RESUMO
Alcohol-associated liver disease (ALD) is a major health problem with limited effective treatment options. Alcohol-associated hepatitis (AH) is a subset of severe ALD with a high rate of mortality due to infection, severe inflammation, and ultimately multi-organ failure. There is an urgent need for novel therapeutic approaches to alleviate the human suffering associated with this condition. Resolvin D1 (RvD1) promotes the resolution of inflammation and regulates immune responses. The current study aimed to test the therapeutic efficacy and mechanisms of RvD1-mediated effects on liver injury and inflammation in an experimental animal model that mimics severe AH in humans. Our data demonstrated that mice treated with RvD1 had attenuated liver injury and inflammation caused by EtOH and LPS exposure by limiting hepatic neutrophil accumulation and decreasing hepatic levels of pro-inflammatory cytokines. In addition, RvD1 treatment attenuated hepatic pyroptosis, an inflammatory form of cell death, via downregulation of pyroptosis-related genes such as GTPase family member b10 and guanylate binding protein 2, and reducing cleavage of caspase 11 and gasdermin-D. In vitro experiments with primary mouse hepatocytes and bone marrow-derived macrophages confirmed the effectiveness of RvD1 in the attenuation of pyroptosis. In summary, our data demonstrated that RvD1 treatment provided beneficial effects against liver injury and inflammation in an experimental animal model recapitulating features of severe AH in humans. Our results suggest that RvD1 may be a novel adjunct strategy to traditional therapeutic options for AH patients.
Assuntos
Etanol , Lipopolissacarídeos , Humanos , Camundongos , Animais , Lipopolissacarídeos/toxicidade , Etanol/toxicidade , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácidos Docosa-Hexaenoicos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fígado/metabolismoRESUMO
BACKGROUND: Resolvin D1 (RvD1), a specialized pro-resolving lipid mediator (SPM), is derived from docosahexaenoic acid (DHA). It plays a key role in actively resolving inflammatory responses, which further reduces small intestinal damage. However, its regulation of the apoptosis triggered by endoplasmic reticulum (ER) stress in intestinal epithelial cells is still poorly understood. The intestinal porcine epithelial cells (IPEC-J2) were stimulated with tunicamycin to screen an optimal stimulation time and concentration to establish an ER stress model. Meanwhile, RvD1 (0, 1, 10, 20, and 50 nM) cytotoxicity and its impact on cell viability and the effective concentration for reducing ER stress and apoptosis were determined. Finally, the effects of RvD1 on ER stress and associated apoptosis were furtherly explored by flow cytometry analysis, AO/EB staining, RT-qPCR, and western blotting. RESULTS: The ER stress model of IPEC-J2 cells was successfully built by stimulating the cells with 1 µg/mL tunicamycin for 9 h. Certainly, the increased apoptosis and cell viability inhibition also appeared under the ER stress condition. RvD1 had no cytotoxicity, and its concentration of 1 nM significantly decreased cell viability inhibition (p= 0.0154) and the total apoptosis rate of the cells from 14.13 to 10.00% (p= 0.0000). RvD1 at the concentration of 1 nM also significantly reduced the expression of glucose-regulated protein 78 (GRP-78, an ER stress marker gene) (p= 0.0000) and pro-apoptotic gene Caspase-3 (p= 0.0368) and promoted the expression of B cell lymphoma 2 (Bcl-2, an anti-apoptotic gene)(p= 0.0008). CONCLUSIONS: Collectively, the results shed light on the potential of RvD1 for alleviating apoptosis triggered by ER stress, which may indicate an essential role of RvD1 in maintaining intestinal health and homeostasis.
