RESUMO
The use of direct injection ion mobility mass spectrometry (DI-IM-MS) to detect and identify betacyanin pigments in A. hortensis 'rubra' extracts was explored for the first time, with results compared to conventional LC-MS/MS analysis. The anti-inflammatory activities of leaf and seed extracts, alongside purified amaranthin and celosianin pigments, were investigated using a model of lipopolysaccharide (LPS)-activated murine macrophages. Extracts and purified pigments significantly inhibited the production of prostaglandin E2 and NO by up to 90% and 70%, respectively, and reduced the expression of Il6, Il1b, Nos2, and Cox2. Leaf and seed extracts also decreased secretion of Il6 and Il1b cytokines and reduced protein levels of Nos2 and Cox2. Furthermore, extracts and purified pigments demonstrated potent dose-dependent radical scavenging activity in a cellular antioxidant activity assay (CAA) without any cytotoxic effects. Our research highlights the promising biological potential of edible, climate-resilient A. hortensis 'rubra' as a valuable source of bioactive compounds.
Assuntos
Lipopolissacarídeos , Macrófagos , Estresse Oxidativo , Extratos Vegetais , Camundongos , Animais , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Células RAW 264.7 , Estresse Oxidativo/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Lipopolissacarídeos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Ciclo-Oxigenase 2/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Espectrometria de Massas em TandemRESUMO
One of the characteristics of aging and age-related disorders is the formation and evolution of a chronic, low-grade, and hence subclinical, inflammatory state known as inflammaging. Although the progression of inflammaging is now recognized as one of the main driving forces of aging and one of the main risk factors for morbidity and mortality in older subjects, current knowledge on the causative agents of inflammaging itself and chronic, aging-related diseases is still incomplete. In this chapter, we offer a methodological approach for assessing inflammation associated with aging through the use of multiplex immunoassay, which enables the rapid, reproducible, and simultaneous dosage of several cytokines, chemokines, and inflammatory mediators with little biological sample usage.
Assuntos
Envelhecimento , Citocinas , Envelhecimento/imunologia , Humanos , Imunoensaio/métodos , Citocinas/metabolismo , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , BiomarcadoresRESUMO
To investigate the associations between isocarbophos and isofenphos with impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM), and to assess the mediation roles of inflammation cells. There were 2701 participants in the case-control study, including 896 patients with T2DM, 900 patients with IFG, 905 subjects with NGT. Plasma isocarbophos and isofenphos concentrations were measured using gas chromatography and triple quadrupole tandem mass spectrometry. Generalized linear models were used to calculate the relationships between plasma isofenphos and isocarbophos levels with inflammatory factor levels and T2DM. Inflammatory cell was used as mediators to estimate the mediating effects on the above associations. Isocarbophos and isofenphos were positively related with T2DM after adjusting for other factors. The odds ratio (95% confidence interval) (OR (95%CI)) for T2DM was 1.041 (1.015, 1.068) and for IFG was 1.066 (1.009, 1.127) per unit rise in ln-isocarbophos. The prevalence of T2DM increased by 6.4% for every 1 unit more of ln-isofenphos (OR (95% CI): 1.064 (1.041, 1.087)). Additionally, a 100% rise in ln-isocarbophos was linked to 3.3% higher ln-HOMA2IR and a 0.029 mmol/L higher glycosylated hemoglobin (HbA1c) (95% CI: 0.007, 0.051). While a 100% rise in ln-isofenphos was linked to increase in ln-HOMA2 and ln-HOMA2IR of 5.8% and 3.4%, respectively. Furthermore, white blood cell (WBC) and neutrophilic (NE) were found to be mediators in the relationship between isocarbophos and T2DM, and the corresponding proportions were 17.12% and 17.67%, respectively. Isofenphos and isocarbophos are associated with IFG and T2DM in the rural Chinese population, WBC and NE have a significant role in this relationship.
Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Estudos de Casos e Controles , Inseticidas , Glicemia/análise , Malation/análogos & derivados , Compostos Organotiofosforados , China , Adulto , InflamaçãoRESUMO
Inflammation-resident cells within arthritic sites undergo a metabolic shift towards glycolysis, which greatly aggravates rheumatoid arthritis (RA). Reprogramming glucose metabolism can suppress abnormal proliferation and activation of inflammation-related cells without affecting normal cells, holding potential for RA therapy. Single 2-deoxy-d-glucose (2-DG, glycolysis inhibitor) treatment often cause elevated ROS, which is detrimental to RA remission. The rational combination of glycolysis inhibition with anti-inflammatory intervention might cooperatively achieve favorable RA therapy. To improve drug bioavailability and exert synergetic effect, stable co-encapsulation of drugs in long circulation and timely drug release in inflamed milieu is highly desirable. Herein, we designed a stimulus-responsive hyaluronic acid-triglycerol monostearate polymersomes (HTDD) co-delivering 2-DG and dexamethasone (Dex) to arthritic sites. After intravenous injection, HTDD polymersomes facilitated prolonged circulation and preferential distribution in inflamed sites, where overexpressed matrix metalloproteinases and acidic pH triggered drug release. Results indicated 2-DG can inhibit the excessive cell proliferation and activation, and improve Dex bioavailability by reducing Dex efflux. Dex can suppress inflammatory signaling and prevent 2-DG-induced oxidative stress. Thus, the combinational strategy ultimately mitigated RA by inhibiting glycolysis and hindering inflammatory signaling. Our study demonstrated the great potential in RA therapy by reprogramming glucose metabolism in arthritic sites.
