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Secretion of IL-1ß, a potent cytokine that plays a key role in gout pathogenesis, is regulated by inflammasomes. TRAF1 has been linked to heightened risk to inflammatory arthritis. In this article, we show that TRAF1 negatively regulates inflammasome activation to limit caspase-1 and IL-1ß secretion in human and mouse macrophages. TRAF1 reduces linear ubiquitination and subsequent oligomerization of the adapter protein, ASC. i.p. injection of monosodium urate crystals resulted in increased inflammatory cell infiltrates and IL-1ß production in Traf1 knockout mice compared with wild type littermates. In a model of monosodium urate crystal-induced gout, Traf1 knockout mice exhibited more swelling in the knee joints, increased infiltration of inflammatory cells, and higher expression of proinflammatory cytokines. In summary, this study identifies TRAF1 as a key regulator of IL-1ß production and a potential therapeutic target for inflammasome-driven diseases such as gout.
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Gota , Inflamasomas , Animales , Humanos , Ratones , Proteínas Adaptadoras Transductoras de Señales , Citocinas , Interleucina-1beta , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Factor 1 Asociado a Receptor de TNF/genética , Ácido ÚricoRESUMEN
Inflammasomes are important in human health and disease, whereby they control the secretion of IL-1ß and IL-18, two potent proinflammatory cytokines that play a key role in inflammatory responses to pathogens and danger signals. Several inflammasomes have been discovered over the past two decades. NLRP3 inflammasome is the best characterized and can be activated by a wide variety of inducers. It is composed of a sensor, NLRP3, an adapter protein, ASC, and an effector enzyme, caspase-1. After activation, caspase-1 mediates the cleavage and secretion of bioactive IL-1ß and IL-18 via gasdermin-D pores in the plasma membrane. Aberrant activation of NLRP3 inflammasomes has been implicated in a multitude of human diseases, including inflammatory, autoimmune, and metabolic diseases. Therefore, several mechanisms have evolved to control their activity. In this review, we describe the posttranslational modifications that regulate NLRP3 inflammasome components, including ubiquitination, phosphorylation, and other forms of posttranslational modifications.
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Proteínas Adaptadoras de Señalización CARD/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Procesamiento Proteico-Postraduccional/genética , Animales , Proteínas Adaptadoras de Señalización CARD/genética , Caspasa 1/genética , Caspasa 1/metabolismo , Membrana Celular/metabolismo , Activación Enzimática/fisiología , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteínas de Unión a Fosfato/metabolismo , Fosforilación/fisiología , Ubiquitinación/fisiologíaRESUMEN
BACKGROUND: Oral health is a significant measure of overall health, and regular dental visits are recommended for the maintenance of oral health. The purpose of this study is to determine the pattern (amount and type) of, and factors associated with dental care use among Ontarians. METHODS: Data from the 2014 cycle of the Canadian Community Health Survey was used and analysis was restricted to individuals aged 12 and above residing in Ontario. Dental care use was defined by two distinct outcomes: not visiting a dentist within the past year and visiting a dentist only for emergencies. Multivariable logistic regression was performed to examine the association between socio-demographic, health behavior, oral health, and other health-related factors and the two outcomes. RESULTS: More than a quarter of participants reported not visiting the dentist in the last year, and 19% reported usually visiting a dentist only for emergencies. Multivariable logistic regression analysis suggested that males, individuals of Aboriginal status, those with low educational attainment, low household income, no dental insurance, who smoked, less frequent teeth brushing, poor health of teeth and mouth, or had diabetes were at a significant increased likelihood of not visiting the dentist within the past year, and only visiting a dentist for emergency care. CONCLUSIONS: Socioeconomic status, self-reported oral health, and general health behaviors were associated with dental care use. These findings highlight the need for focusing efforts toward improving dental care use among Ontarians.
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Atención Odontológica/estadística & datos numéricos , Adolescente , Adulto , Femenino , Conductas Relacionadas con la Salud , Estado de Salud , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Ontario , Salud Bucal , Factores Socioeconómicos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
The COVID-19 pandemic prompted adaptations to the delivery of healthcare services across Canada. In response to associated health risks and physical distancing protocols, some physicians adopted telemedicine procedures into their practice where possible. The present study aimed to investigate the impact that mode of healthcare delivery had on physicians' intention to quit their jobs due to stress, burnout, or mental health. The study utilized data collected by Statistics Canada from the Health Care Workers' Experience (SHCWEP) survey during the COVID-19 pandemic. The sample included 2,198 participants, weighted to represent 93,952 Canadian physicians aged 18 and above. Modes of healthcare delivery were categorized as either in-person, online, or blended. A multivariable logistic regression analysis was performed to examine the relationship between mode of healthcare delivery and intention to quit due to stress, burnout, or mental health, after adjusting for sociodemographic, job-, and health-related factors. Intention to quit within the next two years due to stress, burnout, or mental health was reported by 7.5% of physicians. Compared to the in-person modality, online or blended healthcare delivery was associated with decreased the odds of intention to quit (OR = 0.67, 95% CI: 0.63-0.72 and OR = 0.66, 95% CI: 0.58-0.75, respectively). The present study sheds light on factors associated with medical frontline worker well-being and retention, factors which can subsequently impact the quality of patient care. Future considerations regarding healthcare policy should incorporate strategies that protect and enhance physicians' mental health into its framework to mitigate future risks.
