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1.
Toxicon ; 247: 107831, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38936670

RESUMO

Establishing humane endpoints to minimize animal suffering in studies on snake venom toxicity and antivenom potency tests is crucial. Our findings reveal that Swiss mice exhibit early temperature drop following exposure to different snake venoms and combinations of venoms and antivenoms, predicting later mortality. Evaluating temperature we can identify within 3 h post-inoculation, the animals that will not survive in a period of 48 h. Implementing temperature as a criterion would significantly reduce animal suffering in these studies without compromising the outcomes.

2.
J Clin Ultrasound ; 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867304

RESUMO

PURPOSE: The gastrocnemius venous system presents different anatomical variants. There have been described four locations of myofascial trigger points (MTrPs) in this muscle. However, no studies have analyzed the coincidence between vessels and MTrPs present in the gastrocnemius. Therefore, the main objective was to study the anatomical variability of the venous system by ultrasound and its coincidence with the location of the MTrPs. METHODS: A total of 100 lower limbs were studied. The gastrocnemius vessels were analyzed one by one by sector (medial, central, and lateral), quantifying the number of vessels, their distribution, and the coincidence with MTrPs. RESULTS: All muscle heads showed at least one vessel per section. A large variability was observed, from one to eight vessels per muscle head, with the most frequent number being three in the gastrocnemius medialis and two in the gastrocnemius lateralis. In all cases, the location of the vessels coincided with the MTrPs. CONCLUSIONS: The proximal gastrocnemius venous pattern is very variable between subjects in number of vessels and distribution, which has made it impossible to define a "safe" approach window for invasive procedures without ultrasound guidance. The coincidence between the clinical location of MTrPs of the gastrocnemius and the presence of vessels is total.

3.
Indian J Med Microbiol ; : 100654, 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38925277

RESUMO

PURPOSE: Patients with hematologic malignancies (HM) are at high risk of invasive lung fungal infections (ILFI). To describe the main characteristics, treatment, and outcomes for five years in adult patients with HM and fungal pneumonia. METHODS: We conducted a retrospective study at Instituto Nacional de Cancerología (INCan), a referral tertiary care oncology hospital with 135 beds in Mexico City, Mexico. We included all cases of fungal pneumonia in patients with HM from January 1, 2017, to December 31, 2022. Cases were classified as proven, probable, and possible according to EORTC/MSG criteria 2021. RESULTS: Two hundred ten patients were included; the mean age was 40 years. The most frequent HM was acute lymphoblastic leukemia (n=74) and acute myeloid leukemia (n=68). One hundred forty patients (66.7%) had severe neutropenia for a median of 16 days. All patients had a CT thorax scan; in 132 (62.9%), multiple nodules were documented. Serum galactomannan (GM) was positive in 21/192 (10.9%) and bronchoalveolar lavage in 9/36 (25%). Fifty-three patients (25.2%) died in the first month. In the multivariate analysis for mortality in the first 30 days, hypoalbuminemia, shock, possible ILFI, and inappropriate antifungal treatment were statistically associated. CONCLUSIONS: In high-risk HM patients, CT thorax scan and GM help diagnose ILFI. An appropriate antifungal improves mortality.

4.
Sci Rep ; 14(1): 12416, 2024 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-38816440

RESUMO

Klebsiella pneumoniae releases the peptides AKTIKITQTR and FNEMQPIVDRQ, which bind the pneumococcal proteins AmiA and AliA respectively, two substrate-binding proteins of the ABC transporter Ami-AliA/AliB oligopeptide permease. Exposure to these peptides alters pneumococcal phenotypes such as growth. Using a mutant in which a permease domain of the transporter was disrupted, by growth analysis and epifluorescence microscopy, we confirmed peptide uptake via the Ami permease and intracellular location in the pneumococcus. By RNA-sequencing we found that the peptides modulated expression of genes involved in metabolism, as pathways affected were mostly associated with energy or synthesis and transport of amino acids. Both peptides downregulated expression of genes involved in branched-chain amino acid metabolism and the Ami permease; and upregulated fatty acid biosynthesis genes but differed in their regulation of genes involved in purine and pyrimidine biosynthesis. The transcriptomic changes are consistent with growth suppression by peptide treatment. The peptides inhibited growth of pneumococcal isolates of serotypes 3, 8, 9N, 12F and 19A, currently prevalent in Switzerland, and caused no detectable toxic effect to primary human airway epithelial cells. We conclude that pneumococci take up K. pneumoniae peptides from the environment via binding and transport through the Ami permease. This changes gene expression resulting in altered phenotypes, particularly reduced growth.