Assuntos
Artrite Reumatoide , Desoxiglucose , Dexametasona , Glucose , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Animais , Glucose/metabolismo , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Camundongos , Desoxiglucose/farmacologia , Inflamação/tratamento farmacológico , Glicólise/efeitos dos fármacos , Polímeros/química , Ácido Hialurônico/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Masculino , Humanos , Proliferação de Células/efeitos dos fármacosRESUMO
The associations of polycyclic aromatic hydrocarbon (PAH) exposure with serum uric acid (SUA) or hyperuricemia have been rarely assessed. We aimed to investigate the relationships between urinary PAH metabolites and SUA or hyperuricemia among US adults and to explore the mediating role of systemic inflammation in the associations. A total of 10,307 US adults were conducted to assess the associations of seven urinary hydroxyPAH with SUA and hyperuricemia and evaluate the role of C-reactive protein (CRP), a biomarker of systemic inflammation, in such associations. Results showed that each 1-unit increase in ln-transformed 2-hydroxynaphthalene (2-OHNa), 1-hydroxyphenanthrene (1-OHPh), 2&3-hydroxyphenanthrene (2&3-OHPh) and total hydroxyphenanthrene (ΣOHPh) was associated with a 1.68 (95% confidence interval (CI): 0.19 to 3.17), 2.46 (0.78 to 4.13), 3.34 (1.59 to 5.09), and 2.99 (1.23 to 4.75) µmol/L increase in SUA, and a 8% (odds ratio (OR): 1.08, 1.02 to 1.15), 9% (OR: 1.09, 1.02 to 1.18), 13% (OR: 1.13, 1.05 to 1.22), and 12% (OR: 1.12, 95% CI: 1.03, 1.21) increase in hyperuricemia, respectively. Co-exposure of seven PAHs was positively associated with SUA and hyperuricemia, with 2&3-OHPh showing the highest weight (components weights: 0.83 and 0.78, respectively). The CRP mediated 11.47% and 10.44% of the associations of ΣOHPh and 2&3-OHPh with SUA and mediated 8.60% and 8.62% in associations of ΣOHPh and 2&3-OHPh with hyperuricemia, respectively. In conclusion, internal levels of PAH metabolites were associated with elevated SUA levels and the increased risk of hyperuricemia among US adults, and CRP played a mediating role in the associations.
Assuntos
Exposição Ambiental , Hiperuricemia , Inflamação , Hidrocarbonetos Policíclicos Aromáticos , Ácido Úrico , Humanos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Ácido Úrico/sangue , Inflamação/sangue , Hiperuricemia/sangue , Adulto , Masculino , Feminino , Exposição Ambiental/estatística & dados numéricos , Exposição Ambiental/efeitos adversos , Pessoa de Meia-Idade , Biomarcadores/sangue , Proteína C-Reativa/análise , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: We aimed to examine the relationship of 2 dietary scores [dietary inflammatory index (DII) and composite dietary antioxidant index (CDAI)] with frailty in elderly adults with diabetes. METHODS: Data were gathered from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2018. The frailty index was calculated using 49 deficits across various systems to define frailty. To examine the relationship of 2 dietary scores (DII and CDAI) with frailty in elderly adults with diabetes, multiple logistic regression analyses were performed. In logistic regression model, DII and CDAI were calculated as both continuous and tertiles. Subgroup analyses were performed to demonstrate stability of results. Restricted cubic splines were utilized to examine the non-linear correlations. RESULTS: A total of 2,795 elderly adults with diabetes were included in this study. In the multivariate logistic regression model, the odds ratio (OR) of DII for risk of frailty was 1.08 (95% CI 1.02-1.15) and the OR of CDAI for risk of frailty was 0.96 (95% CI 0.93-0.99). The ORs of DII for risk of frailty were 1.36 (95% CI 1.09-1.70) and 1.33 (95% CI 1.04-1.70) for tertiles 2 and 3, respectively (p for trend 0.027). The ORs of CDAI for risk of frailty were 0.94 (95% CI 0.75-1.17) and 0.75 (95% CI 0.58-0.98) for tertiles 2 and 3, respectively (p for trend 0.036). The subgroup analysis demonstrated reliable and enduring connections between 2 dietary scores and frailty (all p for interaction > 0.05). In the restricted cubic spline analyses, we discovered the non-linear relationship between DII and frailty (P for nonlinearity = 0.045) and linear relationship between CDAI and frailty (P for nonlinearity = 0.769). CONCLUSION: The research showed connections between 2 dietary scores (DII and CDAI) and frailty as measured by frailty index in elderly adults with diabetes.
