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1.
JCI Insight ; 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-39352743

RESUMEN

Psoriasis is a chronic and recurrent inflammatory skin disease characterized by abnormal proliferation and differentiation of keratinocytes and activation of immune cells. However, the molecular driver that triggers this immune response in psoriatic skin remains unclear. The inflammation-related gene absent in melanoma 2 (AIM2) was identified as a susceptibility gene/locus associated with psoriasis. In this study, we investigated the role of AIM2 in the pathophysiology of psoriasis. We found elevated levels of mitochondrial DNA in patients with psoriasis, along with high expression of AIM2 in both the human psoriatic epidermis and a mouse model of psoriasis induced by topical imiquimod (IMQ) application. Genetic ablation of AIM2 reduced the development of IMQ-induced psoriasis by decreasing the production of type 3 cytokines (such as IL-17A and IL-23) and infiltration of immune cells into the inflammatory site. Furthermore, we demonstrate that IL-17A induced AIM2 expression in keratinocytes. Finally, the genetic absence of inflammasome components downstream AIM2, ASC, and caspase-1 alleviated IMQ-induced skin inflammation. Collectively, our data show that AIM2 is involved in developing psoriasis through its canonical activation.

2.
J Infect Dis ; 2024 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-39328079

RESUMEN

Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare, potentially fatal complication of SARS-CoV-2 infection. Genetic defects in inflammation-related pathways have been linked to MIS-C, but additional research is needed, especially in diverse ethnic groups. The present study aimed to identify genetic variants underlying MIS-C in Brazilian patients. Whole-exome sequencing was performed, focusing on genes involved in the host immune response to SARS-CoV-2. Functional assays assessed the impact of selected variants on NF-κB signaling. Nine rare, potentially deleterious variants were found in eight of 21 patients, located in IL17RC, IFNA10, or NLRP12 genes. Unlike the wild-type NLRP12 protein, which inhibits NF-κB activation in HEK 293T cells, the mutant NLRP12 proteins have significantly reduced inhibitory properties. In conclusion, our results indicate that rare autosomal variants in immune-related genes may underlie MIS-C, highlighting the potential role of NLRP12 in its predisposition. These findings provide new insights for the appropriate management of MIS-C.

3.
Biochem Pharmacol ; 224: 116245, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38685281

RESUMEN

Cardiovascular disease (CVD) is the leading cause of death in rheumatoid arthritis (RA). Resistin is an adipokine that induces adipose tissue inflammation and activation of monocytes/macrophages via adenylate cyclase-associated protein-1 (CAP1). Resistin levels are increased in RA and might cause perivascular adipose tissue (PVAT) dysfunction, leading to vascular damage and CVD. This study aimed to investigate the role of resistin in promoting PVAT dysfunction by increasing local macrophage and inflammatory cytokines content in antigen-induced arthritis (AIA). Resistin pharmacological effects were assessed by using C57Bl/6J wild-type (WT) mice, humanized resistin mice expressing human resistin in monocytes-macrophages (hRTN+/-/-), and resistin knockout mice (RTN-/-) with AIA and respective controls. We investigated AIA disease activity and functional, cellular, and molecular parameters of the PVAT. Resistin did not contribute to AIA disease activity and its concentrations were augmented in the PVAT and plasma of WT AIA and hRTN+/-/- AIA animals. In vitro exposure of murine arteries to resistin impaired vascular function by decreasing the anti-contractile effect of PVAT. WT AIA mice and hRTN+/-/- AIA mice exhibited PVAT dysfunction and knockdown of resistin prevented it. Macrophage-derived cytokines, markers of types 1 and 2 macrophages, and CAP1 expression were increased in the PVAT of resistin humanized mice with AIA, but not in knockout mice for resistin. This study reveals that macrophage-derived resistin promotes PVAT inflammation and dysfunction regardless of AIA disease activity. Resistin might represent a translational target to reduce RA-driven vascular dysfunction and CVD.


