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1.
FASEB J ; 37(11): e23233, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37823221

RESUMEN

Mucus plugging and non-resolving inflammation are inherent features of cystic fibrosis (CF) that may lead to progressive lung disease and exercise intolerance, which are the main causes of morbidity and mortality for people with CF. Therefore, understanding the influence of mucus on basic mechanisms underlying the inflammatory response and identifying strategies to resolve mucus-driven airway inflammation and consequent morbidity in CF are of wide interest. Here, we investigated the effects of the proresolving lipid mediator resolvin (Rv) D1 on mucus-related inflammation as a proof-of-concept to alleviate the burden of lung disease and restore exercise intolerance in CF. We tested the effects of RvD1 on inflammatory responses of human organotypic airways and leukocytes to CF mucus and of humanized mice expressing the epithelial Na + channel (ßENaC-Tg) having CF-like mucus obstruction, lung disease, and physical exercise intolerance. RvD1 reduced pathogenic phenotypes of CF-airway supernatant (ASN)-stimulated human neutrophils, including loss of L-selectin shedding and CD16. RNASeq analysis identified select transcripts and pathways regulated by RvD1 in ASN-stimulated CF bronchial epithelial cells that are involved in sugar metabolism, NF-κB activation and inflammation, and response to stress. In in vivo inflammation using ßENaC TG mice, RvD1 reduced total leukocytes, PMN, and interstitial Siglec-MΦ when given at 6-8 weeks of age, and in older mice at 10-12 weeks of age, along with the decrease of pro-inflammatory chemokines and increase of anti-inflammatory IL-10. Furthermore, RvD1 treatment promoted the resolution of pulmonary exacerbation caused by Pseudomonas aeruginosa infection and significantly enhanced physical activity and energy expenditure associated with mucus obstruction, which was impaired in ßENaC-Tg mice compared with wild-type. These results demonstrate that RvD1 can rectify features of CF and offer proof-of-concept for its therapeutic application in this and other muco-obstructive lung diseases.


Asunto(s)
Fibrosis Quística , Humanos , Ratones , Animales , Fibrosis Quística/genética , Tolerancia al Ejercicio , Pulmón/metabolismo , Inflamación/metabolismo
2.
Prostaglandins Other Lipid Mediat ; 168: 106762, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37355222

RESUMEN

The COVID-19 pandemics has made sparkly evident the importance of acute inflammation and its timely resolution to protect humans from pathogenic viruses while sparing them from collateral damages due to an uncontrolled immune response. It is clear now that resolution of inflammation is an active process regulated by endogenous specialized proresolving lipid mediators (SPM) biosynthesized from essential polyunsaturated fatty acids. Accruing evidence indicates that SPM are produced during viral infections and play key roles in controlling the magnitude and duration of the inflammatory response and in regulating adaptive immunity. Here, we reviewed biosynthesis and bioactions of SPM in virus-mediated human diseases. Harnessing SPM and their proresolutive actions can help in providing new therapeutic approaches to current and future human viral diseases by controlling infection, stimulating host immunity, and protecting from organ damage.


Asunto(s)
COVID-19 , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Eicosanoides , Mediadores de Inflamación , Ácidos Docosahexaenoicos
3.
FASEB J ; 35(4): e21441, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33749902

RESUMEN

An excessive, non-resolving inflammatory response underlies severe COVID-19 that may have fatal outcomes. Therefore, the investigation of endogenous pathways leading to resolution of inflammation is of interest to uncover strategies for mitigating inflammation in people with SARS-CoV-2 infection. This becomes particularly urgent in individuals with preexisting pathologies characterized by chronic respiratory inflammation and prone to bacterial infection, such as cystic fibrosis (CF). Here, we analyzed the immune responses to SARS-CoV-2 virion spike 1 glycoprotein (S1) of macrophages (MΦ) from volunteers with and without CF and tested the efficacy of resolvins (Rv) D1 and D2 in regulating the inflammatory and antimicrobial functions of MΦ exposed to S1. S1 significantly increased chemokine release, including interleukin (IL)-8, in CF and non-CF MΦ, while it enhanced IL-6 and tumor necrosis factor (TNF)-α in non-CF MΦ, but not in CF cells. S1 also triggered the biosynthesis of RvD1 and modulated microRNAs miR-16, miR-29a, and miR-103, known to control the inflammatory responses. RvD1 and RvD2 treatment abated S1-induced inflammatory responses in CF and non-CF MΦ, significantly reducing the release of select chemokines and cytokines including IL-8 and TNF-α. RvD1 and RvD2 both restored the expression of miR-16 and miR-29a, while selectively increasing miR-223 and miR-125a, which are involved in NF-κB activation and MΦ inflammatory polarization. During Pseudomonas aeruginosa infection, S1 stimulated the MΦ phagocytic activity that was further enhanced by RvD1 and RvD2. These results provide a map of molecular responses to SARS-CoV-2 in MΦ, key determinants of COVID-19-related inflammation, unveiling some peculiarity in the response of cells from individuals with CF. They also demonstrate beneficial, regulatory actions of RvD1 and RvD2 on SARS-CoV-2-induced inflammation.