Assuntos
Antioxidantes , Diabetes Mellitus , Fragilidade , Inflamação , Humanos , Idoso , Masculino , Feminino , Fragilidade/epidemiologia , Antioxidantes/administração & dosagem , Inquéritos Nutricionais , Dieta , Idoso Fragilizado , Idoso de 80 Anos ou mais , Fatores de Risco , Pessoa de Meia-Idade , Modelos LogísticosRESUMO
The phosphodiesterases type 5 (PDE5) are catalytic enzymes converting the second messenger cyclic guanosine monophosphate (cGMP) to 5' GMP. While intracellular cGMP reduction is associated with several detrimental effects, cGMP stabilization associates with numerous benefits. The PDE5 specific inhibitors, PDE5i, found their explosive fortune as first-line treatment for erectile dysfunction (ED), due to their powerful vasoactive properties. The favorable effect for ED emerged as side-effect when PDE5i were originally proposed for coronary artery disease (CAD). From that point on, the use of PDE5i captured the attention of researchers, clinicians, and companies. Indeed, PDE5-induced intracellular cGMP stabilization offers a range of therapeutic opportunities associated not only with vasoactive effects, but also with immune regulatory/anti-inflammatory actions. Chronic inflammation is acknowledged as the common link underlying most non-communicable diseases, including metabolic and cardiac diseases, autoimmune and neurodegenerative disorders, cancer. In this scenario, the clinical exploitation of PDE5i is undeniably beyond ED, representing a potential therapeutic tool in several human diseases. This review aims to overview the biological actions exerted by PDE5i, focusing on their ability as modulators of inflammation-related human diseases, with particular attention to inflammatory-related disorders, like cardiac diseases and cancer.
Assuntos
Disfunção Erétil , Inibidores da Fosfodiesterase 5 , Humanos , Inibidores da Fosfodiesterase 5/uso terapêutico , Disfunção Erétil/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Animais , MasculinoRESUMO
Objective: Tracheal collapse (TC) is an obstructive respiratory disorder in dogs that can affect lifespan and quality of life. Systemic inflammation has been identified in other obstructive airway conditions in dogs and humans. We hypothesized a systemic pro-inflammatory state exists in dogs with TC. Animals: Dogs with TC (TC, n = 15) and healthy, non-affected controls (C, n = 15), were prospectively enrolled. Procedure: Signalment and body condition score (BCS) were recorded for all dogs. For TC dogs, cough duration, pharyngeal collapse, bronchial collapse, and previous stent placement were recorded. Plasma samples were banked at -80°C and batch-analyzed for interleukin-8 (IL-8). Differences between groups were evaluated. Results: Yorkshire terriers were overrepresented in the TC group. The TC group was older than the C group and had a higher BCS. Interleukin-8 was significantly greater in the TC compared to the C group. Interleukin-8 was not correlated with age sex, BCS, breed, cough duration, pharyngeal collapse, bronchial collapse, or stent placement. Conclusion and clinical relevance: Increased plasma IL-8 concentration supports the presence of systemic inflammation in canine TC. Dogs with TC were older than controls, with a higher BCS, but this did not account for the increased IL-8. Further investigation of IL-8 as a potential biomarker for monitoring TC progression and therapeutic response is warranted.
Évaluation du médiateur inflammatoire circulant interleukine-8 chez les chiens présentant un collapsus trachéal. Objectif: Le collapsus trachéal (TC) est un trouble respiratoire obstructif chez les chiens qui peut affecter la durée de vie et la qualité de vie. Une inflammation systémique a été identifiée dans d'autres affections obstructives des voies respiratoires chez les chiens et les humains. Nous avons émis l'hypothèse qu'un état pro-inflammatoire systémique existe chez les chiens atteints de TC. Animaux: Des chiens atteints de TC (TC, n = 15) et des témoins sains et non affectés (C, n = 15) ont été recrutés de manière prospective. Procédure: Les informations et le score d'état corporel (BCS) ont été enregistrés pour tous les chiens. Pour les chiens atteints de TC, la durée de la toux, le collapsus pharyngé, le collapsus bronchique et la mise en place antérieure d'un stent ont été enregistrés. Des échantillons de plasma ont été conservés à −80 °C et analysés par lots pour l'interleukine-8 (IL-8). Les différences entre les groupes ont été évaluées. Résultats: Les Yorkshire terriers étaient surreprésentés dans le groupe TC. Le groupe TC était plus âgé que le groupe C et avait un BCS plus élevé. L'interleukine-8 était significativement plus élevée dans le groupe TC que dans le groupe C. L'interleukine-8 n'était pas corrélée à l'âge, au sexe, au BCS, à la race, à la durée de la toux, au collapsus pharyngé, au collapsus bronchique ou à la mise en place d'un stent. Conclusion et pertinence clinique: L'augmentation de la concentration plasmatique d'IL-8 confirme la présence d'une inflammation systémique dans le TC canin. Les chiens atteints de TC étaient plus âgés que les témoins, avec un BCS plus élevé, mais cela n'expliquait pas l'augmentation de l'IL-8. Une étude plus approfondie de l'IL-8 en tant que biomarqueur potentiel pour surveiller la progression du TC et la réponse thérapeutique est justifiée.(Traduit par Dr Serge Messier).