Assuntos
Proteínas de Bactérias , Regulação Bacteriana da Expressão Gênica , Klebsiella pneumoniae , Streptococcus pneumoniae , Transcriptoma , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/metabolismo , Klebsiella pneumoniae/efeitos dos fármacos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/metabolismo , Streptococcus pneumoniae/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Humanos , Ligantes , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Peptídeos/metabolismo , Peptídeos/farmacologia
5.
Artigo em Inglês | MEDLINE | ID: mdl-38558292

RESUMO

OBJECTIVE: Musculoskeletal ultrasound (MSUS) is widely used in adult rheumatology practice for diagnosis of arthritis and procedural guidance; however, it is not yet common practice in pediatric rheumatology. MSUS is advantageous to the pediatric population because it lacks radiation and eliminates need for sedation. This study aims to assess interest in, access to, and barriers to MSUS training in pediatric rheumatology fellowship programs in North America. METHODS: A survey was developed by pediatric rheumatology providers with experience in medical and/or MSUS education and distributed via REDCap anonymously in March 2022 (Supplementary Material). Eligible participants included current and recently graduated (<1 year) pediatric rheumatology fellows at a North American program. Descriptive statistics and bivariate analyses using design-based Pearson chi-squared tests were performed. RESULTS: Overall response rate was 78% (88/113), and 75% reported some form of MSUS training during fellowship. Only 36% indicated their program had a formal MSUS curriculum. Of those with MSUS training, 23% reported adult-only MSUS education. Eighty-four percent felt MSUS would be beneficial to their career. Major barriers to MSUS training included lack of MSUS-trained faculty, lack of time, and lack of hands-on MSUS sessions. Those who had access to MSUS training were significantly more interested in MSUS than those without (P = 0.0036). CONCLUSION: This study demonstrates that North American pediatric rheumatology fellows have a strong interest in learning MSUS, but they face significant challenges in accessing MSUS training (lack of MSUS-trained faculty, time, and access to hands-on training). MSUS should be incorporated into fellowship curriculum; however, implementation remains a challenge.

6.
J Infect Dev Ctries ; 18(2): 235-242, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38484344

RESUMO

INTRODUCTION: Patients with severe neutropenia who develop septic shock (SS) have high mortality. This study aimed to evaluate the risk factors and mortality of SS in patients with HM and febrile neutropenia. METHODOLOGY: We included all patients with hematological malignancies (HM) who presented fever and severe neutropenia, admitted to an oncological tertiary care center in Mexico City for one year. RESULTS: Two hundred ninety-two episodes of fever and severe neutropenia were documented; 68 patients (23.2%) developed SS. Documented clinical infection was different between SS and non-SS patients (94.1% vs. 63.4%, p < 0.001); pneumonia was the most frequent infection (36.8% vs. 23.2%, p = 0.02). Also, in SS vs. non-SS, there were more positive cultures (69.1% vs. 38.4%, p < 0.001), higher frequency of Gram-negative bacteria (89.3% vs. 63.9%, p < 0.001), particularly Escherichia coli (68% vs. 44.2%) and Klebsiella spp. (23.4% vs. 15.1%). There were no differences when multidrug-resistant (MDR) microorganisms were compared. In the multivariate analysis, associated risk factors for SS were: prolonged neutropenia, a documented site of infection, and having received highly myelosuppressive chemotherapy. Risk factors for mortality at 30 days were: older patients, prolonged neutropenia, and SS. CONCLUSIONS: Severe and prolonged neutropenia was associated with SS development and mortality at 30 days. ICU management should be offered to all critically ill patients with HM if long-term survival of the underlying malignancy is expected.