Asunto(s)
COVID-19 , Fibrosis Quística , Ácidos Docosahexaenoicos/farmacología , Macrófagos , Infecciones por Pseudomonas , Pseudomonas aeruginosa/inmunología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , COVID-19/inmunología , COVID-19/microbiología , COVID-19/patología , Fibrosis Quística/inmunología , Fibrosis Quística/microbiología , Fibrosis Quística/patología , Fibrosis Quística/virología , Citocinas/inmunología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Inflamación/inmunología , Inflamación/microbiología , Inflamación/patología , Inflamación/virología , Macrófagos/inmunología , Macrófagos/microbiología , Macrófagos/patología , Macrófagos/virología , Masculino , MicroARNs/inmunología , Infecciones por Pseudomonas/inmunología , Infecciones por Pseudomonas/patología , Infecciones por Pseudomonas/virología
4.
Int J Mol Sci ; 23(12)2022 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-35742918

RESUMEN

In human medicine, the progression from early neoplasia development to either complete resolution of tumorigenesis and associated inflammation or chronicity and fatal outcomes remain difficult to predict. Resolution of inflammation is an active process that stimulates the termination of the inflammatory response and promotes return to homeostasis, while failure in resolution contributes to the development of a number of diseases. To understand how resolution pathways contribute to tumorigenesis, we defined and employed a cumulative score based on the expression level of genes involved in synthesis, signaling, and metabolism of the D-series resolvin (RvD). This score was used for comparative analyses of clinical, cellular, and molecular features of tumors, based on RNA-sequencing (RNA-seq) datasets collected within The Cancer Genome Atlas (TCGA) program. Our results indicate that higher RvD scores are associated with better clinical outcome of patients with head and neck squamous cell carcinoma (HNSC), and with molecular and cellular signatures indicative of enhanced anti-tumor immunity and better response to immune-checkpoint inhibitors (ICI), also in human papilloma virus (HPV) negative HNSC subtypes. Thus, higher activity of the RvD pathway identifies patients with improved resolution and a more efficient immune reaction against cancer.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Biomarcadores de Tumor/genética , Carcinogénesis , Carcinoma de Células Escamosas/metabolismo , Transformación Celular Neoplásica , Expresión Génica , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Humanos , Inflamación , Carcinoma de Células Escamosas de Cabeza y Cuello
5.
Curr Issues Mol Biol ; 35: 1-16, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31422930

RESUMEN

Small ubiquitin-like modifier (SUMO)ylation is a crucial post-translational modification that controls functions of a wide collection of proteins and biological processes. Hence, given its pleiotropic role, viruses have developed many approaches to usurp SUMO conjugation to exploit the cellular host environment for their own benefit. Consistently, cancer cells also frequently impact on SUMO to force cellular transformation, underlining the importance of SUMO in health and diseases. Therefore, after a brief introduction to the multistep SUMOylation pathway, in this review we will focus our attention on several examples of strategies adopted by oncogenic viruses to hijack SUMOylation in order to promote infection, persistence and malignant transformation of host cells.