Assuntos
Doenças do Cão , Interleucina-8 , Animais , Cães , Interleucina-8/sangue , Doenças do Cão/sangue , Masculino , Feminino , Inflamação/veterinária , Inflamação/sangue , Doenças da Traqueia/veterinária , Doenças da Traqueia/sangue , Estudos de Casos e Controles , Traqueia , Estudos ProspectivosRESUMO
Disrupted N6-methyladenosine (m6A) modification modulates various inflammatory disorders. However, the role of m6A in regulating cutaneous inflammation remains elusive. Here, we reveal that the m6A and its methyltransferase METTL3 are down-regulated in keratinocytes in inflammatory skin diseases. Inducible deletion of Mettl3 in murine keratinocytes results in spontaneous skin inflammation and increases susceptibility to cutaneous inflammation with activation of neutrophil recruitment. Therapeutically, restoration of m6A alleviates the disease phenotypes in mice and suppresses inflammation in human biopsy specimens. We support a model in which m6A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m6A reader IGF2BP3, leading to a rewiring of fatty acid metabolism with a reduction in palmitic acid accumulation and, consequently, suppressing neutrophil chemotaxis in cutaneous inflammation. Our findings highlight a previously unrecognized epithelial-intrinsic m6A modification-lipid metabolism pathway that is essential for maintaining epidermal and immune homeostasis and lay the basis for potential therapeutic targeting of m6A modulators to attenuate inflammatory skin diseases.
Assuntos
Adenosina , Homeostase , Queratinócitos , Metabolismo dos Lipídeos , Metiltransferases , Neutrófilos , Pele , Adenosina/análogos & derivados , Adenosina/metabolismo , Animais , Neutrófilos/metabolismo , Neutrófilos/imunologia , Camundongos , Queratinócitos/metabolismo , Humanos , Metiltransferases/metabolismo , Metiltransferases/genética , Pele/metabolismo , Pele/patologia , Pele/imunologia , Inflamação/metabolismo , Inflamação/patologia , Quimiotaxia , Elongases de Ácidos Graxos/metabolismo , Elongases de Ácidos Graxos/genéticaRESUMO
Unlike mammals, some nonmammalian species recruit Müller glia for retinal regeneration after injury. Identifying the underlying mechanisms may help to foresee regenerative medicine strategies. Using a Xenopus model of retinitis pigmentosa, we found that Müller cells actively proliferate upon photoreceptor degeneration in old tadpoles but not in younger ones. Differences in the inflammatory microenvironment emerged as an explanation for such stage dependency. Functional analyses revealed that enhancing neuroinflammation is sufficient to trigger Müller cell proliferation, not only in young tadpoles but also in mice. In addition, we showed that microglia are absolutely required for the response of mouse Müller cells to mitogenic factors while negatively affecting their neurogenic potential. However, both cell cycle reentry and neurogenic gene expression are allowed when applying sequential pro- and anti-inflammatory treatments. This reveals that inflammation benefits Müller glia proliferation in both regenerative and nonregenerative vertebrates and highlights the importance of sequential inflammatory modulation to create a regenerative permissive microenvironment.
Assuntos
Proliferação de Células , Células Ependimogliais , Regeneração , Retina , Animais , Células Ependimogliais/metabolismo , Células Ependimogliais/patologia , Camundongos , Retina/patologia , Retina/metabolismo , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Doenças Neuroinflamatórias/etiologia , Microglia/metabolismo , Microglia/patologia , Modelos Animais de Doenças , Retinose Pigmentar/patologia , Retinose Pigmentar/metabolismo , Inflamação/patologia , Inflamação/metabolismo , LarvaRESUMO
OBJECTIVE: The aim of this study was to investigate the effect of different dietary inflammatory index diets on inflammatory markers, anthropometric measurements, and sleep quality in obese subjects. METHODS: This study was conducted in a public hospital in Turkey between November 2021 and May 2022. Participants with pro-inflammatory dietary habits were included in the study. Randomly divided into two groups of 33 participants, they were subjected to an anti-inflammatory diet or a control diet for 8 weeks. The study evaluated the anthropometric parameters, inflammatory biomarkers, and sleep quality indices of the diet groups. RESULTS: Significant reductions in body mass index were observed in both groups, more marked in the anti-inflammatory diet cohort. C-reactive protein levels, indicative of inflammation, also decreased substantially in both groups, with a more marked reduction in the anti-inflammatory diet cohort. Despite the improvement in sleep quality in both groups, the variation was not statistically significant. CONCLUSION: This study demonstrates the importance of anti-inflammatory diets in nutritional strategies for obesity by reducing body mass index and inflammation.