Assuntos
Neutropenia Febril , Neoplasias Hematológicas , Neoplasias , Choque Séptico , Humanos , Choque Séptico/epidemiologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias/complicações , Fatores de Risco , Escherichia coli , Neutropenia Febril/microbiologia , Estudos Retrospectivos
7.
Clin Park Relat Disord ; 10: 100246, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38444738

RESUMO

Parkinsonism-hyperpyrexia syndrome (PHS) is a rare neurological emergency that shares clinical features with neuroleptic malignant syndrome. It is usually due to sudden deprivation of dopaminergic treatment, although there are cases related to failure of the deep brain stimulation system.

8.
J Vis Exp ; (203)2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38345234

RESUMO

Many protein-protein interactions involve the binding of short protein segments to peptide-binding domains. Usually, such interactions require the recognition of linear motifs with variable conservation. The combination of highly conserved and more variable regions in the same ligands often contributes to the multispecificity of binding, a common property of enzymes and cell signaling proteins. Characterization of amino acid preferences of peptide-binding domains is important for the design of mediators of protein-protein interactions (PPIs). Computational methods are an efficient alternative to the often costly and cumbersome experimental techniques, enabling the design of potential mediators that can be later validated in downstream experiments. Here, we described a methodology using the Pepspec application of the Rosetta molecular modeling package to predict the amino acid preferences of peptide-binding domains. This methodology is useful when the structure of the receptor protein and the nature of the peptide ligand are both known or can be inferred. The methodology starts with a well-characterized anchor from the ligand, which is extended by randomly adding amino acid residues. The binding affinity of peptides generated this way is then evaluated by flexible-backbone peptide docking in order to select the peptides with the best predicted binding scores. These peptides are then used to calculate amino acid preferences and to optionally compute a position-weight matrix (PWM) that can be used in further studies. To illustrate the application of this methodology, we used the interaction between subunits of human interferon regulatory factor 5 (IRF5), previously known to be multispecific but globally guided by a short conserved motif called pLxIS. The estimated amino acid preferences were consistent with previous knowledge about the IRF5 binding surface. Positions occupied by phosphorylatable serine residues exhibited a high frequency of aspartate and glutamate, likely because their negatively charged side chains are similar to phosphoserine.


Assuntos
Aminoácidos , Peptídeos , Humanos , Sequência de Aminoácidos , Aminoácidos/metabolismo , Ligantes , Peptídeos/química , Proteínas/metabolismo , Fatores Reguladores de Interferon/metabolismo , Ligação Proteica , Sítios de Ligação , Motivos de Aminoácidos
9.
Antioxidants (Basel) ; 13(2)2024 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-38397799

RESUMO

Retinitis pigmentosa is a common cause of inherited blindness in adults, which in many cases is associated with an increase in the formation of reactive oxygen species (ROS) that induces DNA damage, triggering Poly-ADP-Ribose Polymerase 1 (PARP1) activation and leading to parthanatos-mediated cell death. Previous studies have shown that resveratrol (RSV) is a promising molecule that can mitigate PARP1 overactivity, but its low bioavailability is a limitation for medical use. This study examined the impact of a synthesized new acylated RSV prodrug, piceid octanoate (PIC-OCT), in the 661W cell line against H2O2 oxidative stress and in rd10 mice. PIC-OCT possesses a better ADME profile than RSV. In response to H2O2, 661W cells pretreated with PIC-OCT preserved cell viability in more than 38% of cells by significantly promoting SIRT1 nuclear translocation, preserving NAD+/NADH ratio, and suppressing intracellular ROS formation. These effects result from expressing antioxidant genes, maintaining mitochondrial function, reducing PARP1 nuclear expression, and preventing AIF nuclear translocation. In rd10 mice, PIC-OCT inhibited PAR-polymer formation, increased SIRT1 expression, significantly reduced TUNEL-positive cells in the retinal outer nuclear layer, preserved ERGs, and enhanced light chamber activity (all p values < 0.05). Our findings corroborate that PIC-OCT protects photoreceptors by modulating the SIRT1/PARP1 axis in models of retinal degeneration.

