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INTRODUCTION: Influenza A is a virus from the Orthomixoviridae family responsible for high lethality rates and morbidity, despite clinically proven vaccination strategies and some anti-viral therapies. The eicosanoid Lipoxin A4 (LXA4) promotes the resolution of inflammation by decreasing cell recruitment and pro-inflammatory cytokines release, but also for inducing activation of apoptosis, efferocytosis, and macrophage reprogramming. OBJECTIVE: Here, we evaluated whether a synthetic lipoxin mimetic, designated AT-01-KG, would improve the course of influenza A infection in a murine model. METHOD: Mice were infected with influenza A/H1N1 and treated with AT-01-KG (1.7 µg/kg/day, i.p.) at day 3 post-infection. RESULTS: AT-01-KG attenuated mortality, reducing leukocyte infiltration and lung damage at day 5 and day 7 post-infection. AT-01-KG is a Formyl Peptide Receptor 2 (designated FPR2/3 in mice) agonist, and the protective responses were not observed in fpr2/3 -/- animals. In mice treated with LXA4 (50 µg/kg/day, i.p., days 3-6 post-infection), at day 7, macrophage reprogramming was observed, as seen by a decrease in classically activated macrophages and an increase in alternatively activated macrophages in the lungs. Furthermore, the number of apoptotic cells and cells undergoing efferocytosis was increased in the lavage of treated mice. Treatment also modulated the adaptive immune response, increasing the number of T helper 2 cells (Th2) and regulatory T (Tregs) cells in the lungs of the treated mice. CONCLUSION: Therefore, treatment with a lipoxin A4 analog was beneficial in a model of influenza A infection in mice. The drug decreased inflammation and promoted resolution and beneficial immune responses, suggesting it may be useful in patients with severe influenza.
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Protectin DX (PDX), a specialized pro-resolving lipid mediator, presents potential therapeutic applications across various medical conditions due to its anti-inflammatory and antioxidant properties. Since type-1 diabetes mellitus (T1DM) is a disease with an inflammatory and oxidative profile, exploring the use of PDX in addressing T1DM and its associated comorbidities, including diabetic neuropathic pain, depression, and anxiety becomes urgent. Thus, in the current study, after 2 weeks of T1DM induction with streptozotocin (60 mg/kg) in Wistar rats, PDX (1, 3, and 10 ng/animal; i.p. injection of 200 µl/animal) was administered specifically on days 14, 15, 18, 21, 24, and 27 after T1DM induction. We investigated the PDX's effectiveness in alleviating neuropathic pain (mechanical allodynia; experiment 1), anxiety-like and depressive-like behaviors (experiment 2). Also, we studied whether the PDX treatment would induce antioxidant effects in the blood plasma, hippocampus, and prefrontal cortex (experiment 3), brain areas involved in the modulation of emotions. For evaluating mechanical allodynia, animals were repeatedly submitted to the Von Frey test; while for studying anxiety-like responses, animals were submitted to the elevated plus maze (day 26) and open field (day 28) tests. To analyze depressive-like behaviors, the animals were tested in the modified forced swimming test (day 28) immediately after the open field test. Our data demonstrated that PDX consistently increased the mechanical threshold throughout the study at the two highest doses, indicative of antinociceptive effect. Concerning depressive-like and anxiety-like behavior, all PDX doses effectively prevented these behaviors when compared to vehicle-treated T1DM rats. The PDX treatment significantly protected against the increased oxidative stress parameters in blood plasma and in hippocampus and prefrontal cortex. Interestingly, treated animals presented improvement on diabetes-related parameters by promoting weight gain and reducing hyperglycemia in T1DM rats. These findings suggest that PDX improved diabetic neuropathic pain, and induced antidepressant-like and anxiolytic-like effects, in addition to improving parameters related to the diabetic condition. It is worth noting that PDX also presented a protective action demonstrated by its antioxidant effects. To conclude, our findings suggest PDX treatment may be a promising candidate for improving the diabetic condition per se along with highly disabling comorbidities such as diabetic neuropathic pain and emotional disturbances associated with T1DM.