Asunto(s)
Neoplasias/metabolismo , Neoplasias/virología , Retroviridae/metabolismo , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Sumoilación , Cromatina/genética , Cromatina/metabolismo , Hepacivirus/genética , Hepacivirus/metabolismo , Hepacivirus/patogenicidad , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/metabolismo , Virus de la Hepatitis B/patogenicidad , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Herpesvirus Humano 4/patogenicidad , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/metabolismo , Herpesvirus Humano 8/patogenicidad , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Virus Linfotrópico T Tipo 1 Humano/patogenicidad , Humanos , Poliomavirus de Células de Merkel/genética , Poliomavirus de Células de Merkel/metabolismo , Poliomavirus de Células de Merkel/patogenicidad , Neoplasias/genética , Papillomaviridae/genética , Papillomaviridae/metabolismo , Papillomaviridae/patogenicidad , Retroviridae/genética , Retroviridae/crecimiento & desarrollo , Retroviridae/patogenicidad , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genética , Ubiquitina-Proteína Ligasas/metabolismo
6.
Int J Mol Sci ; 21(18)2020 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-32927853

RESUMEN

Autophagy is a catabolic pathway that accounts for degradation and recycling of cellular components to extend cell survival under stress conditions. In addition to this prominent role, recent evidence indicates that autophagy is crucially involved in the regulation of the inflammatory response, a tightly controlled process aimed at clearing the inflammatory stimulus and restoring tissue homeostasis. To be efficient and beneficial to the host, inflammation should be controlled by a resolution program, since uncontrolled inflammation is the underlying cause of many pathologies. Resolution of inflammation is an active process mediated by a variety of mediators, including the so-called specialized pro-resolving lipid mediators (SPMs), a family of endogenous lipid autacoids known to regulate leukocyte infiltration and activities, and counterbalance cytokine production. Recently, regulation of autophagic mechanisms by these mediators has emerged, uncovering unappreciated connections between inflammation resolution and autophagy. Here, we summarize mechanisms of autophagy and resolution, focusing on the contribution of autophagy in sustaining paradigmatic examples of chronic inflammatory disorders. Then, we discuss the evidence that SPMs can restore dysregulated autophagy, hypothesizing that resolution of inflammation could represent an innovative approach to modulate autophagy and its impact on the inflammatory response.


Asunto(s)
Autofagia , Ácidos Docosahexaenoicos/metabolismo , Eicosanoides/metabolismo , Inflamación/metabolismo , Animales , Enfermedad Crónica , Humanos
7.
PLoS Pathog ; 13(3): e1006262, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28253371

RESUMEN

UBC9, the sole E2-conjugating enzyme required for SUMOylation, is a key regulator of essential cellular functions and, as such, is frequently altered in cancers. Along these lines, we recently reported that its expression gradually increases during early stages of human papillomavirus (HPV)-mediated cervical lesions transformation. However, a better understanding of how UBC9 is exploited by transforming viral oncoproteins is still needed. In the present study, we show that in human samples HPV drives UBC9 up-regulation also in very early steps of head and neck tumorigenesis, pointing to the important role for UBC9 in the HPV-mediated carcinogenic program. Moreover, using HPV-infected pre-cancerous tissues and primary human keratinocytes as the natural host of the virus, we investigate the pathological meaning and the cellular mechanisms responsible for UBC9 de-regulation in an oncoviral context. Our results show that UBC9 overexpression is promoted by transforming viral proteins to increase host cells' resistance to apoptosis. In addition, ultrastuctural, pharmacological and genetic approaches crucially unveil that UBC9 is physiologically targeted by autophagy in human cells. However, the presence of HPV E6/E7 oncoproteins negatively impacts the autophagic process through selective inhibition of autophagosome-lysosome fusion, finally leading to p53 dependent UBC9 accumulation during viral-induced cellular transformation. Therefore, our study elucidates how UBC9 is manipulated by HPV oncoproteins, details the physiological mechanism by which UBC9 is degraded in cells, and identifies how HPV E6/E7 impact on autophagy. These findings point to UBC9 and autophagy as novel hallmarks of HPV oncogenesis, and open innovative avenues towards the treatment of HPV-related malignancies.


Asunto(s)
Autofagia/fisiología , Transformación Celular Viral/fisiología , Infecciones por Papillomavirus/metabolismo , Enzimas Ubiquitina-Conjugadoras/metabolismo , Apoptosis , Transformación Celular Neoplásica , Femenino , Citometría de Flujo , Humanos , Immunoblotting , Inmunohistoquímica , Microscopía Confocal , Proteínas Oncogénicas Virales , Papillomaviridae/metabolismo , Infecciones por Papillomavirus/patología , Reacción en Cadena de la Polimerasa , Transducción Genética , Transfección
8.
Int J Mol Sci ; 19(6)2018 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-29914057