11.
Arthritis Care Res (Hoboken) ; 76(2): 251-258, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37587869

RESUMO

OBJECTIVE: We undertook this study to validate the Pediatric Arthritis Ultrasound Scoring System for the knee joint (PAUSS-knee) in children with juvenile idiopathic arthritis (JIA). METHODS: Children with JIA were enrolled to prospectively receive a musculoskeletal ultrasound (MSUS) examination of the knee and a physical examination to determine presence/absence of clinical arthritis. MSUS images were scored using the PAUSS-knee, a semiquantitative MSUS scoring system (0-3, normal to severe) for B-mode and power Doppler mode. In addition to MSUS, a subset of participants also received magnetic resonance imaging (MRI) of the knee, which was scored according to the combined Juvenile Arthritis MRI Scoring (JAMRIS) system. Spearman's correlations (rs ) were used to calculate associations between variables. Test characteristics of the PAUSS-knee were calculated with MRI as the reference standard. Inflammatory biomarkers were assessed in synovial fluid from involved knees. RESULTS: Eighty children with JIA contributed 112 MSUSs and 25 MRIs of the knee. Of the knees, 41% (n = 46) had clinical evidence of arthritis. The B-mode PAUSS-knee score moderately correlated with clinically determined arthritis (rs = 0.54, P < 0.001) and strongly correlated with the JAMRIS score (rs = 0.75, P < 0.001). Compared with MRI, the area under the curve for the B-mode PAUSS-knee was 0.92. For a cutoff of >1, the B-mode PAUSS-knee had a sensitivity of 83% and specificity of 82%. Biomarker analysis indicates that interleukin-2R levels correlate with PAUSS score. CONCLUSION: Our data indicate that the PAUSS-knee has excellent accuracy for the diagnosis of arthritis when compared with MRI. The PAUSS-knee has the potential to effectively inform JIA medical decision-making in real time.


Assuntos
Artrite Juvenil , Humanos , Criança , Artrite Juvenil/diagnóstico por imagem , Artrite Juvenil/patologia , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/patologia , Imageamento por Ressonância Magnética/métodos , Ultrassonografia , Biomarcadores
12.
Clin Exp Immunol ; 215(2): 190-201, 2024 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-37904542

RESUMO

Valganciclovir (VGC) was used in a randomized clinical trial in patients with disseminated Kaposi Sarcoma/human immunodeficiency virus (DKS/HIV) as add-on therapy to evaluate the proinflammatory axis tumor necrosis factor (TNF) and its receptors (TNFRs) in T cells. Two treatment schedules were used: an experimental regime (ER) and a conventional treatment (CT). Mononuclear cells from patients with DKS/HIV were obtained at baseline (W0), 4 (W4), and 12 weeks (W12). Ten DKS/HIV patients received CT (antiretroviral therapy [cART]) and 10 ER (valganciclovir [VGC] initially, plus cART at the fourth week). HIV+ without KS and HIV- patient groups were included as controls. Correlation between T-cell subsets and HHV-8 viral load (VL) and a multivariate linear regression was performed. Data showed that DKS/HIV patients have an increased frequency of CD8+ T cells, which display a high density of CD8 expression. The ER scheme increases naïve and central memory CD4+ T cells at W4 and W12 of follow-up and induces a balanced distribution of activated CD4+ T-cell subsets. Moreover, ER decreases solTNFR2 since W4 and CT decreased the transmembrane forms of TNF axis molecules. Although CT induces a positive correlation between HHV-8 VL and TNFRs, the use of ER positively correlates with TNF and TNFRs levels through follow-up and a moderate correlation with HHV-8 VL and TNF soluble levels. In conclusion, VGC, as an add-on therapy in DKS/HIV patients, gradually modulates the activation of CD4+ T-cell subsets and the TNF/TNFRs axis, suggesting a better regulation of the inflammatory status.