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Food insecurity has been linked to adverse health outcomes, particularly among vulnerable populations such as refugees. The aim of this study was to assess the prevalence of food insecurity and its association with depression, anxiety, and stress among resettled Syrian refugee parents in Ontario. This was a cross-sectional study with a total of 540 Syrian refugee parents who resided in Ontario for an average of four years and had at least one child less than 18 years who were interviewed. Information about food insecurity was collected based on the question "During the past year, did you ever eat less because there was not enough food or money for food?". Levels of depression, anxiety, and stress were assessed using the Depression Anxiety Stress Scales (DASS-21). Multiple linear regression analyses were performed to evaluate the relationship between food insecurity and depression, anxiety, and stress after adjusting for sociodemographic, migration-, and health-related factors. 44.6% of respondents reported experiencing food insecurity. Of participants, 7.6%, 8.9%, and 8.5% reported severe to extremely severe levels of depression, anxiety, and stress, respectively. Results of the multiple linear regression analysis showed that food insecurity was significantly associated with higher levels of depression (Adjß = 2.00, p = 0.008), anxiety (Adjß = 1.53, p = 0.013), and stress (Adjß = 1.87, p = 0.019). Implementation of effective government interventions and frameworks are essential to reduce food insecurity among resettled Syrian refugees to ultimately improve their mental health outcomes and overall well-being.
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The COVID-19 pandemic resulted in a major shift in the delivery of healthcare services with the adoption of care modalities to address the diverse needs of patients. Besides, nurses, the largest profession in the healthcare sector, were imposed with challenges caused by the pandemic that influenced their intention to leave their profession. The aim of the study was to examine the influence of mode of healthcare delivery on nurses' intention to quit job due to lack of satisfaction during the pandemic in Canada. This cross-sectional study utilized data from the Health Care Workers' Experiences During the Pandemic (SHCWEP) survey, conducted by Statistics Canada, that targeted healthcare workers aged 18 and over who resided in the ten provinces of Canada during the COVID-19 pandemic. The main outcome of the study was nurses' intention to quit within two years due to lack of job satisfaction. The mode of healthcare delivery was categorized into; in-person, online, or blended. Multivariable logistic regression was performed to examine the association between mode of healthcare delivery and intention to quit job after adjusting for sociodemographic, job-, and health-related factors. Analysis for the present study was restricted to 3,430 nurses, weighted to represent 353,980 Canadian nurses. Intention to quit job, within the next two years, due to lack of satisfaction was reported by 16.4% of the nurses. Results showed that when compared to participants who provided in-person healthcare services, those who delivered online or blended healthcare services were at decreased odds of intention to quit their job due to lack of job satisfaction (OR = 0.47, 95% CI: 0.43-0.50 and OR = 0.64, 95% CI: 0.61-0.67, respectively). Findings from this study can inform interventions and policy reforms to address nurses' needs and provide organizational support to enhance their retention and improve patient care during times of crisis.
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While inflammation is an important immune response for protection from infections, excessive or prolonged inflammation can lead to a variety of debilitating diseases including skin disease, diabetes, heart disease, stroke, autoimmune diseases and cancer. Inflammation is a graded response that is typically initiated when resident macrophages sense the presence of pathogens or damage in the tissue and produce inflammatory cytokines and chemokines to kill the pathogen, clear debris and dead tissue, and initiate tissue repair. Here we show that copper-infused fabrics can prevent inflammation by blocking the production of inflammatory cytokines from macrophages after being exposed to LPS, a component of bacterial cell wall. Mechanistically, we show that copper-infused fabrics can significantly reduce the NF-κB and IRF3 activation in LPS-stimulated macrophages. Given the importance of excessive inflammation in diabetes, we show that copper can reduce insulin resistance mediated by inflammatory cytokines in muscle cells. Our data show that copper infused fabrics may be useful to reduce excessive inflammation in macrophages and improve insulin sensitivity in skeletal muscles.
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Cobre , Resistencia a la Insulina , Humanos , Cobre/farmacología , Lipopolisacáridos , Citocinas , Inflamación , MacrófagosRESUMEN
Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) is an adaptor protein that is essential for the activation of several inflammasome complexes. Activation of inflammasomes leads to pathogenic clearance and inflammatory cell death called pyroptosis. Upon inflammasome activation, ASC oligomerization leads to the recruitment and activation of caspase-1, which in turn converts pro-inflammatory cytokines (e.g., pro-IL-1ß, pro-IL-18) to their mature active form. Given its central role in inflammasome activation, ASC oligomerization is used as an indicator of inflammasome activation. Here we describe how ASC oligomerization can be detected by Western blotting.
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Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Western Blotting , Proteínas Adaptadoras de Señalización CARD/metabolismo , Caspasa 1/metabolismo , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , PiroptosisRESUMEN
TRAF1 is a pro-survival adaptor molecule in TNFR superfamily (TNFRSF) signaling. TRAF1 is overexpressed in many B cell cancers including refractory chronic lymphocytic leukemia (CLL). Little has been done to assess the role of TRAF1 in human cancer. Here we show that the protein kinase C related kinase Protein Kinase N1 (PKN1) is required to protect TRAF1 from cIAP-mediated degradation during constitutive CD40 signaling in lymphoma. We show that the active phospho-Thr774 form of PKN1 is constitutively expressed in CLL but minimally detected in unstimulated healthy donor B cells. Through a screen of 700 kinase inhibitors, we identified two inhibitors, OTSSP167, and XL-228, that inhibited PKN1 in the nanomolar range and induced dose-dependent loss of TRAF1 in RAJI cells. OTSSP167 or XL-228 treatment of primary patient CLL samples led to a reduction in TRAF1, pNF-κB p65, pS6, pERK, Mcl-1 and Bcl-2 proteins, and induction of activated caspase-3. OTSSP167 synergized with venetoclax in inducing CLL death, correlating with loss of TRAF1, Mcl-1, and Bcl-2. Although correlative, these findings suggest the PKN1-TRAF1 signaling axis as a potential new target for CLL. These findings also suggest the use of the orally available inhibitor OTSSP167 in combination treatment with venetoclax for TRAF1 overexpressing CLL.