RESUMEN

Human papilloma viruses (HPVs) are a group of double-stranded DNA viruses known to be the primary cause of cervical cancer. In addition, evidence has now established their role in non-melanoma skin cancers, head and neck cancer (HNC), and the development of other anogenital malignancies. The prevalence of HPV-related HNC, in particular oropharyngeal cancers, is rapidly increasing, foreseeing that HPV-positive oropharyngeal cancers will outnumber uterine cervical cancers in the next 15⁻20 years. Therefore, despite the successful advent of vaccines originally licensed for cervical cancer prevention, HPV burden is still very high, and a better understanding of HPV biology is urgently needed. Autophagy is the physiological cellular route that accounts for removal, degradation, and recycling of damaged organelles, proteins, and lipids in lysosomal vacuoles. In addition to this scavenger function, autophagy plays a fundamental role during viral infections and cancers and is, therefore, frequently exploited by viruses to their own benefit. Recently, a link between HPV and autophagy has clearly emerged, leading to the conceivable development of novel anti-viral strategies aimed at restraining HPV infectivity. Here, recent findings on how oncogenic HPV16 usurp autophagy are described, highlighting similarities and differences with mechanisms adopted by other oncoviruses.


Asunto(s)
Autofagia , Papillomaviridae/patogenicidad , Neoplasias del Cuello Uterino/virología , Femenino , Interacciones Huésped-Patógeno , Humanos , Papillomaviridae/genética , Papillomaviridae/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo
9.
Proc Natl Acad Sci U S A ; 110(45): 18168-73, 2013 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-24145437

RESUMEN

The tumor suppressor VHL (von Hippel-Lindau) protein is a substrate receptor for Ubiquitin Cullin Ring Ligase complexes (CRLs), containing a BC-box domain that associates to the adaptor Elongin B/C. VHL targets hypoxia-inducible factor 1α to proteasome-dependent degradation. Gam1 is an adenoviral protein, which also possesses a BC-box domain that interacts with the host Elongin B/C, thereby acting as a viral substrate receptor. Gam1 associates with both Cullin2 and Cullin5 to form CRL complexes targeting the host protein SUMO enzyme SAE1 for proteasomal degradation. We show that Gam1 protein expression induces VHL protein degradation leading to hypoxia-inducible factor 1α stabilization and induction of its downstream targets. We also characterize the CRL-dependent mechanism that drives VHL protein degradation via proteasome. Interestingly, expression of Suppressor of Cytokine Signaling (SOCS) domain-containing viral proteins and cellular BC-box proteins leads to VHL protein degradation, in a SOCS domain-containing manner. Our work underscores the exquisite ability of viral domains to uncover new regulatory mechanisms by hijacking key cellular proteins.


Asunto(s)
Proteolisis , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Complejos de Ubiquitina-Proteína Ligasa/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Línea Celular Tumoral , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Cartilla de ADN/genética , Elonguina , Técnicas de Silenciamiento del Gen , Humanos , Immunoblotting , Inmunoprecipitación , Luciferasas , Estructura Terciaria de Proteína , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteína 1 Supresora de la Señalización de Citocinas , Factores de Transcripción/metabolismo , Proteínas Virales/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/fisiología
10.
Future Oncol ; 11(11): 1599-610, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26043214

RESUMEN

SUMOylation is a key post-translational modification that regulates crucial cellular functions and pathological processes. Recently, Small Ubiquitin-related MOdifier (SUMO) modification has emerged as a fundamental route that may drive different steps of human tumorigenesis. Indeed, alteration in expression or activity of one of the different SUMO pathway components may completely subvert cellular properties through fine-tuning modulation of protein(s) involved in carcinogenic pathways, leading to altered cell proliferation, apoptosis resistance and metastatic potential. Here we describe some of the most interesting findings pointing to a clear link between SUMO pathway and human malignancies. Importantly, a putative role for SUMO enzymes to predict cancer behavior can be speculated, and thus the possible application of alterations in SUMO pathway components as tumor biomarkers is discussed.