Asunto(s)
Tejido Adiposo , Artritis Experimental , Macrófagos , Ratones Endogámicos C57BL , Resistina , Animales , Resistina/metabolismo , Resistina/genética , Humanos , Tejido Adiposo/metabolismo , Ratones , Macrófagos/metabolismo , Artritis Experimental/metabolismo , Ratones Noqueados , Masculino
4.
Proc Natl Acad Sci U S A ; 120(21): e2217119120, 2023 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-37186819

RESUMEN

Occurrence of hyperglycemia upon infection is associated with worse clinical outcome in COVID-19 patients. However, it is still unknown whether SARS-CoV-2 directly triggers hyperglycemia. Herein, we interrogated whether and how SARS-CoV-2 causes hyperglycemia by infecting hepatocytes and increasing glucose production. We performed a retrospective cohort study including patients that were admitted at a hospital with suspicion of COVID-19. Clinical and laboratory data were collected from the chart records and daily blood glucose values were analyzed to test the hypothesis on whether COVID-19 was independently associated with hyperglycemia. Blood glucose was collected from a subgroup of nondiabetic patients to assess pancreatic hormones. Postmortem liver biopsies were collected to assess the presence of SARS-CoV-2 and its transporters in hepatocytes. In human hepatocytes, we studied the mechanistic bases of SARS-CoV-2 entrance and its gluconeogenic effect. SARS-CoV-2 infection was independently associated with hyperglycemia, regardless of diabetic history and beta cell function. We detected replicating viruses in human hepatocytes from postmortem liver biopsies and in primary hepatocytes. We found that SARS-CoV-2 variants infected human hepatocytes in vitro with different susceptibility. SARS-CoV-2 infection in hepatocytes yields the release of new infectious viral particles, though not causing cell damage. We showed that infected hepatocytes increase glucose production and this is associated with induction of PEPCK activity. Furthermore, our results demonstrate that SARS-CoV-2 entry in hepatocytes occurs partially through ACE2- and GRP78-dependent mechanisms. SARS-CoV-2 infects and replicates in hepatocytes and exerts a PEPCK-dependent gluconeogenic effect in these cells that potentially is a key cause of hyperglycemia in infected patients.


Asunto(s)
COVID-19 , Hiperglucemia , Humanos , COVID-19/complicaciones , SARS-CoV-2 , Gluconeogénesis , Glucemia , Estudios Retrospectivos , Hepatocitos , Hiperglucemia/complicaciones , Glucosa
5.
Sci Rep ; 12(1): 9998, 2022 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-35705722

RESUMEN

Bee pollen is recommended as dietary supplement due to immunostimulating functions including antioxidant, anti-inflammatory and anti-carcinogenic properties. Nevertheless, the effectiveness of such properties is still not well understood. As diet can be associated with animal performance, microbiota modulation and potentially factor for cancer, this study aimed to analyze if bee pollen could influence growth, gut microbial and skin cutaneous melanoma development in zebrafish. Control diets based on commercial flakes and Artemia were compared with the same diet supplemented with bee pollen. Fish weight gain, increased length, intestinal bacteria metagenomics analysis, serum amyloid A gene expression and cutaneous melanoma transplantation assays were performed. Bee pollen affected microbiota composition and melanoma development. Differential abundance revealed higher abundance in the control group for Aeromonadaceae family, Aeromonas and Pseudomonas genus, A. sobria, A. schubertii, A. jandaei and P. alcaligenes species compared with pollen diet group. Pollen group presented higher abundance for Chromobacterium genus and for Gemmobacter aquaticus, Flavobacterium succinicans and Bifidobacterium breve compared with control group. Unexpectedly, fish fed with bee pollen showed higher tumor growth rate and larger tumor size than control group. This is the first study to report intestinal microbial changes and no protective cancer properties after bee pollen administration.


Asunto(s)
Microbioma Gastrointestinal , Melanoma , Neoplasias Cutáneas , Animales , Abejas , Dieta , Melanoma/etiología , Polen , Neoplasias Cutáneas/etiología , Pez Cebra , Melanoma Cutáneo Maligno
6.
Front Neurosci ; 15: 674576, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34887719

RESUMEN

Oropouche virus (OROV) is an emerging arbovirus in South and Central Americas with high spreading potential. OROV infection has been associated with neurological complications and OROV genomic RNA has been detected in cerebrospinal fluid from patients, suggesting its neuroinvasive potential. Motivated by these findings, neurotropism and neuropathogenesis of OROV have been investigated in vivo in murine models, which do not fully recapitulate the complexity of the human brain. Here we have used slice cultures from adult human brains to investigate whether OROV is capable of infecting mature human neural cells in a context of preserved neural connections and brain cytoarchitecture. Our results demonstrate that human neural cells can be infected ex vivo by OROV and support the production of infectious viral particles. Moreover, OROV infection led to the release of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and diminished cell viability 48 h post-infection, indicating that OROV triggers an inflammatory response and tissue damage. Although OROV-positive neurons were observed, microglia were the most abundant central nervous system (CNS) cell type infected by OROV, suggesting that they play an important role in the response to CNS infection by OROV in the adult human brain. Importantly, we found no OROV-infected astrocytes. To the best of our knowledge, this is the first direct demonstration of OROV infection in human brain cells. Combined with previous data from murine models and case reports of OROV genome detection in cerebrospinal fluid from patients, our data shed light on OROV neuropathogenesis and help raising awareness about acute and possibly chronic consequences of OROV infection in the human brain.