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Ansiedade , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Ácidos Docosa-Hexaenoicos , Ratos Wistar , Animais , Masculino , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/psicologia , Ratos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/psicologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Depressão/tratamento farmacológico , Depressão/etiologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Hiperalgesia/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Neuropatias Diabéticas/tratamento farmacológicoRESUMO
The complex interplay between dietary factors, inflammation, and macrophage polarization is pivotal in the pathogenesis and progression of chronic liver diseases (CLDs). Omega-3 fatty acids (FAs) have brought in attention due to their potential to modulate inflammation and exert protective effects in various pathological conditions. Omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown promise in mitigating inflammation and enhancing the resolution of inflammatory responses. They influence the M1/M2 macrophage phenotype balance, promoting a shift towards the M2 anti-inflammatory phenotype. Specialized pro-resolving mediators (SPMs), such as resolvins (Rvs), protectins (PDs), and maresins (MaRs), have emerged as potent regulators of inflammation and macrophage polarization. They show anti-inflammatory and pro-resolving properties, by modulating the expression of cytokines, facilitate the phagocytosis of apoptotic cells, and promote tissue repair. MaR1, in particular, has demonstrated significant hepatoprotective effects by promoting M2 macrophage polarization, reducing oxidative stress, and inhibiting key inflammatory pathways such as NF-κB. In the context of CLDs, such as nonalcoholic fatty liver disease (NAFLD) and cirrhosis, omega-3s and their SPMs have shown promise in attenuating liver injury, promoting tissue regeneration, and modulating macrophage phenotypes. The aim of this article was to analyze the emerging role of omega-3 FAs and their SPMs in the context of macrophage polarization, with special interest in the mechanisms underlying their effects and their interactions with other cell types within the liver microenvironment, focused on CLDs and the development of novel therapeutic strategies.
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Ácidos Graxos Ômega-3 , Hepatopatias , Humanos , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Macrófagos/metabolismo , Inflamação/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Anti-Inflamatórios/uso terapêutico , Hepatopatias/metabolismo , Fenótipo , Mediadores da Inflamação/metabolismoRESUMO
Docosahexaenoic acid (C22:6n-3, DHA) is the precursor of specialized pro-resolving lipid mediators (SPMs), such as resolvin, protectin, and maresin families which have been considered therapeutic bioactive compounds for human health. Growing evidence indicates that DHA and SPMs are beneficial strategies in the amelioration, regulation, and duration of inflammatory processes through different biological actions. The present review discusses the reported therapeutic benefits of SPMs on various diseases and their potential clinical applications.
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Ácidos Docosa-Hexaenoicos , Eicosanoides , Humanos , Inflamação/tratamento farmacológico , Mediadores da InflamaçãoRESUMO
Prior research demonstrated that glucagon has protective roles against inflammation, but its effect on the resolution of inflammation remains elusive. Using in vitro and in vivo approaches, this study aimed to investigate the pro-resolving potential of glucagon on pulmonary neutrophilic inflammation caused by lipopolysaccharide. Lipopolysaccharide induced an increase in the proportions of neutrophils positives to glucagon receptor (GcgR) in vitro. In addition, lipopolysaccharide induced an increase in the neutrophil accumulation and expression of GcgR by the inflammatory cells in the lungs, however, without altering glucagon levels. Intranasal treatment with glucagon, at the peak of neutrophilic inflammation, reduced the neutrophil number in the bronchoalveolar lavage (BAL), and lung tissue within 24 h. The reduction of neutrophilic inflammation provoked by glucagon was accompanied by neutrophilia in the blood, an increase in the apoptosis rate of neutrophils in the BAL, enhance in the pro-apoptotic Bax protein expression, and decrease in the anti-apoptotic Bcl-2 protein levels in the lung. Glucagon also induced a rise in the cleavage of caspase-3 in the lungs; however, it was not significant. Glucagon inhibited the levels of IL-1ß and TNF-α while increasing the content of pro-resolving mediators transforming growth factor (TGF-ß1) and PGE2 in the BAL and lung. Finally, glucagon inhibited lipopolysaccharide-induced airway hyper-reactivity, as evidenced by the reduction in lung elastance values in response to methacholine. In conclusion, glucagon-induced resolution of neutrophilic inflammation by promoting cessation of neutrophil migration and a rise of neutrophil apoptosis and the levels of pro-resolving mediators TGF-ß1 and PGE2.