Assuntos
Apoptose , Ácidos Docosa-Hexaenoicos , Animais , Suínos , Ácidos Docosa-Hexaenoicos/farmacologia , Tunicamicina/farmacologia , Estresse do Retículo EndoplasmáticoRESUMO
BACKGROUND: Inflammation has become a critical pathological mechanism of Major Depressive Disorder (MDD). NLRP3 is a critical inflammatory pathway to maintain the immune balance. Recently, preclinical evidence showed that Resolvin D1 might potentially offer a new option for antidepressant treatment due to its protective effects through the inhibition of neuroinflammation. However, whether they have clinical value in the diagnosis and treatment evaluation of adolescent depression was unclear. METHODS: Forty-eight untreated first-episode adolescent patients with moderate to severe major depressive disorder, as well as 30 healthy adolescents (HCs, age and gender-matched), were enrolled for this study. Their ages ranged from 13 to 18 (15.75 ± 1.36) years. The patients were treated with fluoxetine for 6-8 weeks. HDRS-17 was used to evaluate the severity of depressive symptoms. Venous blood samples were collected at baseline for the two groups and at the time-point of post-antidepressant treatment for the patients. Serum concentrations of RvD1, NLRP3, IL-1ß, IL-18, and IL-4 were measured by enzyme-linked immunosorbent assays (ELISA) pre- and post-fluoxetine treatment. RESULTS: Serum levels of RvD1 and anti-inflammatory cytokine IL-4 were significantly elevated in adolescents with MDD compared to healthy adolescents, but no significant difference in NLRP3, IL-1ß, and IL-18 between the two groups. Meanwhile, RvD1 (positively) and IL-4 (negatively) were correlated with the severity of symptoms (HDRS-17 scores) after adjusting age, gender, and BMI. Interestingly, fluoxetine treatment significantly reduced the serum levels of RvD1, NLRP3, IL-1ß, and IL-18 in MDD adolescents but increased the levels of IL-4 relative to baseline. Furthermore, we observed that serum levels of RvD1 might be an excellent distinguishing indicator for depression and healthy adolescents. CONCLUSIONS: Our study is the first to compare RvD1 and NLRP3 between adolescent MDD and HCs. Our findings of reactive increase of RvD1 in adolescent MDD comprised a novel and critical contribution. Our results showed the presence of inflammation resolution unbalanced in adolescents with MDD and indicated that RvD1 might be an ideal biomarker for diagnosing and treating adolescent MDD.
Assuntos
Citocinas , Transtorno Depressivo Maior , Ácidos Docosa-Hexaenoicos , Adolescente , Humanos , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Fluoxetina/uso terapêutico , Inflamação/tratamento farmacológico , Interleucina-18 , Interleucina-4 , Proteína 3 que Contém Domínio de Pirina da Família NLRRESUMO
Resolvin D1 (RvD1) is potentially associated with fetal growth retardation (FGR) through alleviating maternal inflammation and its linkage with several pregnancy complications. Thus, this study detected RvD1 levels at different trimesters of pregnancy, aiming to investigate its role in predicting FGR risk of elderly pregnant women. This prospective, observational cohort study enrolled 165 elderly pregnant women aged ≥35 years. Serum RvD1 was detected at 10-13 weeks (early pregnancy), 20-23 weeks (middle pregnancy), and 30-33 weeks (late pregnancy) of gestational week by enzyme-linked immunosorbent assay. RvD1 was varied among different trimesters of pregnancy in elderly pregnant women (p < 0.001). FGR occurred in 25 (15.2%) women in this study. RvD1 at early (p = 0.009), middle (p = 0.002), and late (p = 0.003) pregnancy was decreased in women with FGR versus those without. By multivariate analysis, RvD1 at middle pregnancy (odds ratio (OR): 0.477, p < 0.001), pre-pregnancy body mass index (OR: 0.763, p = 0.025), and gestational diabetes mellitus (yes versus no) (OR: 0.071, p = 0.031) were independently correlated with declined FGR risk. While age (OR: 1.382, p = 0.009) was independently associated with elevated risk of FGR. Furthermore, the combination of these independent factors as a predictive model exhibited a good potential for assessing FGR risk (area under the curve: 0.802, 95% confidence interval: 0.711-0.894). In conclusion, RvD1 at different trimesters of pregnancy is negatively linked with the risk of FGR, whose level at middle pregnancy serves as an independent factor for FGR risk in elderly pregnant women.