Assuntos
Índice de Massa Corporal , Proteína C-Reativa , Inflamação , Obesidade , Qualidade do Sono , Humanos , Obesidade/dietoterapia , Obesidade/complicações , Masculino , Inflamação/dietoterapia , Feminino , Adulto , Proteína C-Reativa/análise , Pessoa de Meia-Idade , Biomarcadores/sangue , Biomarcadores/análise , Dieta , Resultado do Tratamento , Sono/fisiologiaRESUMO
OBJECTIVE: The aim of this study was to investigate the role of systemic immune-inflammation index, neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, and platelet-lymphocyte ratios calculated in the first trimester as inflammatory markers in predicting gestational diabetes mellitus diagnosis. METHODS: This study was conducted retrospectively at a tertiary center between January 2020 and June 2023. A total of 111 pregnant women with gestational diabetes and 378 pregnant women in the control group were included in the study. Systemic immune-inflammation index, neutrophil-lymphocyte ratio, lymphocyte-monocyte ratio, and platelet-lymphocyte ratios values were compared between the gestational diabetes mellitus group patients and the healthy group. Receiver operating characteristic analysis curve was used for predicting gestational diabetes mellitus using systemic immune-inflammation index and lymphocyte-monocyte ratio. RESULTS: In pregnant women in the first trimester, systemic immune-inflammation index and lymphocyte-monocyte ratio values based on routine complete blood count parameters were found to be statistically significantly higher in gestational diabetes mellitus patients compared to healthy patients, while neutrophil-lymphocyte ratio and platelet-lymphocyte ratios values were found to be similar (p=0.033, p=0.005, p=0.211, and p=0.989). For predicting gestational diabetes mellitus, a cut-off value of 655.75 for systemic immune-inflammation index resulted in 80.2% sensitivity and 34.4% specificity, and a cut-off value of 3.62 for lymphocyte-monocyte ratio resulted in 56.8% sensitivity and 63.2% specificity, indicating good discriminatory ability. CONCLUSION: We believe that systemic immune-inflammation index and lymphocyte-monocyte ratio values measured in the first-trimester complete blood count parameters are effective in predicting gestational diabetes mellitus but are not effective in determining insulin requirement.
Assuntos
Biomarcadores , Diabetes Gestacional , Neutrófilos , Primeiro Trimestre da Gravidez , Curva ROC , Humanos , Diabetes Gestacional/sangue , Diabetes Gestacional/imunologia , Diabetes Gestacional/diagnóstico , Feminino , Gravidez , Primeiro Trimestre da Gravidez/sangue , Primeiro Trimestre da Gravidez/imunologia , Estudos Retrospectivos , Adulto , Biomarcadores/sangue , Inflamação/sangue , Inflamação/imunologia , Linfócitos/imunologia , Valor Preditivo dos Testes , Monócitos/imunologia , Estudos de Casos e Controles , Contagem de Plaquetas , Contagem de Linfócitos , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: Although joint swelling is traditionally interpreted as synovitis, recent imaging studies showed that there is also inflammation of tenosynovium and intermetatarsal bursae in the forefoot. We aimed to increase our understanding of differences and similarities regarding forefoot involvement between ACPA-positive and ACPA-negative rheumatoid arthritis (RA) at diagnosis. Therefore, we (1) compared metatarsophalangeal (MTP) joint counts, walking disabilities and inflamed tissues between ACPA groups and (2) studied associations of joint swelling/tenderness and walking disabilities with underlying inflamed tissues within ACPA groups. METHODS: 171 ACPA-positive and 203 ACPA-negative consecutively diagnosed patients with RA had a physical joint examination (swollen joint count-66/tender joint count-68), filled a Health Assessment Questionnaire including the domain walking and underwent MRI of the MTP joints at diagnosis. Synovitis, tenosynovitis, osteitis and intermetatarsal bursitis (IMB) were assessed. Findings in age-matched healthy controls were applied to define abnormalities on MRI. RESULTS: While ACPA-negative RA patients had more swollen joints (mean SJC 8 vs 6 in ACPA-positives, p=0.003), the number of swollen MTP joints was similar (mean 1 in both groups); walking disabilities were also equally common (49% vs 53%). In contrast, inflamed tissues were all more prevalent in ACPA-positive compared with ACPA-negative RA. Within ACPA-positive RA, IMB was associated independently with MTP-joint swelling (OR 2.6, 95% CI 1.4 to 5.0) and tenderness (OR 3.0, 95% CI 1.8 to 5.0). While in ACPA-negatives, synovitis was associated independently with MTP-joint swelling (OR 2.8, 95% CI 1.4 to 5.8) and tenderness (OR 2.5, 95% CI 1.3 to 4.8). Tenosynovitis contributed most to walking disabilities. CONCLUSIONS: Although the forefoot of ACPA-positives and ACPA-negatives share clinical similarities at diagnosis, there are differences in underlying inflamed tissues. This reinforces that ACPA-positive and ACPA-negative RA are different entities.