Assuntos
Infecções por HIV , Sarcoma de Kaposi , Sulfonamidas , Humanos , Sarcoma de Kaposi/tratamento farmacológico , Sarcoma de Kaposi/metabolismo , Infecções por HIV/metabolismo , Valganciclovir/metabolismo , Valganciclovir/uso terapêutico , Linfócitos T CD4-Positivos/metabolismo , Subpopulações de Linfócitos T , Linfócitos T CD8-Positivos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Carga Viral
13.
Molecules ; 28(23)2023 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-38067518

RESUMO

Tetrahydrocurcumin, the most abundant curcumin transformation product in biological systems, can potentially be a new alternative therapeutic agent with improved anti-inflammatory activity and higher bioavailability than curcumin. In this article, we describe the synthesis and evaluation of the anti-inflammatory activities of tetrahydrocurcumin derivatives. Eleven tetrahydrocurcumin derivatives were synthesized via Steglich esterification on both sides of the phenolic rings of tetrahydrocurcumin with the aim of improving the anti-inflammatory activity of this compound. We showed that tetrahydrocurcumin (2) inhibited TNF-α and IL-6 production but not PGE2 production. Three tetrahydrocurcumin derivatives inhibited TNF-α production, five inhibited IL-6 production, and three inhibited PGE2 production. The structure-activity relationship analysis suggested that two factors could contribute to the biological activities of these compounds: the presence or absence of planarity and their structural differences. Among the tetrahydrocurcumin derivatives, cyclic compound 13 was the most active in terms of TNF-α production, showing even better activity than tetrahydrocurcumin. Acyclic compound 11 was the most effective in terms of IL-6 production and retained the same effect as tetrahydrocurcumin. Moreover, acyclic compound 12 was the most active in terms of PGE2 production, displaying better inhibition than tetrahydrocurcumin. A 3D-QSAR analysis suggested that the anti-inflammatory activities of tetrahydrocurcumin derivatives could be increased by adding bulky groups at the ends of compounds 2, 11, and 12.


Assuntos
Curcumina , Curcumina/química , Fator de Necrose Tumoral alfa , Interleucina-6 , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Relação Estrutura-Atividade
14.
Reumatol Clin (Engl Ed) ; 19(10): 593-595, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38056984

RESUMO

The term "autoimmune/inflammatory syndrome induced by adjuvants" (ASIA) describes a variety of autoimmune conditions triggered by exposure to substances with adjuvant activity. We present the case of a patient with a history of biopolymer infiltration in both glutes, who years later experienced progressive weakness and pain in the lower limbs, myalgias, cramps, and progressive functional impotence following a mild COVID-19 infection. Laboratory test results were not consistent with any autoimmune disease. Physical examination revealed diffuse bilateral subcutaneous nodules. After an extensive etiological study, a gluteal biopsy was performed, which showed findings compatible with sclerosing lipogranuloma. Our patient required treatment with high-dose glucocorticoids and showed significant improvement in symptoms during long-term follow-up. We suggest the role of COVID-19 infection as a possible trigger for ASIA, as it has already been described as a trigger for several other autoimmune diseases.


Assuntos
Doenças Autoimunes , COVID-19 , Masculino , Humanos , COVID-19/complicações , Adjuvantes Imunológicos/efeitos adversos , Doenças Autoimunes/induzido quimicamente , Síndrome , Dor
15.
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1535331