Assuntos
Ácidos Docosa-Hexaenoicos , Retardo do Crescimento Fetal , Trimestres da Gravidez , Humanos , Feminino , Gravidez , Retardo do Crescimento Fetal/sangue , Trimestres da Gravidez/sangue , Ácidos Docosa-Hexaenoicos/sangue , Estudos Prospectivos , Adulto , Fatores de Risco , Curva ROC , Idoso , Índice de Massa CorporalRESUMO
Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, leukocyte infiltration, and vascular remodeling. Resolvin D1 (RvD1) is derived from ω-3 polyunsaturated fatty acids and is involved in the resolution phase of chronic inflammatory diseases. The aim of this study was to decipher the protective role of RvD1 via formyl peptide receptor 2 (FPR2) receptor signaling in attenuating abdominal aortic aneurysms (AAA). The elastase-treatment model of AAA in C57BL/6 (WT) mice and human AAA tissue was used to confirm our hypotheses. Elastase-treated FPR2-/- mice had a significant increase in aortic diameter, proinflammatory cytokine production, immune cell infiltration (macrophages and neutrophils), elastic fiber disruption, and decrease in smooth muscle cell α-actin expression compared to elastase-treated WT mice. RvD1 treatment attenuated AAA formation, aortic inflammation, and vascular remodeling in WT mice, but not in FPR2-/- mice. Importantly, human AAA tissue demonstrated significantly decreased FPR2 mRNA expression compared to non-aneurysm human aortas. Mechanistically, RvD1/FPR2 signaling mitigated p47phox phosphorylation and prevented hallmarks of ferroptosis, such as lipid peroxidation and Nrf2 translocation, thereby attenuating HMGB1 secretion. Collectively, this study demonstrates RvD1-mediated immunomodulation of FPR2 signaling on macrophages to mitigate ferroptosis and HMGB1 release, leading to resolution of aortic inflammation and remodeling during AAA pathogenesis.
Assuntos
Aneurisma da Aorta Abdominal , Ferroptose , Proteína HMGB1 , Actinas/metabolismo , Animais , Aneurisma da Aorta Abdominal/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Proteína HMGB1/metabolismo , Humanos , Inflamação/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Elastase Pancreática/metabolismo , RNA Mensageiro/metabolismo , Receptores de Formil Peptídeo/genética , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas , Remodelação VascularRESUMO
BACKGROUND: Mast cells are initiators and main effectors of allergic inflammation, together with eosinophils, with whom they can interact in a physical and soluble cross-talk with marked pro-inflammatory features, the Allergic Effector Unit. The pro-resolution role of mast cells, alone or in co-culture with eosinophils, has not been characterized yet. OBJECTIVES: We aimed to investigate select pro-resolution pathways in mast cells in vitro and in vivo in allergic inflammation. METHODS: In vitro, we employed human and murine mast cells and analyzed release of resolvin D1 and expression of 15-lipoxygenase after IgE-mediated activation. We performed co-culture of IgE-activated mast cells with peripheral blood eosinophils and investigated 15-lipoxygenase expression and Resolvin D1 release. In vivo, we performed Ovalbumin/Alum and Ovalbumin/S. aureus enterotoxin B allergic peritonitis model in Wild Type mice following a MC "overshoot" protocol. RESULTS: We found that IgE-activated mast cells release significant amounts of resolvin D1 30 min after activation, while 15-lipoxygenase expression remained unchanged. Resolvin D1 release was found to be decreased in IgE-activated mast cells co-cultured with peripheral blood eosinophils for 30 min In vivo, mast cell-overshoot mice exhibited a trend of reduced inflammation, together with increased peritoneal resolvin D1 release. CONCLUSIONS: Mast cells can actively contribute to resolution of allergic inflammation by releasing resolvin D1.
Assuntos
Mastócitos , Staphylococcus aureus , Camundongos , Humanos , Animais , Mastócitos/metabolismo , Ovalbumina/metabolismo , Staphylococcus aureus/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Inflamação/metabolismo , Imunoglobulina ERESUMO
PURPOSE: Over the last years, the number of vertebral arthrodesis has been steadily increasing. The use of iliac crest bone autograft remains the "gold standard" for bone graft substitute in these procedures. However, this solution has some side effects, such as the problem of donor site morbidity indicating that there is a real need for adequate alternatives. This pilot study aimed to evaluate the usefulness of chitosan (Ch) porous 3D scaffolds incorporated with resolvin D1 (RvD1) as an alternative implant to iliac bone autograft. METHODS: We have performed bilateral posterolateral lumbar vertebral arthrodesis in a rat animal model. Three experimental groups were used: (i) non-operated animals; (ii) animals implanted with Ch scaffolds incorporated with RvD1 and (iii) animals implanted with iliac bone autograft. RESULTS: The collagenous fibrous capsule formed around the Ch scaffolds with RvD1 is less dense when compared with the iliac bone autograft, suggesting an important anti-inflammatory effect of RvD1. Additionally, new bone formation was observed in the Ch scaffolds with RvD1. CONCLUSION: These results demonstrate the potential of these scaffolds for bone tissue repair applications.