Asunto(s)
Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Sumoilación , Animales , Humanos , Chaperonas Moleculares/genética , Proteínas de Complejo Poro Nuclear/genética , Péptido Hidrolasas/genética , Péptido Hidrolasas/metabolismo , Proteínas Inhibidoras de STAT Activados/genética , Proteínas Inhibidoras de STAT Activados/metabolismo , Proteína SUMO-1/metabolismo , Transducción de Señal , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genética , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Enzimas Activadoras de Ubiquitina/genética , Enzimas Activadoras de Ubiquitina/metabolismo , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo
11.
IUBMB Life ; 66(1): 27-33, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24395713

RESUMEN

Viruses alter specific host cell targets to counteract possible defense mechanisms aimed at eliminating infectivity and viral propagation. The SUMO conjugating enzyme Ubc9 functions as a hub for protein sumoylation, whilst also providing an interactive surface for sumoylated proteins through noncovalent interactions. The targeting of Ubc9 by viruses and viral proteins is thus highly beneficial for the disruption of both protein modification and protein-protein interaction mechanisms with which proteins increase their functional repertoire in cells. This review explores some of the clever mechanisms adopted by viruses to deregulate Ubc9, influence effector pathways and positively impact viral persistence consequently.


Asunto(s)
Interacciones Huésped-Patógeno , Procesamiento Proteico-Postraduccional , Proteína SUMO-1/metabolismo , Enzimas Ubiquitina-Conjugadoras/metabolismo , Replicación Viral , Animales , Humanos , Sumoilación , Ubiquitinas/metabolismo
12.
Antioxidants (Basel) ; 13(4)2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38671902

RESUMEN

Aging is characterized by increased oxidation and reduced efficiency of cytoprotective mechanisms. Nuclear factor erythroid-2-related factor (Nrf2) is a key transcription factor, controlling the expression of multiple antioxidant proteins. Here, we show that Nrf2-/- mice displayed an age-dependent anemia, due to the combined contributions of reduced red cell lifespan and ineffective erythropoiesis, suggesting a role of Nrf2 in erythroid biology during aging. Mechanistically, we found that the expression of antioxidants during aging is mediated by activation of Nrf2 function by peroxiredoxin-2. The absence of Nrf2 resulted in persistent oxidation and overactivation of adaptive systems such as the unfolded protein response (UPR) system and autophagy in Nrf2-/- mouse erythroblasts. As Nrf2 is involved in the expression of autophagy-related proteins such as autophagy-related protein (Atg) 4-5 and p62, we found impairment of late phase of autophagy in Nrf2-/- mouse erythroblasts. The overactivation of the UPR system and impaired autophagy drove apoptosis of Nrf2-/- mouse erythroblasts via caspase-3 activation. As a proof of concept for the role of oxidation, we treated Nrf2-/- mice with astaxanthin, an antioxidant, in the form of poly (lactic-co-glycolic acid) (PLGA)-loaded nanoparticles (ATS-NPs) to improve its bioavailability. ATS-NPs ameliorated the age-dependent anemia and decreased ineffective erythropoiesis in Nrf2-/- mice. In summary, we propose that Nrf2 plays a key role in limiting age-related oxidation, ensuring erythroid maturation and growth during aging.

13.
FASEB J ; 26(3): 1323-33, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22131270

RESUMEN

Lipoxin (LX) A(4,) a main endogenous stop-signal of inflammation, activates the G-protein-coupled receptor FPR2/ALX, which triggers potent anti-inflammatory signaling in vivo. Thus, the regulation of FPR2/ALX expression may have pathophysiological and therapeutic relevance. Here, we mapped a nucleotide sequence with strong FPR2/ALX promoter activity. Chromatin immunoprecipitation revealed specificity protein 1 (Sp1) binding to the core promoter. Site-directed mutagenesis of the Sp1 cis-acting element and Sp1 overexpression established that this transcription factor is key for maximal promoter activity, which is instead suppressed by DNA methylation. LXA(4) enhanced FPR2/ALX promoter activity (+74%) and mRNA expression (+87.5%) in MDA-MB231 cells. A single nucleotide mutation (A/G) was detected in the core promoter of one subject with history of cardiovascular disease and of his two daughters. This mutation reduced by ∼35-90% the promoter activity in vitro. Moreover, neutrophils from individuals carrying the A/G variant displayed ∼10- and 3-fold reduction in FPR2/ALX mRNA and protein, respectively, compared with cells from their relatives or healthy volunteers expressing the wild-type allele. These results uncover FPR2/ALX transcriptional regulation and provide the first evidence of mutations that affect FPR2/ALX transcription, thus opening new opportunities for the understanding of the LXA(4)-FPR2/ALX axis in human disease.