RESUMO

Introducción: CAPE-V es ampliamente utilizado para evaluación perceptual vocal y ha sido adaptado y validado en múltiples idiomas. A través de un análisis exhaustivo, este estudio buscó avanzar en establecer un estándar en el método utilizado para su adaptación y validación. Objetivo: Revisar los artículos publicados entre 2002 y 2022 que han adaptado y validado CAPE-V a distintos idiomas, para evaluar exhaustivamente la adaptación, metodología y estadísticas utilizadas. Métodos: Se realizó una revisión sistemática utilizando Scopus, Google Scholar y PubMed para identificar artículos que adaptaran y/o validaran CAPE-V entre 2002 y 2022. Se analizó el título y resumen para preseleccionar la muestra. Para evaluar el riesgo de sesgo de los estudios incluidos se analizó de forma crítica el texto completo. Resultados: La búsqueda inicial identificó 568 artículos. Al eliminar duplicados se revisaron 559 y 23 fueron preseleccionados. 12 se incluyeron finalmente y fueron analizados, considerando adaptación, metodología y análisis estadístico. Los resultados revelan que la adaptación y validación de CAPE-V a diversos idiomas es fundamental para garantizar mediciones precisas y confiables en diferentes poblaciones. Análisis y discusión: Existe heterogeneidad en la forma de realizar la adaptación y validación de CAPE-V. No obstante, todos los estudios tuvieron éxito en producir resultados válidos, subrayando la importancia de estos procesos para la práctica clínica. Conclusiones: Las adaptaciones y validaciones de CAPE-V se realizaron heterogéneamente por ausencia de un protocolo estándar. Es necesario generar orientaciones para realizar estos procesos por el aporte de esta escala a la clínica, asegurando calidad y confiabilidad de los resultados.


Introduction: CAPE-V is widely used for vocal perceptual evaluation and has been adapted and validated in multiple languages. Through an exhaustive analysis, this study sought to advance in establishing a standard in the method used in its adaptation and validation. Objective: To review articles published between 2002 and 2022 that have adapted and validated CAPE-V in different languages, to thoroughly evaluate the adaptation, methodology, and statistics used. Methods: A systematic review was conducted using Scopus, Google Scholar and PubMed to identify articles that adapted and/or validated CAPE-V between 2002 and 2022. The title and summary were analyzed to pre-select the sample. To evaluate the risk of bias of the included studies, the full text was critically analyzed. Results: The initial search identified 568 items. When duplicates were removed, 559 were reviewed and 23 were pre-selected. 12 were finally included and analyzed considering adaptation, methodology, and statistical analysis. The results show that the adaptation and validation of CAPE-V to different languages is essential to ensure accurate and reliable measurements in different populations. Analysis and discussion: There is heterogeneity in how CAPE-V is adapted and validated. However, all studies were successful in producing valid results, underlining the importance of these processes for clinical practice. Conclusions: Adaptations and validations of CAPE-V were performed heterogeneously due to the absence of a standard protocol. It is necessary to generate guidelines to perform these processes by providing this scale to the clinic, ensuring quality and reliability of results.

16.
POCUS J ; 8(2): 146-152, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38099160

RESUMO

Point of care pediatric musculoskeletal POCUS scanning and scoring protocols for childhood arthritis have emerged in recent years. However, pediatric musculoskeletal POCUS curricula in rheumatology fellowship programs are limited due to availability of trained faculty and resources. This proof-of-concept study investigated the effectiveness of educational methods for a pediatric musculoskeletal POCUS scoring protocol among fellows and physicians of differing subspecialties. Educational methods assessed included recorded videos and virtual review sessions. Effectiveness was assessed by calculating interrater reliability for the musculoskeletal POCUS scoring systems using the intra-class correlation coefficient (ICC). Following training sessions, participants then underwent scoring exercise(s) until the goal of an excellent ICC ≥ 0.75 was reached. Four participants completed two rounds of virtual education, review, and scoring sessions. Excellent interrater reliability was achieved for most views. This proof-of-concept study demonstrated virtual education covering advanced concepts of pediatric musculoskeletal POCUS provides a knowledge base for physicians from different subspecialties and various experience.

17.
Cell Rep ; 42(12): 113508, 2023 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-38019650

RESUMO

Group 3 innate lymphoid cells (ILC3s) are vital for defending tissue barriers from invading pathogens. Hypoxia influences the production of intestinal ILC3-derived cytokines by activating HIF. Yet, the mechanisms governing HIF-1α in ILC3s and other innate RORγt+ cells during in vivo infections are poorly understood. In our study, transgenic mice with specific Hif-1a gene inactivation in innate RORγt+ cells (RAG1KO HIF-1α▵Rorc) exhibit more severe colitis following Citrobacter rodentium infection, primarily due to the inability to upregulate IL-22. We find that HIF-1α▵Rorc mice have impaired IL-22 production in ILC3s, while non-ILC3 innate RORγt+ cells, also capable of producing IL-22, remain unaffected. Furthermore, we show that IL-18, induced by Toll-like receptor 2, selectively triggers IL-22 in ILC3s by transcriptionally upregulating HIF-1α, revealing an oxygen-independent regulatory pathway. Our results highlight that, during late-stage C. rodentium infection, IL-18 induction in the colon promotes IL-22 through HIF-1α in ILC3s, which is crucial for protection against this pathogen.