Assuntos
Substitutos Ósseos , Quitosana , Fusão Vertebral , Ratos , Animais , Quitosana/farmacologia , Projetos Piloto , Fusão Vertebral/métodos , Vértebras Lombares/cirurgia , Transplante Ósseo/métodosRESUMO
Spinal cord injury (SCI), primarily caused by trauma, leads to permanent and lasting loss of motor, sensory, and autonomic functions. Current therapeutic strategies are focused on mitigating secondary injury, a crucial aspect of SCI pathophysiology. Among these strategies, stem cell therapy has shown considerable therapeutic potential. This study builds on our previous work, which demonstrated the functional recovery and neuronal regeneration capabilities of peripheral nerve-derived stem cell (PNSC) spheroids, which are akin to neural crest stem cells, in SCI models. However, the limited anti-inflammatory capacity of PNSC spheroids necessitates a combined therapeutic approach. As a result, we investigated the potential of co-administering resolvin D1 (RvD1), known for its anti-inflammatory and neuroprotective properties, with PNSC spheroids. In vitro analysis confirmed RvD1's anti-inflammatory activity and its inhibitory effect on pro-inflammatory cytokines. In vivo studies involving a rat SCI model demonstrated that combined therapy of RvD1 and PNSC spheroids outperformed monotherapies, exhibiting enhanced neuronal regeneration and anti-inflammatory effects as validated through behavior tests, quantitative reverse transcription polymerase chain reaction, and immunohistochemistry. Thus, our findings suggest that the combined application of RvD1 and PNSC spheroids may represent a novel therapeutic approach for SCI management.
Assuntos
Traumatismos da Medula Espinal , Ratos , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Nervos Periféricos , Células-Tronco , Medula EspinalRESUMO
It has been proven that neuroinflammation triggered by microglial activation is the pathogenesis of depression associated with sepsis. An endogenous lipid mediator known as resolvin D1 (RvD1) is known to have anti-inflammatory effects in a sepsis model. However, it remains unknown if the effects of RvD1 on inflammatory responses are regulated by microglial autophagy. The current study investigated the role of RvD1-induced microglial autophagy in neuroinflammation. The findings showed that RvD1 reverses LPS-induced autophagy inhibition in microglia. RvD1 treatment significantly inhibits inflammatory responses by preventing NF-κB nuclear translocation and microglial M1 phenotypic transition. RvD1 exhibits an attenuation of neurotoxicity in both in vivo and in vitro models of sepsis. Following RvD1 injection, depressive-like behaviors in SAE mice were significantly improved. Notably, the aforesaid effects of RvD1 were eliminated by 3-MA, demonstrating that microglial autophagy was modulated. In conclusion, our findings shed new light on the involvement of microglial autophagy in SAE and emphasize the potential benefits of RvD1 as a promising therapeutic agent in the treatment of depression.
Assuntos
Sepse , Transdução de Sinais , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Microglia , Doenças NeuroinflamatóriasRESUMO
The liver is a parenchymatous organ closely related to immunity, detoxification and metabolism of the three major nutrients. The inflammatory response is a protective mechanism of the body to eliminate harmful stimuli. However, continuous inflammatory stimulation leads to occurrence of many liver diseases and brings great social burden. Resolvin D1, a member of the specialized pro-resolving lipid mediators family, exerts anti-inflammatory, anti-oxidant stress, anti-fibrosis, anti-apoptotic, and anti-tumor effects by binding to ALX/FPR2 or GPR32. RvD1 plays an important role and has great therapeutic potential in liver diseases, which has been validated in multiple models of preclinical disease. This review will provide a detailed summary of the role of RvD1 in different liver diseases, including acute liver injury, liver ischemia/reperfusion injury, non-alcoholic fatty liver disease, liver fibrosis, and liver cancer, so as to help people have a more comprehensive understanding of RvD1 and promote its further research.