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Anticorpos Antiproteína Citrulinada , Artrite Reumatoide , Imageamento por Ressonância Magnética , Sinovite , Humanos , Artrite Reumatoide/imunologia , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/complicações , Feminino , Masculino , Pessoa de Meia-Idade , Anticorpos Antiproteína Citrulinada/sangue , Idoso , Sinovite/imunologia , Sinovite/diagnóstico , Sinovite/diagnóstico por imagem , Sinovite/patologia , Sinovite/etiologia , Inflamação/imunologia , Inflamação/diagnóstico , Inflamação/patologia , Articulação Metatarsofalângica/patologia , Articulação Metatarsofalângica/diagnóstico por imagem , Antepé Humano/patologia , Adulto , Tenossinovite/diagnóstico , Tenossinovite/imunologia , Tenossinovite/diagnóstico por imagem , Tenossinovite/patologia , Estudos de Casos e ControlesRESUMO
BACKGROUND: Neuroinflammation plays a critical role in various neurological disorders. Oxycodone has anti-inflammatory properties. The purpose of this work was to look into the effect of oxycodone in controlling lipopolysaccharide (LPS)-induced neuroinflammation in microglia. METHODS: LPS-induced HMC3 cells were subjected to oxycodone (2.5, 5, 10 and 20 µg/mL). The mRNA and protein expressions were examined by qRT-PCR and western blotting. TNF-α, IL-1ß, IL-6, and IL-8 levels were assessed by ELISA. MTT assay was adopted to measure cell viability. The interactions between CREB, miR-181c and PDCD4 were analyzed by dual-luciferase reporter assay, ChIP and/or RIP assays. RESULTS: Oxycodone treatment alleviated LPS-induced inflammation in HMC3 cells and increased p-CREB level, but reduced PDCD4 and iNOS levels in LPS-treated cells. Mechanistically, oxycodone mitigated LPS-induced neuroinflammation by upregulating miR-181c. In addition, CREB promoted miR-181c expression by directly binding to the MIR181C promoter, and miR-181c inhibited PDCD4 expression by directly binding to PDCD4 3'UTR. As expected, oxycodone alleviated LPS-induced neuroinflammation by regulating the CREB/miR-181c/PDCD4 axis. CONCLUSION: Oxycodone attenuated LPS-induced neuroinflammation in microglia by regulating the CREB/miR-181c/PDCD4 axis. These findings proved that oxycodone is a potential drug for treating neuroinflammation and elucidate the mechanisms involved.
Assuntos
Proteínas Reguladoras de Apoptose , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Lipopolissacarídeos , MicroRNAs , Microglia , Doenças Neuroinflamatórias , Oxicodona , Proteínas de Ligação a RNA , MicroRNAs/genética , MicroRNAs/metabolismo , Oxicodona/farmacologia , Oxicodona/efeitos adversos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Humanos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doenças Neuroinflamatórias/induzido quimicamente , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/genética , Anti-Inflamatórios/farmacologia , Linhagem Celular , Inflamação/induzido quimicamente , Inflamação/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Early dissemination to distant organs accounts for the dismal prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Chronic, dysregulated, persistent and unresolved inflammation provides a preferred tumor microenvironment (TME) for tumorigenesis, development, and metastasis. A better understanding of the key regulators that maintain inflammatory TME and the development of predictive biomarkers to identify patients who are most likely to benefit from specific inflammatory-targeted therapies is crucial for advancing personalized cancer treatment. METHODS: This study identified cell-specific expression of CALB2 in human PDAC through single-cell RNA sequencing analysis and assessed its clinicopathological correlations in tissue microarray using multi-color immunofluorescence. Co-culture systems containing cancer-associated fibroblasts (CAFs) and patient-derived organoids (PDOs) in vitro and in vivo were employed to elucidate the effects of CALB2-activated CAFs on PDAC malignancy. Furthermore, CUT&RUN assays, luciferase reporter assays, RNA sequencing, and gain- or loss-of-function assays were used to unravel the molecular mechanisms of CALB2-mediated inflammatory reprogramming and metastasis. Additionally, immunocompetent KPC organoid allograft models were constructed to evaluate CALB2-induced immunosuppression and PDAC metastasis, as well as the efficacy of inflammation-targeted therapy. RESULTS: CALB2 was highly expressed both in CAFs and cancer cells and correlated with an unfavorable prognosis and immunosuppressive TME in PDAC patients. CALB2 collaborated with hypoxia to activate an inflammatory fibroblast phenotype, which promoted PDAC cell migration and PDO growth in vitro and in vivo. In turn, CALB2-activated CAFs upregulated CALB2 expression in cancer cells through IL6-STAT3 signaling-mediated direct transcription. In cancer cells, CALB2 further activated Ca2+-CXCL14 inflammatory axis to facilitate PDAC metastatic outgrowth and immunosuppression. Genetic or pharmaceutical inhibition of CXCL14 significantly suppressed CALB2-mediated metastatic colonization of PDAC cells in vivo and extended mouse survival. CONCLUSIONS: These findings identify CALB2 as a key regulator of inflammatory reprogramming to promote PDAC metastatic progression. Combination therapy with αCXCL14 monoclonal antibody and gemcitabine emerges as a promising strategy to suppress distant metastasis and improve survival outcomes in PDAC with CALB2 overexpression.