7.
Brain Behav ; 10(12): e01879, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33094916

RESUMEN

Gene prioritization approaches are useful tools to explore and select candidate genes in transcriptome studies. Knowing the importance of processes such as neuronal activity, intracellular signal transduction, and synapse plasticity to the development and maintenance of compulsive ethanol drinking, the aim of the present study was to explore and identify functional candidate genes associated with these processes in an animal model of inflexible pattern of ethanol intake. To do this, we applied a guilt-by-association approach, using the GUILDify and ToppGene software, in our previously published microarray data from the prefrontal cortex (PFC) and striatum of inflexible drinker mice. We then tested some of the prioritized genes that showed a tissue-specific pattern in postmortem brain tissue (PFC and nucleus accumbens (NAc)) from humans with alcohol use disorder (AUD). In the mouse brain, we prioritized 44 genes in PFC and 26 in striatum, which showed opposite regulation patterns in PFC and striatum. The most prioritized of them (i.e., Plcb1 and Prkcb in PFC, and Dnm2 and Lrrk2 in striatum) were associated with synaptic neuroplasticity, a neuroadaptation associated with excessive ethanol drinking. The identification of transcription factors among the prioritized genes suggests a crucial role for Irf4 in the pattern of regulation observed between PFC and striatum. Lastly, the differential transcription of IRF4 and LRRK2 in PFC and nucleus accumbens in postmortem brains from AUD compared to control highlights their involvement in compulsive ethanol drinking in humans and mice.


Asunto(s)
Consumo de Bebidas Alcohólicas , Alcoholismo , Consumo de Bebidas Alcohólicas/genética , Animales , Etanol , Humanos , Ratones , Núcleo Accumbens , Corteza Prefrontal
8.
J Exp Med ; 217(12)2020 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-32926098

RESUMEN

Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Trampas Extracelulares/fisiología , Neumonía Viral/inmunología , Neumonía Viral/virología , Células A549 , Adulto , Enzima Convertidora de Angiotensina 2 , COVID-19 , Muerte Celular , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/patología , Células Epiteliales/patología , Células Epiteliales/virología , Femenino , Células HeLa , Humanos , Masculino , Activación Neutrófila , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/sangre , Neumonía Viral/patología , SARS-CoV-2 , Serina Proteasas/metabolismo , Succión , Tráquea/inmunología
9.
Environ Sci Pollut Res Int ; 25(12): 11527-11535, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29427274

RESUMEN

Spent pot liner (SPL) is a solid waste generated during the primary smelting of aluminum, and its toxicity is attributed to the presence of fluoride, cyanide, and aluminum salts, which can be leached into aquatic ecosystems. Since the effects of this waste on aquatic life forms have not yet been investigated, the objective of our study was to evaluate the toxicity of simulated leachates of SPL on zebrafish (Danio rerio). Animals were exposed to 0 (control), 0.32, 0.64, or 0.95 g L-1 of SPL for 24, 72, and 96 h, and genotoxicity was accessed through micronucleus and comet assays. All of the tested treatments induced DNA fragmentation, and the observed frequency of micronuclei and damaged nucleoids generally increased with increasing SPL concentration. The highest frequency of micronuclei (3.3 per 3000 erythrocytes) was detected after 96 h of exposure with 0.95 g L-1 SPL. In the comet assay, nucleoids classified with highest level of damage in relation to the control were observed principally after 24 and 96 h of exposure. The data obtained in this study confirm the genotoxicaction and mutagenic potential of SPL and indicate that open-air deposits of the waste material could represent a health risk to humans and ecosystems alike.


Asunto(s)
Daño del ADN , Residuos Industriales/efectos adversos , Micronúcleos con Defecto Cromosómico/inducido químicamente , Modelos Teóricos , Mutágenos/toxicidad , Pez Cebra/genética , Aluminio/toxicidad , Animales , Ensayo Cometa , Cianuros/toxicidad , Fluoruros/toxicidad , Humanos , Pruebas de Micronúcleos
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