Assuntos
Hepatopatias , Traumatismo por Reperfusão , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Humanos , Hepatopatias/tratamento farmacológico , Traumatismo por Reperfusão/patologiaRESUMO
OBJECTIVE: Periodontal ligament cells (PDLCs) are critical for wound healing and regenerative capacity of periodontal diseases. Within an inflammatory periodontal pocket, a hypoxic environment can aggravate periodontal inflammation, where PDLCs response to the inflammation would change. Resolvin D1 (RvD1) is an endogenous lipid mediator, which can impact intracellular inflammatory pathways of periodontal/oral cells and periodontal regeneration. It is not clear how hypoxia and RvD1 impact the inflammatory responses of pro-inflammatory PDLCs phenotype. Therefore, this study aimed to test hypoxia could induce changes in pro-inflammatory phenotype of PDLCs and RvD1 could reverse it. METHODS: Human PDLCs were cultured from periodontal tissues from eight healthy individuals and were characterized by immunofluorescence staining of vimentin and cytokeratin. Cell viability was examined by Methyl-thiazolyl-tetrazolium (MTT) assay. To examine the effects of hypoxia and RvD1 on the inflammatory responses of pro-inflammatory PDLCs phenotype, protein levels and gene expressions of inflammatory cytokines and signal transduction molecules were measured by enzyme-linked immunosorbent assay (ELISA), western blotting (WB), and real-time quantitative reverse transcription PCR (real-time qRT-PCR). Alizarin red S staining and real-time qRT-PCR were employed to study the effects of hypoxia and RvD1 on the osteogenic differentiation of pro-inflammatory PDLCs phenotype. RESULTS: It was found that hypoxia increases the expression of inflammatory factors at the gene level (p < .05). RvD1 reduced the expression of IL-1ß (p < .05) in PDLCs under hypoxia both at the protein and RNA levels. There were increases in the expression of p38 mitogen-activated protein kinase (p38 MAPK, p < .01) and protein kinase B (Akt, p < .05) in response to RvD1. Also, a significantly higher density of calcified nodules was observed after treatment with RvD1 for 21 days under hypoxia. CONCLUSION: Our results indicate that hypoxia up-regulated the inflammatory level of PDLCs. RvD1 can reduce under-hypoxia-induced pro-inflammatory cytokines in the inflammatory phenotype of PDLCs. Moreover, RvD1 promotes the calcium nodules in PDLCs, possibly by affecting the p38 MAPK signaling pathway through Akt and HIF-1α.
Assuntos
Osteogênese , Ligamento Periodontal , Células Cultivadas , Ácidos Docosa-Hexaenoicos , Humanos , Hipóxia , Inflamação , Fenótipo , Proteínas Proto-Oncogênicas c-akt , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
BACKGROUND: Intestinal fibrosis is the most common complication of inflammatory bowel disease; nevertheless, specific therapies are still unavailable. Resolvin D1 (RvD1), a typical endogenous ω-3 fatty acid-derived lipid mediator, has attracted wide attention due to its remarkable anti-fibrosis effects. However, the efficacy and mechanisms of RvD1 in intestinal fibrosis remain unclear. AIM: To investigate the protective effect of RvD1 in a dextran sulfate sodium (DSS)-induced intestinal fibrosis model and explore the molecular mechanisms underlying its anti-fibrotic effect. METHODS: A DSS-induced intestinal fibrosis model and intestinal epithelial-to-mesenchymal transition (EMT) model were used to observe the efficacy of RvD1, and fibroblasts were stimulated with conditioned medium with or without TGF-ß1 to investigate the probable mechanisms of RvD1 in intestinal fibrosis disease. RESULTS: Intestinal fibrosis was effectively alleviated by RvD1 in a DSS-induced model, both preventively and therapeutically, and autophagy inhibition-induced EMT in intestinal epithelial cells was significantly suppressed in vivo and in vitro. Furthermore, RvD1 reduced epithelial cell EMT paracrine signaling, which promoted the differentiation of local fibroblasts into myofibroblasts. CONCLUSIONS: Our results suggested that RvD1 reduces autophagy-induced EMT in intestinal epithelial cells and ameliorates intestinal fibrosis by disrupting epithelial-fibroblast crosstalk.