Assuntos
Metástase Neoplásica , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Camundongos , Animais , Inflamação/patologia , Inflamação/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Feminino , Masculino , PrognósticoRESUMO
BACKGROUND: Glucagon-like peptide-1 receptor agonists are a viable option for the prevention of Alzheimer's disease (AD) but the mechanisms of this potential disease modifying action are unclear. We investigated the effects of once-weekly exenatide (EQW) on AD associated proteomic clusters. METHODS: The Exenatide Study of Cardiovascular Event Lowering study compared the cardiovascular effects of EQW 2 mg with placebo in 13,752 people with type 2 diabetes mellitus. 4,979 proteins were measured (Somascan V0.4) on baseline and 1-year plasma samples of 3,973 participants. C-reactive protein (CRP), ficolin-2 (FCN2), plasminogen activator inhibitor 1 (PAI-1), soluble vascular cell adhesion protein 1 (sVCAM1) and 4 protein clusters were tested in multivariable mixed models. RESULTS: EQW affected FCN2 (Cohen's d -0.019), PAI-1 (Cohen's d -0.033), sVCAM-1 (Cohen's d 0.035) and a cytokine-cytokine cluster (Cohen's d 0.037) significantly compared with placebo. These effects were sustained in individuals over the age of 65 but not in those under 65. CONCLUSIONS: EQW treatment was associated with significant change in inflammatory proteins associated with AD. TRIAL REGISTRATION: EXSCEL is registered on ClinicalTrials.gov: NCT01144338 on 10th of June 2010.
Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Exenatida , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/sangue , Masculino , Feminino , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Exenatida/uso terapêutico , Pessoa de Meia-Idade , Hipoglicemiantes/uso terapêutico , Método Duplo-Cego , Inibidor 1 de Ativador de Plasminogênio/sangue , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Inflamação/tratamento farmacológicoRESUMO
BACKGROUND: Acute kidney injury (AKI) represents a significant post-cardiac surgery complication, particularly prevalent among individuals with pre-existing renal dysfunction. Chronic kidney disease (CKD) is frequently accompanied by persistent, low-grade inflammation, which is known to exacerbate systemic stress responses during surgical procedures. This study hypothesizes that these inflammatory responses might influence the incidence and severity of postoperative acute kidney injury (AKI), potentially serving as a protective mechanism by preconditioning the kidney to stress. METHODS: This retrospective study enrolled patients with preoperative renal dysfunction (eGFR between 15 and 60 ml/min/1.73 m²) who underwent cardiac surgery between January 2020 and December 2022. Preoperative inflammatory biomarkers were evaluated. The primary outcome was the incidence of postoperative AKI, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Multivariate regression models and sensitivity analyses were conducted to ascertain the relationship between inflammatory biomarkers and AKI. Restricted cubic spines (RCS) was conducted to explore nonlinear associations between inflammatory biomarkers and AKI. RESULTS: AKI occurred in 53.4% (392/734) of patients, accompanied by significant mortality and length of hospital stay increases in cases of AKI (P < 0.005). After full adjustment of confounders, neutrophil percentage-to-albumin ratio (OR = 0.28), systemic inflammation response index (OR = 0.70), systemic immune inflammation index (OR = 0.69), neutrophil-to-lymphocyte ratio (OR = 0.70), monocyte/high-density lipoprotein cholesterol ratio (OR = 0.53), neutrophil/high-density lipoprotein cholesterol ratio (OR = 0.43) demonstrated an inverse association with AKI. Sensitivity analyses revealed that patients in the highest quartile of these biomarkers exhibited a significantly lower prevalence of AKI compared to those in the lowest quartile (p for trend < 0.05). The RCS analysis suggested an "Inverted U-shaped" association of both LnNPAR and LnSIRI with AKI. CONCLUSIONS: This study identified an inverse association between preoperative inflammatory biomarkers and postoperative AKI in patients with preoperative renal dysfunction. The findings implied that preoperative inflammation may play a protective role against postoperative AKI in this patient population undergoing cardiac surgery.