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Glucagon , Lipopolissacarídeos , Camundongos , Animais , Lipopolissacarídeos/farmacologia , Glucagon/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Dinoprostona/farmacologia , Pulmão , Inflamação/metabolismo , Neutrófilos/metabolismoRESUMO
Resolvin D5 (RvD5) is a specialized pro-resolving lipid mediator with potent anti-inflammatory and analgesic properties. Orofacial pain conditions, especially those that are chronic, present clinical challenges in terms of pharmacological management. Thus, new therapeutic options are clearly warranted. Herein, we investigated the antinociceptive effect of RvD5 in the chronic constriction injury of the infraorbital nerve (CCI-ION) model and in the orofacial formalin test in female and male Wistar rats. Our results indicated that repeated subarachnoid medullary injections of RvD5 at 10 ng resulted in a significant reduction of heat and mechanical hyperalgesia induced by the CCI-ION in male and female rats, but males were more sensitive to RvD5 effects. In addition, after CCI-ION, interleukin-6 (IL-6) level was increased in the trigeminal nucleus caudalis of male, but not female rats, which was reduced by RvD5 repeated treatment. No changes in the levels of IL-1ß were found. Minocycline blocked the effect of RvD5 in male rats but failed to affect RvD5 antinociceptive effect in females. Moreover, a single medullary injection of RvD5 caused a significant reduction of formalin-induced facial grooming, in phases I and II of the test, but only in male rats. This study demonstrated for the first time the analgesic effect of RvD5 in trigeminal pain models, and corroborated previous evidence of sex dichotomy, with a greater effect in males. This article presents a translational potential of RvD5 for targeted therapies aiming at the control of acute and chronic trigeminal pain, but further studies are needed to elucidate its sex-related mechanisms. PERSPECTIVE: This study demonstrated that RvD5 may provide the benefits for trigeminal neuropathic pain treatment in male and female rats, but its effect on inflammatory orofacial pain seems to be restricted only to males. Also, it provided the evidence for sex dichotomy in the mechanisms related to the antinociceptive effect of RvD5.
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Analgesia , Dor Crônica , Feminino , Ratos , Masculino , Animais , Caracteres Sexuais , Ratos Sprague-Dawley , Ratos Wistar , Dor Facial/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Analgésicos/uso terapêutico , Dor Crônica/tratamento farmacológico , Modelos Animais de DoençasRESUMO
Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by autoantibody production and synovial membrane damage. It significantly impairs overall function and quality of life. Consumption of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and regular aerobic exercise (AEx) training are reported to have positive effects on the progression of RA. However, the mechanisms behind these benefits are still inconclusive. This study protocol will investigate the effects of n-3 PUFA supplementation and AEx training on disease progression, cardiometabolic health, and quality of life, and their association with the plasma and synovial fluid levels of specialized pro-resolving mediators (SPMs) in subjects with RA. Methods: The study consists of a 16-week intervention period, during which participants will be randomly assigned in a double-blinded manner to one of four groups: placebo control (PLA), PLA+AEx, n-3, or n-3+AEx. The PLA groups will be given a gelatin-filled capsule, while the n-3 groups will be given n-3 PUFAs equivalent to 2.5 g/d of docosahexaenoic acid and 0.5 g/d of eicosapentaenoic acid. The AEx groups will perform exercise three times per week on a stationary electronically braked cycle ergometer at 60-70% of their VO2peak for 50-60 minutes. Before and after the intervention, participants will undergo RA-specific and functional measurements, peak aerobic capacity test, and a dietary and physical activity assessment. Venous blood and synovial fluid from the knee joint will be collected. Changes in disease progression, cardiometabolic health, and quality of life, as well as erythrocyte membrane composition to assess n-3 incorporation, SPM levels, inflammatory markers, and gene expression from blood and synovial fluid will be analyzed. Conclusions: The study aims to elucidate the SPMs that regulate the inflammatory gene expression pathways and associate them with the improvements in disease progression, cardiometabolic health, and quality of life after n-3 PUFA supplementation and AEx training. Registration: ClinicalTrials.gov #NCT05945693.
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Artrite Reumatoide , Suplementos Nutricionais , Progressão da Doença , Exercício Físico , Ácidos Graxos Ômega-3 , Inflamação , Qualidade de Vida , Humanos , Artrite Reumatoide/tratamento farmacológico , Ácidos Graxos Ômega-3/uso terapêutico , Ácidos Graxos Ômega-3/administração & dosagem , Método Duplo-Cego , Masculino , Feminino , Pessoa de Meia-Idade , AdultoRESUMO
INTRODUCTION: Pain is a multidimensional experience involving the biological, psychological, and social dimensions of each individual. Particularly, the biological aspects of pain conditions are a response of the neuroimmunology system and the control of painful conditions is a worldwide challenge for researchers. Although years of investigation on pain experience and treatment exist, the high prevalence of chronic pain is still a fact. AREAS COVERED: Peroxisome proliferator-activated receptor-gamma (PPARγ) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. It regulates several metabolic pathways, including lipid biosynthesis and glucose metabolism, when activated. However, PPARγ activation also has a critical immunomodulatory and neuroprotective effect. EXPERT OPINION: This review summarizes the evidence of synthetic or natural PPARγ ligands such as 15d-PGJ2, epoxyeicosatrienoic acids, thiazolidinediones, and specialized pro-resolving mediators, representing an interesting therapeutic tool for pain control.