Asunto(s)
Regulación de la Expresión Génica , Receptores de Formil Péptido/genética , Receptores de Lipoxina/genética , Transcripción Genética/genética , Secuencia de Bases , Sitios de Unión/genética , Western Blotting , Línea Celular , Línea Celular Tumoral , Metilación de ADN , Variación Genética , Humanos , Modelos Genéticos , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Unión Proteica , Receptores de Formil Péptido/metabolismo , Receptores de Lipoxina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción Sp1/metabolismo , Sitio de Iniciación de la Transcripción
14.
Hemasphere ; 7(3): e848, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36874380

RESUMEN

Drug repurposing is a valuable strategy for rare diseases. Sickle cell disease (SCD) is a rare hereditary hemolytic anemia accompanied by acute and chronic painful episodes, most often in the context of vaso-occlusive crisis (VOC). Although progress in the knowledge of pathophysiology of SCD have allowed the development of new therapeutic options, a large fraction of patients still exhibits unmet therapeutic needs, with persistence of VOCs and chronic disease progression. Here, we show that imatinib, an oral tyrosine kinase inhibitor developed for the treatment of chronic myelogenous leukemia, acts as multimodal therapy targeting signal transduction pathways involved in the pathogenesis of both anemia and inflammatory vasculopathy of humanized murine model for SCD. In addition, imatinib inhibits the platelet-derived growth factor-B-dependent pathway, interfering with the profibrotic response to hypoxia/reperfusion injury, used to mimic acute VOCs. Our data indicate that imatinib might be considered as possible new therapeutic tool for chronic treatment of SCD.

15.
Blood ; 115(5): 1054-61, 2010 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-19887674

RESUMEN

We tested whether cyclooxygenase 2 (COX-2) expression and unacetylated COX-1 in newly formed platelets might contribute to persistent thromboxane (TX) biosynthesis in aspirin-treated essential thrombocythemia (ET). Forty-one patients on chronic aspirin (100 mg/day) and 24 healthy subjects were studied. Platelet COX-2 expression was significantly increased in patients and correlated with thiazole orange-positive platelets (r = 0.71, P < .001). The rate of TXA(2) biosynthesis in vivo, as reflected by urinary 11-dehydro-TXB(2) (TXM) excretion, and the maximal biosynthetic capacity of platelets, as reflected by serum TXB(2), were higher in patients compared with aspirin-treated healthy volunteers. Serum TXB(2) was significantly reduced by the selective COX-2 inhibitor NS-398 added in vitro. Patients were randomized to adding the selective COX-2 inhibitor, etoricoxib, or continuing aspirin for 7 days. Etoricoxib significantly reduced by approximately 25% TXM excretion and serum TXB(2). Fourteen of the 41 patients were studied again 21 (+/- 7) months after the first visit. Serum TXB(2) was consistently reduced by approximately 30% by adding NS398 in vitro, while it was completely suppressed with 50 microM aspirin. Accelerated platelet regeneration in most aspirin-treated ET patients may explain aspirin-persistent TXA(2) biosynthesis through enhanced COX-2 activity and faster renewal of unacetylated COX-1. These findings may help in reassessing the optimal antiplatelet strategy in ET.


Asunto(s)
Aspirina/uso terapéutico , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Piridinas/uso terapéutico , Sulfonas/uso terapéutico , Trombocitemia Esencial/tratamiento farmacológico , Tromboxanos/biosíntesis , Adulto , Inhibidores de la Ciclooxigenasa/uso terapéutico , Quimioterapia Combinada , Etoricoxib , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/uso terapéutico , Trombocitemia Esencial/metabolismo , Trombocitemia Esencial/patología , Tromboxano A2/biosíntesis , Tromboxano A2/sangre , Tromboxano A2/orina , Tromboxano B2/análogos & derivados , Tromboxano B2/biosíntesis , Tromboxano B2/sangre , Tromboxano B2/orina , Tromboxanos/sangre , Tromboxanos/orina , Resultado del Tratamiento
16.
FASEB J ; 24(10): 3970-80, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20530751