Assuntos
Transição Epitelial-Mesenquimal , Fator de Crescimento Transformador beta1 , Autofagia , Colágeno , Meios de Cultivo Condicionados/farmacologia , Sulfato de Dextrana/toxicidade , Ácidos Docosa-Hexaenoicos/farmacologia , Fibrose , Humanos , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
BACKGROUND: Metabolic syndrome (MetS) exacerbates susceptibility to inhalation exposures such as particulate air pollution, however, the mechanisms responsible remain unelucidated. Previously, we determined a MetS mouse model exhibited exacerbated pulmonary inflammation 24 h following AgNP exposure compared to a healthy mouse model. This enhanced response corresponded with reduction of distinct resolution mediators. We hypothesized silver nanoparticle (AgNP) exposure in MetS results in sustained pulmonary inflammation. Further, we hypothesized treatment with resolvin D1 (RvD1) will reduce exacerbations in AgNP-induced inflammation due to MetS. RESULTS: To evaluate these hypotheses, healthy and MetS mouse models were exposed to vehicle (control) or AgNPs and a day later, treated with resolvin D1 (RvD1) or vehicle (control) via oropharyngeal aspiration. Pulmonary lung toxicity was evaluated at 3-, 7-, 14-, and 21-days following AgNP exposure. MetS mice exposed to AgNPs and receiving vehicle treatment, demonstrated exacerbated pulmonary inflammatory responses compared to healthy mice. In the AgNP exposed mice receiving RvD1, pulmonary inflammatory response in MetS was reduced to levels comparable to healthy mice exposed to AgNPs. This included decreases in neutrophil influx and inflammatory cytokines, as well as elevated anti-inflammatory cytokines. CONCLUSIONS: Inefficient resolution may contribute to enhancements in MetS susceptibility to AgNP exposure causing an increased pulmonary inflammatory response. Treatments utilizing specific resolution mediators may be beneficial to individuals suffering MetS following inhalation exposures.
Assuntos
Síndrome Metabólica , Nanopartículas Metálicas , Pneumonia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos , Inflamação/induzido quimicamente , Nanopartículas Metálicas/toxicidade , Camundongos , Pneumonia/induzido quimicamente , Prata/toxicidadeRESUMO
This study evaluated the protective effect of resolvin D1 (RVD1) against cadmium chloride (CdCl2 )-induced hippocampal damage and memory loss in rats and investigated if such protection is mediated by modulating the PTEN/PI3K/Akt/mTOR pathway. Adult male Wistar rats (n = 18/group) were divided as control, control + RVD1, CdCl2 , CdCl2 + RVD1 and CdCl2 + RVD1 + bpV(pic), a PTEN inhibitor. All treatments were conducted for 4 weeks. Resolvin D1 improved the memory function as measured by Morris water maze (MWM), preserved the structure of CA1 area of the hippocampus, and increased hippocampal levels of RVD1 in the CdCl2 -treated rats. Resolvin D1 also suppressed the generation of reactive oxygen species (ROS), tumour necrosis factor-α and interleukine-6 (IL-6), inhibited nuclear factor κB (NF-κB) p65, stimulated levels of glutathione (GSH), manganese superoxide dismutase (MnSOD), and Bcl2 but reduced the expression of Bax and cleaved caspase 3 in hippocampi of CdCl2 -treated rats. Concomitantly, it stimulated levels and activity of PTEN and reduced the phosphorylation (activation) of PI3K, Akt and mTOR in hippocampi of CdCl2 -treated rats. In conclusion, RVD1 attenuates CdCl2 -induced memory loss and hippocampal damage in rats mainly by activating PTEN-induced suppression of PI3K/Akt/mTOR, an effect that seems secondary to its' anti-oxidant and anti-inflammatory potential.
Assuntos
Cloreto de Cádmio , Proteínas Proto-Oncogênicas c-akt , Animais , Cloreto de Cádmio/metabolismo , Cloreto de Cádmio/toxicidade , Ácidos Docosa-Hexaenoicos/farmacologia , Hipocampo , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/prevenção & controle , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Regulação para CimaRESUMO
PURPOSE: The study aims to investigate the role of the lipid mediator resolvin D1 (RvD1) in bacterial keratitis in a murine model. METHODS: The effect of RvD1 on Pseudomonas aeruginosa-stimulated human corneal epithelial cells (HCECs) and mouse macrophages and dendritic cells (DCs) was assessed. C57BL/6 mouse corneas were abraded and treated with RvD1 after stimulation with P. aeruginosa, following which cytokine production level in the cornea and drainage lymph nodes was compared with that in controls. Corneal opacity and thickness were assessed using anterior segment photographs, and optical coherence tomography and corneal infiltrates were analyzed using immunohistochemistry for neutrophils. RESULTS: RvD1 significantly inhibited pro-inflammatory cytokine production in HCECs, mouse macrophages, and DCs. Corneal opacity and corneal thickness were reduced, and the development of corneal infiltrates, specifically neutrophils, was also significantly inhibited by RvD1 in response to stimulation with P. aeruginosa. CONCLUSIONS: RvD1 inhibits P. aeruginosa-induced corneal inflammation. This finding supports a potential therapeutic approach for patients with bacterial keratitis.