Assuntos
Injúria Renal Aguda , Biomarcadores , Procedimentos Cirúrgicos Cardíacos , Inflamação , Complicações Pós-Operatórias , Humanos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/sangue , Injúria Renal Aguda/epidemiologia , Masculino , Estudos Retrospectivos , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Feminino , Biomarcadores/sangue , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/epidemiologia , Idoso , Pessoa de Meia-Idade , Inflamação/sangue , Projetos Piloto , Incidência , Taxa de Filtração Glomerular , Fatores de Risco , Período Pré-OperatórioRESUMO
OBJECTIVE: Tumour necrosis factor (TNF)-α is a proinflammatory marker and has been shown to affect mitochondrial function in different tissues. We investigated the effect on adipose tissue (AT) inflammation and mitochondrial respiration in patients with hidradenitis suppurativa (HS) after 12 weeks of treatment with adalimumab, a TNF-α inhibitor. METHODS: We sampled blood and an AT biopsy from 13 patients with HS and 10 control subjects after an overnight fast. The patients were retested after at least 12 weeks of treatment with adalimumab (40 mg/week). We measured macrophage content and mitochondrial respiration in the AT and interleukin (IL)-1ß, IL-6, IL-10, high-sensitivity C-reactive protein (hsCRP), interferon-γ, TNF-α, adiponectin and leptin in plasma. Clinical scores and Dermatology Quality of Life Index (DLQI) were assessed. RESULTS: We found a higher anti-inflammatory macrophage content (CD206+) in the patient group compared with the control group, but no differences between before and after the intervention. No difference in mitochondrial respiration was observed. We observed higher plasma IL-6 and hsCRP concentrations in patients with HS compared to controls, with no differences before and after the intervention. The difference between controls and HS patients was abolished after the intervention. HS patients improved their DLQI after the intervention with no change in clinical scores. CONCLUSION: Treatment with adalimumab in patients with HS does not alter AT inflammation or mitochondrial respiratory capacity; however, we did see a higher content of anti-inflammatory macrophages in the patient group compared with the control group.
Assuntos
Adalimumab , Tecido Adiposo , Hidradenite Supurativa , Inflamação , Mitocôndrias , Humanos , Adalimumab/uso terapêutico , Adalimumab/farmacologia , Masculino , Hidradenite Supurativa/tratamento farmacológico , Hidradenite Supurativa/metabolismo , Feminino , Adulto , Mitocôndrias/metabolismo , Tecido Adiposo/metabolismo , Inflamação/tratamento farmacológico , Pessoa de Meia-Idade , Respiração Celular/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Macrófagos/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
In recent years, systemic inflammation has emerged as a pivotal player in the development and progression of various degenerative diseases. This complex, chronic inflammatory state, often undetected, can have far-reaching consequences for the body's physiology. At the molecular level, markers such as C-reactive protein, cytokines and other inflammatory mediators serve as indicators of systemic inflammation and often act as predictors of numerous musculoskeletal diseases and even certain forms of cancer. The concept of 'meta-inflammation', specifically referring to metabolically triggered inflammation, allows healthcare professionals to understand inflammatory responses in patients with metabolic syndrome. Driven by nutrient excess and the expansion of adipose tissue, meta-inflammation is closely associated with insulin resistance, further propagating the metabolic dysfunction observed in many Western societies. Wound persistence, on the other hand, exacerbates the detrimental effects of prolonged inflammation at the local level. Acute inflammation is a beneficial and essential process for wound healing and infection control. However, when inflammation fails to resolve, it can impede the healing process, leading to chronic wounds, excessive scarring and even the activation of fibrotic pathways. This approach significantly reduces the efficacy of regenerative biological therapies. Our review focuses on the vital role of proteins, vitamins and minerals in collagen synthesis and cell proliferation for tissue healing. We also examine hormonal influences on regeneration, noting the negative effects of imbalances, and emphasize glucose regulation's importance in creating a stable environment for chronic wound healing.
Assuntos
Inflamação , Doenças Musculoesqueléticas , Cicatrização , Humanos , Cicatrização/fisiologia , Doenças Musculoesqueléticas/metabolismo , Doenças Musculoesqueléticas/fisiopatologia , Doença Crônica , Inflamação/metabolismo , Ferimentos e Lesões/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Síndrome Metabólica/metabolismoRESUMO
BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, but the molecular mechanisms underlying IBD are incompletely understood. In this study, we explored the role and regulating mechanism of otubain 2 (OTUB2), a deubiquitinating enzyme, in IBD. METHODS: To study the function of OTUB2 in IBD, we generated Otub2-/- mice and treated them with dextran sulfate sodium (DSS) to induce experimental colitis. Bone marrow transplantation was performed to identify the cell populations that were affected by OTUB2 in colitis. The molecular mechanism of OTUB2 in signal transduction was studied by various biochemical methods. RESULTS: OTUB2 was highly expressed in colon-infiltrating macrophages in both humans with IBD and mice with DSS-induced experimental colitis. Colitis was significantly aggravated in Otub2-/- mice and bone marrow chimeric mice receiving Otub2-/- bone marrow. OTUB2-deficiency impaired the production of cytokines and chemokines in macrophages in response to the NOD2 agonist muramyl dipeptide (MDP). Upon MDP stimulation, OTUB2 promoted NOD2 signaling by stabilizing RIPK2. Mechanistically, OTUB2 inhibited the proteasomal degradation of RIPK2 by removing K48-linked polyubiquitination on RIPK2, which was mediated by the active C51 residue in OTUB2. In mice, OTUB2 ablation abolished the protective effects of MDP administration in colitis. CONCLUSION: This study identified OTUB2 as a novel regulator of intestinal inflammation.