RESUMEN

Inflammatory lung disease is a primary cause of morbidity and mortality in cystic fibrosis (CF). Mechanisms of unresolved acute inflammation in CF are not completely known, although the involvement of cystic fibrosis transmembrane conductance regulator (CFTR) in nonrespiratory cells is emerging. Here we examined CFTR expression and function in human platelets (PLTs) and found that they express a biologically active CFTR. CFTR blockade gave an ∼50% reduction in lipoxin A(4) (LXA(4)) formation during PLT/polymorphonuclear leukocytes (PMN) coincubations by inhibiting the lipoxin synthase activity of PLT 12-lipoxygenase. PLTs from CF patients generated ∼40% less LXA(4) compared to healthy subject PLTs. CFTR inhibition increased PLT-dependent PMN viability (33.0±5.7 vs. 61.2±8.2%; P=0.033), suppressed nitric oxide generation (0.23±0.04 vs. 0.11±0.002 pmol/10(8) PLTs; P=0.004), while reducing AKT (1.02±0.12 vs. 0.71±0.007 U; P=0.04), and increasing p38 MAPK phosphorylation (0.650±0.09 vs. 1.04±0.24 U; P=0.03). Taken together, these findings indicate that PLTs from CF patients are affected by the molecular defect of CFTR. Moreover, this CF PLT abnormality may explain the failure of resolution in CF.


Asunto(s)
Plaquetas/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/sangre , Mediadores de Inflamación/fisiología , Apoptosis , Línea Celular , Femenino , Humanos , Inmunohistoquímica , Masculino , Microscopía Electrónica de Transmisión , Fosforilación , Proteínas Quinasas/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
17.
J Exp Clin Cancer Res ; 40(1): 129, 2021 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-33845864

RESUMEN

BACKGROUND: Innovative therapies to target tumor-associated neutrophils (PMN) are of clinical interest, since these cells are centrally involved in cancer inflammation and tumor progression. Resolvin D1 (RvD1) is a lipid autacoid that promotes resolution of inflammation by regulating the activity of distinct immune and non-immune cells. Here, using human papilloma virus (HPV) tumorigenesis as a model, we investigated whether RvD1 modulates PMN to reduce tumor progression. METHODS: Growth-curve assays with multiple cell lines and in vivo grafting of two distinct HPV-positive cells in syngeneic mice were used to determine if RvD1 reduced cancer growth. To investigate if and how RvD1 modulates PMN activities, RNA sequencing and multiplex cytokine ELISA of human PMN in co-culture with HPV-positive cells, coupled with pharmacological depletion of PMN in vivo, were performed. The mouse intratumoral immune cell composition was evaluated through FACS analysis. Growth-curve assays and in vivo pharmacological depletion were used to evaluate anti-tumor activities of human and mouse monocytes, respectively. Bioinformatic analysis of The Cancer Genome Atlas (TCGA) database was exploited to validate experimental findings in patients. RESULTS: RvD1 decreased in vitro and in vivo proliferation of human and mouse HPV-positive cancer cells through stimulation of PMN anti-tumor activities. In addition, RvD1 stimulated a PMN-dependent recruitment of classical monocytes as key determinant to reduce tumor growth in vivo. In human in vitro systems, exposure of PMN to RvD1 increased the production of the monocyte chemoattractant protein-1 (MCP-1), and enhanced transmigration of classical monocytes, with potent anti-tumor actions, toward HPV-positive cancer cells. Consistently, mining of immune cells infiltration levels in cervical cancer patients from the TCGA database evidenced an enhanced immune reaction and better clinical outcomes in patients with higher intratumoral monocytes as compared to patients with higher PMN infiltration. CONCLUSIONS: RvD1 reduces cancer growth by activating PMN anti-cancer activities and encouraging a protective PMN-dependent recruitment of anti-tumor monocytes. These findings demonstrate efficacy of RvD1 as an innovative therapeutic able to stimulate PMN reprogramming to an anti-cancer phenotype that restrains tumor growth.


Asunto(s)
Ácidos Docosahexaenoicos/uso terapéutico , Monocitos/metabolismo , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Neutrófilos/metabolismo , Animales , Ácidos Docosahexaenoicos/farmacología , Humanos , Ratones
18.
Blood ; 112(4): 1085-90, 2008 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-18541722