Assuntos
Lesões da Córnea , Opacidade da Córnea , Infecções Oculares Bacterianas , Ceratite , Infecções por Pseudomonas , Animais , Citocinas , Ácidos Docosa-Hexaenoicos/farmacologia , Infecções Oculares Bacterianas/microbiologia , Infecções Oculares Bacterianas/prevenção & controle , Humanos , Ceratite/diagnóstico , Ceratite/tratamento farmacológico , Ceratite/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/prevenção & controle , Pseudomonas aeruginosaRESUMO
OBJECTIVE: Osteoarthritis (OA) is a disease characterized by cartilage degradation and structural destruction. Resolvin D1 (RvD1), a specialized proresolving mediator (SPM) derived from omega-3 fatty acids, has been preliminarily proven to show anti-inflammatory and antiapoptotic effects in OA. However, the mechanisms of RvD1 in osteoarthritis fibroblast-like synoviocytes (OA-FLSs) need to be clarified. METHODS: Synovial and fibroblast-like synoviocytes were obtained from OA patients and healthy individuals. MTT and EdU assays were performed to determine cell cytotoxicity and proliferation. The protein expression levels of cyclin D1, cyclin B1, PCNA, p53, MMP-13, YAP, p-YAP, and LATS1 were detected by western blot analysis. The release levels of IL-1ß were detected by ELISA. The cell cycle was assessed by flow cytometry. Immunofluorescence was used to detect the levels of YAP in OA-FLSs. RESULTS: RvD1 inhibited OA-FLS proliferation and reduced MMP-13 and IL-1ß secretion in the concentrations of 20 nM and 200 nM. Furthermore, RvD1 induced G2 cell cycle arrest in OA-FLSs via the Hippo-YAP signaling pathway and promoted YAP phosphorylation. However, RvD1 had no effects on normal FLSs. CONCLUSIONS: RvD1 inhibits OA-FLS proliferation by promoting YAP phosphorylation and protects chondrocytes by inhibiting the secretion of MMP-13 and IL-1ß, providing an experimental basis for RvD1 treatment of OA.
Assuntos
Osteoartrite , Sinoviócitos , Proliferação de Células , Células Cultivadas , Ácidos Docosa-Hexaenoicos , Fibroblastos , Humanos , Osteoartrite/tratamento farmacológico , Transdução de Sinais , Membrana SinovialRESUMO
OBJECTIVE: The aim of this study was to determine the levels of resolvin D1 (RVD1) in the gingival crevicular fluid (GCF) and saliva in the patients with periodontitis and healthy subjects, and also to evaluate the effects of non-surgical periodontal treatments (NSPTs) on RVD1 levels. MATERIALS AND METHODS: Fifteen patients with Stage III Grade B periodontitis (P) and 11 periodontally healthy individuals (H) were included in this study. Clinical periodontal measurements, GCF, and saliva samples were collected from each individual at baseline and 6 weeks after NSPTs in periodontitis group. GCF and saliva levels of RVD1 were analyzed by enzyme-linked immunosorbent assay. RESULTS: GCF total and concentration levels of RVD1 were significantly lower in the periodontitis group than in the healthy group and significantly increased after NSPTs in periodontitis (p < 0.001). There was no statistically significant difference in saliva RVD1 levels between healthy and periodontitis group and also before and after NSPTs in periodontitis (p > 0.05). Significant negative correlations were found between all periodontal clinical parameters and GCF volume with both GCF total amount and concentrations of RVD1 (p < 0.01). There was a positive correlation between GCF total amount and concentrations of RVD1 (r = 0.762, p < 0.01). CONCLUSIONS: GCF levels of RVD1 might be promising biomarkers for monitoring the susceptibility to periodontitis and predicting periodontal status. CLINICAL RELEVANCE: RVD1 may be valuable biomarker to observe the healing process after periodontal treatment as increased GCF levels might project clinical improvements post-treatment. Accordingly, observing GCF RVD1 levels might be helpful to determine individuals require further periodontal treatment.
