células Cultivadas , Ácido Glucurónico , Ácidos Hexurónicos , Humanos , Masculino , Ratones , Células de Sertoli/citología , Células de Sertoli/fisiología , Organismos Libres de Patógenos Específicos , PorcinosRESUMEN
Humans interact with a multitude of microorganisms in various ecological relationships, ranging from commensalism to pathogenicity. The same applies to fungi, long recognized for their pathogenic roles in infection-such as in invasive fungal diseases caused, among others, by Aspergillus fumigatus and Candida spp.-and, more recently, for their beneficial activities as an integral part of the microbiota. Indeed, alterations in the fungal component of the microbiota, or mycobiota, have been associated with inflammatory, infectious and metabolic diseases, and cancer. Whether acting as opportunistic pathogens or symbiotic commensals, fungi possess a complex enzymatic repertoire that intertwines with that of the host. In this metabolic cross-talk, fungal enzymes may be unique, thus providing novel metabolic opportunities to the host, or, conversely, produce toxic metabolites. Indeed, administration of fungal probiotics and fungi-derived products may be beneficial in inflammatory and infectious diseases, but fungi may also produce a plethora of toxic secondary metabolites, collectively known as mycotoxins. Fungal enzymes may also be homologues to human enzymes, but nevertheless embedded in fungal-specific metabolic networks, determined by all the interconnected enzymes and molecules, quantitatively and qualitatively specific to the network, such that the activity and metabolic effects of each enzyme remain unique to fungi. In this Opinion, we explore the concept that targeting this fungal metabolic unicity, either in opportunistic pathogens or commensals, may be exploited to develop novel therapeutic strategies. In doing so, we present our recent experience in different pathological settings that ultimately converge on relevant trans-kingdom metabolic differences.
RESUMEN
Aspergillus fumigatus is an environmental fungus recently included in the fungal high-priority pathogens by the World Health Organization. While immunodeficiency and/or pre-existing lung damage represent a well-recognized fertile ground for fungal growth, it is increasingly being recognized that severe viral infections may similarly favor A. fumigatus colonization and infection, as recently experienced in the Coronavirus disease 2019 (COVID-19) pandemic. Herein, in a murine model of COVID-19-associated pulmonary aspergillosis (CAPA), obtained by the concomitant exposure to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein and A. fumigatus conidia, we found that the microbial compound indole-3-aldehyde (3-IAld) was able to ameliorate CAPA by working at multiple levels during viral infection and fungal superinfection, including epithelial barrier protection, promotion of antiviral responses, and limiting viral replication. As a consequence, 3-IAld limited the pathogenic sequelae of fungal superinfection as revealed by the controlled fungal burden and restrained inflammatory pathology. These results point to indole compounds as potential agents to prevent CAPA.
RESUMEN
Celiac disease (CD) is an autoimmune enteropathy resulting from an interaction between diet, genome, and immunity. Although many patients respond to a gluten-free diet, in a substantive number of individuals, the intestinal injury persists. Thus, other factors might amplify the ongoing inflammation. Candida albicans is a commensal fungus that is well adapted to the intestinal life. However, specific conditions increase Candida pathogenicity. The hypothesis that Candida may be a trigger in CD has been proposed after the observation of similarity between a fungal wall component and two CD-related gliadin T-cell epitopes. However, despite being implicated in intestinal disorders, Candida may also protect against immune pathologies highlighting a more intriguing role in the gut. Herein, we postulated that a state of chronic inflammation associated with microbial dysbiosis and leaky gut are favorable conditions that promote C. albicans pathogenicity eventually contributing to CD pathology via a mast cells (MC)-IL-9 axis. However, the restoration of immune and microbial homeostasis promotes a beneficial C. albicans-MC cross-talk favoring the attenuation of CD pathology to alleviate CD pathology and symptoms.
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Candida albicans , Enfermedad Celíaca , Homeostasis , Mastocitos , Enfermedad Celíaca/inmunología , Enfermedad Celíaca/microbiología , Enfermedad Celíaca/metabolismo , Humanos , Candida albicans/patogenicidad , Candida albicans/inmunología , Mastocitos/inmunología , Mastocitos/metabolismo , Microbioma Gastrointestinal/inmunología , Disbiosis/inmunología , Candidiasis/inmunología , Candidiasis/microbiología , Animales , Candida/patogenicidad , Candida/inmunología , Mucosa Intestinal/microbiología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismoRESUMEN
Multiple sclerosis is a debilitating autoimmune disease, characterized by chronic inflammation of the central nervous system. While the significance of the gut microbiome on multiple sclerosis pathogenesis is established, the underlining mechanisms are unknown. We found that serum levels of the microbial postbiotic tryptophan metabolite indole-3-carboxaldehyde (3-IAld) inversely correlated with disease duration in multiple sclerosis patients. Much like the host-derived tryptophan derivative L-Kynurenine, 3-IAld would bind and activate the Aryl hydrocarbon Receptor (AhR), which, in turn, controls endogenous tryptophan catabolic pathways. As a result, in peripheral lymph nodes, microbial 3-IAld, affected mast-cell tryptophan metabolism, forcing mast cells to produce serotonin via Tph1. We thus propose a protective role for AhR-mast-cell activation driven by the microbiome, whereby natural metabolites or postbiotics will have a physiological role in immune homeostasis and may act as therapeutic targets in autoimmune diseases.
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Esclerosis Múltiple , Triptófano , Humanos , Quinurenina/metabolismo , Ligandos , Receptores de Hidrocarburo de Aril/metabolismo , Triptófano/metabolismo , Triptófano Hidroxilasa/metabolismoRESUMEN
Developing therapeutics for inflammatory diseases is challenging due to physiological mucosal barriers, systemic side effects, and the local microbiota. In the search for novel methods to overcome some of these problems, drug delivery systems that improve tissue-targeted drug delivery and modulate the microbiota are highly desirable. Microbial metabolites are known to regulate immune responses, an observation that has resulted in important conceptual advances in areas such as metabolite pharmacology and metabolite therapeutics. Indeed, the doctrine of "one molecule, one target, one disease" that has dominated the pharmaceutical industry in the 20th century is being replaced by developing therapeutics which simultaneously manipulate multiple targets through novel formulation approaches, including the multitarget-directed ligands. Thus, metabolites may not only represent biomarkers for disease development, but also, being causally linked to human diseases, an unexploited source of therapeutics. We have shown the successful exploitation of this approach: by deciphering how signaling molecules, such as the microbial metabolite, indole-3-aldehyde, and the repurposed drug anakinra, interact with the aryl hydrocarbon receptor may pave the way for novel therapeutics in inflammatory human diseases, for the realization of which drug delivery platforms are instrumental.