RESUMEN

Polycythemia vera (PV) is associated with high morbidity and mortality for thrombosis. We hypothesized that in PV altered sensitivity to aspirin might be related to dysfunction of the endothelial repair and/or of the nitric oxide (NO) system. Urinary thromboxane (TX) A(2) metabolite (TXM), endothelial colony-forming cells (ECFCs), plasma asymmetric dimethylarginine (ADMA) and von Willebrand factor (VWF) were measured in 37 PV patients on low-dose aspirin and 12 healthy controls. Patients showed an approximately 2-fold increase in median TXM and plasma ADMA levels (P < .001), while ECFC numbers were reduced by approximately 7-fold (P < .001) as compared with non-aspirinated control. These differences were more pronounced in patients with previous thrombosis. An 8-week course of aspirin did not affect ECFCs in 6 controls. VWF and TXM correlated directly with ADMA, and inversely with ECFCs. By multiple regression analysis, lower ECFC quartiles (beta = -0.39; SE = 0.17; P = .028) and higher VWF levels (beta = 0.338, SE = 0.002, P = .034) were independent predictors of higher TXM quartiles (R(2) = 0.39). Serum TXB(2), measured in 22 patients, was approximately 10-fold higher than aspirin-treated controls. PV patients appear to have an unbalanced ECFC/NO axis, and an apparent altered sensitivity of platelet TXA(2) production, all potentially contributing to aspirin-insensitive TXM formation. Thus, additional antithrombotic strategies may be beneficial in PV.


Asunto(s)
Aspirina/administración & dosificación , Células Endoteliales/patología , Policitemia Vera/sangre , Policitemia Vera/tratamiento farmacológico , Células Madre/patología , Tromboxanos/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Arginina/análogos & derivados , Arginina/sangre , Aspirina/farmacología , Sangre , Estudios de Casos y Controles , Ensayo de Unidades Formadoras de Colonias , Células Endoteliales/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Células Madre/efectos de los fármacos , Tromboxano A2/sangre , Tromboxano B2/sangre
19.
Front Immunol ; 11: 581, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32528461

RESUMEN

Non-resolving lung inflammation and Pseudomonas aeruginosa infections are the underlying cause of morbidity and mortality in cystic fibrosis (CF). The endogenous lipid mediator resolvin (Rv) D1 is a potent regulator of resolution, and its roles, actions, and therapeutic potential in CF are of interest. Here, we investigated actions and efficacy of RvD1 in preclinical models of cystic fibrosis. Cftr knockout mice with chronic P. aeruginosa lung infection were treated with RvD1 to assess differences in lung bacterial load, inflammation, and tissue damage. Cells from volunteers with CF were treated with RvD1 during ex vivo infection with P. aeruginosa, and effects on phagocytosis and inflammatory signaling were determined. In CF mice, RvD1 reduced bacterial burden, neutrophil infiltration, and histological signs of lung pathology, improving clinical scores of diseases. Mechanistically, RvD1 increased macrophage-mediated bacterial and leukocyte clearance in vivo. The clinical significance of these findings is supported by actions in primary leukocytes and epithelial cells from volunteers with CF where RvD1 enhanced P. aeruginosa phagocytosis and reduced genes and proteins associated to NF-κB activation and leukocyte infiltration. Concentration of RvD1 in sputum from patients with CF was also inversely correlated to those of cytokines and chemokines involved in CF lung pathology. These findings demonstrate efficacy of RvD1 in enhancing resolution of lung inflammation and infections and provide proof of concept for its potential as a prototypic novel pro-resolutive therapeutic approach for CF.


Asunto(s)
Fibrosis Quística/inmunología , Fibrosis Quística/microbiología , Ácidos Docosahexaenoicos/farmacología , Neumonía/inmunología , Infecciones por Pseudomonas , Animales , Fibrosis Quística/patología , Humanos , Ratones , Ratones Noqueados , Infiltración Neutrófila/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Neumonía/microbiología , Neumonía/patología , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa
20.
Front Pharmacol ; 10: 252, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31001110

RESUMEN

Non-resolving inflammation is the main mechanism of morbidity and mortality among patients suffering from cystic fibrosis (CF), the most common life-threatening human genetic disease. Resolution of inflammation is an active process timely controlled by endogenous specialized pro-resolving lipid mediators (SPMs) produced locally in inflammatory loci to restrain this innate response, prevent further damages to the host, and permit return to homeostasis. Lipoxins, resolvins, protectins, and maresins are SPM derived from polyunsaturated fatty acids that limit excessive leukocyte infiltration and pro-inflammatory signals, stimulate innate microbial killing, and enhance resolution. Their unique chemical structures, receptors, and bioactions are being elucidated. Accruing data indicate that SPMs carry protective functions against unrelenting inflammation and infections in preclinical models and human CF systems. Here, we reviewed their roles and actions in controlling resolution of inflammation, evidence for their impairment in CF, and proofs of principle for their exploitation as innovative, non-immunosuppressive drugs to address inflammation and infections in CF.

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