Assuntos
Colite , Interleucinas , Camundongos , Animais , Interleucinas/genética , Interleucinas/metabolismo , Imunidade Inata , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Linfócitos/metabolismo , Interleucina-18 , Inflamação , Camundongos Transgênicos , Camundongos Endogâmicos C57BL
19.
Nucleic Acids Res ; 51(19): 10109-10131, 2023 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-37738673

RESUMO

Enhancer reprogramming has been proposed as a key source of transcriptional dysregulation during tumorigenesis, but the molecular mechanisms underlying this process remain unclear. Here, we identify an enhancer cluster required for normal development that is aberrantly activated in breast and lung adenocarcinoma. Deletion of the SRR124-134 cluster disrupts expression of the SOX2 oncogene, dysregulates genome-wide transcription and chromatin accessibility and reduces the ability of cancer cells to form colonies in vitro. Analysis of primary tumors reveals a correlation between chromatin accessibility at this cluster and SOX2 overexpression in breast and lung cancer patients. We demonstrate that FOXA1 is an activator and NFIB is a repressor of SRR124-134 activity and SOX2 transcription in cancer cells, revealing a co-opting of the regulatory mechanisms involved in early development. Notably, we show that the conserved SRR124 and SRR134 regions are essential during mouse development, where homozygous deletion results in the lethal failure of esophageal-tracheal separation. These findings provide insights into how developmental enhancers can be reprogrammed during tumorigenesis and underscore the importance of understanding enhancer dynamics during development and disease.


The manuscript by Abatti et al. shows that epigenetic reactivation of a pair of distal enhancers that drive Sox2 expression during development (to permit separation of the esophagus and trachea) is responsible for the tumor-promoting re-expression of SOX2 in breast and lung tumors. Intriguingly, the same transcription factors that act on the enhancers during development to either activate or repress them (i.e. FOXA1 and NFIB, respectively) are also required for altering chromatin accessibility of the enhancers and SOX2 transcription in breast and lung cancer cells. With their work, the authors unravel the exact mechanism of how developmentally active enhancers become repurposed in a tumor context and show the relevance of this repurposing event for cancer.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Fatores de Transcrição SOXB1 , Animais , Humanos , Camundongos , Adenocarcinoma de Pulmão/genética , Carcinogênese/genética , Cromatina/genética , Elementos Facilitadores Genéticos , Epigênese Genética , Homozigoto , Neoplasias Pulmonares/genética , Deleção de Sequência , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo
20.
Toxins (Basel) ; 15(9)2023 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-37755951

RESUMO

Snake venom neutralization potency tests are required for quality control assessment by manufacturers and regulatory authorities. These assays require the use of large numbers of mice that manifest severe signs associated with pain and distress and long periods of suffering. Despite this, many animals make a full recovery; therefore, the observation of clinical signs as a predictor of animal death is highly subjective and could affect the accuracy of the results. The use of a more objective parameter such as body temperature measurement could help establish a humane endpoint that would contribute to significantly reducing the suffering of large numbers of animals. We determined the temperature drop in BALB/c mice exposed to the mixtures of Bothrops asper or Lachesis stenophrys venom and a polyvalent antivenom by using an infrared thermometer. Our data show that, based on the temperature change from baseline, it is possible to predict which animals will survive during the first 3 h after inoculation. The data provided in this study may contribute to future reductions in animal suffering, in concordance with general trends in the use of laboratory animals for the quality control of biologicals.


Assuntos
Temperatura Corporal , Venenos de Serpentes , Animais , Camundongos , Testes de Neutralização , Venenos de Serpentes/toxicidade , Antivenenos , Bioensaio , Camundongos Endogâmicos BALB C
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