Assuntos
Periodontite Crônica , Biomarcadores/análise , Periodontite Crônica/terapia , Ácidos Docosa-Hexaenoicos , Líquido do Sulco Gengival/química , HumanosRESUMO
BACKGROUND: Resolvin D1 (RvD1) can play a determining role in inflammatory cell migration and reduce the expression of inflammatory cytokines to enhance cardioprotection. The aim of this study was to compare serum RvD1 levels in patients with ST-segment elevation myocardial infarction (STEMI) and individuals with normal coronary arteries (NCAs) and to evaluate the association between serum RvD1 levels and prognostic markers of STEMI. METHODS: 140 subjects (88 patients diagnosed with the indication of STEMI and 52 healthy individuals with NCA) were studied. RESULTS: Regression analysis revealed that RvD1 levels were independently associated with STEMI. While RvD1 levels were negatively correlated with high-sensitivity C-reactive protein, pro-brain natriuretic peptide, peak troponin, and Thrombolysis in Myocardial Infarction thrombus grade, they were positively correlated with left ventricular ejection fraction. An RvD1 cut-off value of 5.07 (ng/mL) was effective in predicting STEMI with a sensitivity of 79.5% and specificity of 96.2%. CONCLUSION: Serum RvD1 levels were found to be lower in the group with STEMI compared to the control group. Levels of RvD1 at admission were associated with poor prognostic markers of STEMI.
Assuntos
Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Volume Sistólico , Biomarcadores , Função Ventricular Esquerda , PrognósticoRESUMO
Cardiac fibroblasts (CFs) have a key role in the inflammatory response after cardiac injury and are necessary for wound healing. Resolvins are potent agonists that control the duration and magnitude of inflammation. They decrease mediators of pro-inflammatory expression, reduce neutrophil migration to inflammation sites, promote the removal of microbes and apoptotic cells, and reduce exudate. However, whether resolvins can prevent pro-inflammatory-dependent effects in CFs is unknown. Thus, the present work was addressed to study whether resolvin D1 and E1 (RvD1 and RvE1) can prevent pro-inflammatory effects on CFs after lipopolysaccharide (LPS) challenge. For this, CFs were stimulated with LPS, in the presence or absence of RvD1 or RvE1, to analyze its effects on intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion protein 1 (VCAM-1), monocyte adhesion and the cytokine levels of tumor necrosis factor alpha (TNF-α), interleukin-6(IL-6), interleukin-1beta (IL-1ß), monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10). Our results showed that CFs are expressing ALX/FPR2 and ChemR23, RvD1 and RvE1 receptors, respectively. RvD1 and RvE1 prevent the increase of ICAM-1 and VCAM-1 protein levels and the adhesion of spleen mononuclear cells to CFs induced by LPS. Finally, RvD1, but not RvE1, prevents the LPS-induced increase of IL-6, MCP-1, TNF-α, and IL-10. In conclusion, our findings provide evidence that in CFs, RvD1 and RvE1 might actively participate in the prevention of inflammatory response triggered by LPS.
Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/análogos & derivados , Traumatismos Cardíacos/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Movimento Celular/efeitos dos fármacos , Citocinas/genética , Ácido Eicosapentaenoico/farmacologia , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Traumatismos Cardíacos/induzido quimicamente , Traumatismos Cardíacos/patologia , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-1beta/genética , Lipopolissacarídeos/toxicidade , Neutrófilos/efeitos dos fármacos , Ratos , Fator de Necrose Tumoral alfa/genética , Molécula 1 de Adesão de Célula Vascular/genética , Cicatrização/efeitos dos fármacosRESUMO
Resolvin D1 (RvD1) is an endogenous lipid mediator that originated from docosahexaenoic acid that stimulates a bimodal mechanism in the anti-inflammatory activity in addition to regulation of the inflammatory reaction. The study aimed at assessing the tissue level of RvD1 in psoriasis to study its role in the etiopathogenesis of psoriasis, studying the action of NB-UVB on the level of resolvin D1 in psoriasis, and raising the possibility of using resolvin D1 as a new therapy for psoriasis in the future. This case-control study included 20 psoriasis patients and 20 healthy controls. Patients took narrowband ultraviolet B (NB-UVB) for 36 sessions. Skin biopsies were taken before and after treatment from patients and from controls to assess the expression of RvD1 by a quantitative real-time polymerase chain reaction. Our findings revealed a statistically significant difference (P < .001) between psoriasis patients (either before or after treatment) and controls with lower levels of RvD1 in psoriasis patients. On comparing the RvD1 levels in psoriasis patients before and after treatment, a statistically significant increase was detected after treatment (P < .001). Tissue RvD1 levels in psoriasis patients were lower than healthy controls and increased after NB-UVB treatment in psoriasis patients. Thus, it is suggested that RvD1 might have a role in the etiopathogenesis of psoriasis. Moreover, the significantly up-regulated tissue levels of RvD1 in patients after treatment with NB-UVB highlighted a novel mechanism of phototherapy-mediated response in psoriasis by up-regulating RvD1 level.