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Imunomodulação , PPAR gama , Humanos , Imunomodulação/efeitos dos fármacos , Imunomodulação/fisiologia , Ligantes , PPAR gama/metabolismo , Dor , Prostaglandina D2/metabolismo , Tiazolidinedionas/uso terapêuticoRESUMO
Oxylipins play a critical role in regulating the onset and resolution phase of inflammation. Despite inflammation is a pathological hallmark in amyotrophic lateral sclerosis (ALS), the plasma oxylipin profile of ALS patients has not been assessed yet. Herein, we develop an oxylipin profile-targeted analysis of plasma from 74 ALS patients and controls. We found a significant decrease in linoleic acid-derived oxylipins in ALS patients, including 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE. These derivatives have been reported as important regulators of inflammation on different cell systems. In addition, some 5-lipoxygenase metabolites, such as 5-hydroxy- eicosatetraenoic acid also showed a significant decrease in ALS plasma samples. Isoprostanes of the F2α family were detected only in ALS patients but not in control samples, while the hydroxylated metabolite 11-HETE significantly decreased. Despite our effort to analyze specialized pro-resolving mediators, they were not detected in plasma samples. However, we found the levels of 14-hydroxy-docosahexaenoic acid, a marker pathway of the Maresin biosynthesis, were also reduced in ALS patients, suggesting a defective activation in the resolution programs of inflammation in ALS. We further analyze oxylipin concentration levels in plasma from ALS patients to detect correlations between these metabolites and some clinical parameters. Interestingly, we found that plasmatic levels of 13-HODE and 9-HODE positively correlate with disease duration, expressed as days since onset. In summary, we developed a method to analyze "(oxy)lipidomics" in ALS human plasma and found new profiles of metabolites and novel lipid derivatives with unknown biological activities as potential footprints of disease onset.
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Inflammation is an essential reaction of the immune system to infections and sterile tissue injury. However, uncontrolled or unresolved inflammation can cause tissue damage and contribute to the pathogenesis of various inflammatory diseases. Resolution of inflammation is driven by endogenous molecules, known as pro-resolving mediators, that contribute to dampening inflammatory responses, promoting the resolution of inflammation and the recovery of tissue homeostasis. These mediators have been shown to be useful to decrease inflammatory responses and tissue damage in various models of inflammatory diseases. Graft-versus-host disease (GVHD) is a major unwanted reaction following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is characterized by an exacerbated inflammatory response provoked by antigen disparities between transplant recipient and donor. There is no fully effective treatment or prophylaxis for GVHD. This review explores the effects of several pro-resolving mediators and discusses their potential use as novel therapies in the context of GVHD.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doença Aguda , Animais , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Inflamação/imunologia , Inflamação/terapia , Transplante HomólogoRESUMO
The term cardiovascular diseases (CVD) refers to disorders of heart and blood vessels, and include coronary heart disease, cerebrovascular disease, peripheral vascular disease, and heart failure, among others. Atherosclerosis is a common background of these diseases. It is not infrequent that some acute diseases, such as coronary syndromes, appear superimposed on a chronic arterial disease. Acute coronary syndromes (ACS), found worldwide among the leading causes of death, can be the origin of disabling chronic CVD such as heart failure [46]. Clinical and experimental evidence associates this group of alterations with an inflammatory process that takes part in its pathophysiology. In fact, inflammation is one of the most important factors for its initiation, progression, and consolidation [6].
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Biomarcadores , Cardiopatias , Inflamação , Síndrome Coronariana Aguda , Animais , Aterosclerose , Biomarcadores/sangue , Doença Crônica , Cardiopatias/diagnóstico , Cardiopatias/fisiopatologia , HumanosRESUMO
In patients with Alzheimer's disease (AD), a persistent and unresolved neuroinflammatory process can contribute to neuronal loss and a decline in their cognitive and functional abilities. Recent studies have demonstrated that the ability to resolve inflammation is impaired in the brains of patients with AD. Preclinical evidence demonstrates the potential of therapeutic interventions on the resolution phase of inflammation in AD. Supplementation of omega-3 fatty acids (n-3 FAs), precursors for specialized pro-resolving mediators, emerged as a possibility for prevention and management of AD. Here, we provide a narrative review of resolving inflammation in AD and the role of n-3 FA supplementation in AD.
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Doença de Alzheimer/complicações , Suplementos Nutricionais , Encefalite/dietoterapia , Encefalite/etiologia , Ácidos Graxos Ômega-3/metabolismo , Doença de Alzheimer/prevenção & controle , Animais , HumanosRESUMO
Preeclampsia (PE) is one of the leading causes of maternal morbidity and mortality worldwide. This disease is believed to occur in two stages with placental dysfunction in early pregnancy leading to maternal clinical findings after 20 weeks of gestation, as consequence of systemic inflammation, oxidative stress, and endothelial dysfunction. Much evidence suggests that PE women display an overshooting inflammatory response throughout pregnancy due to an unbalanced regulation of innate and adaptive immune responses. Recently, it has been suggested that dysregulation of endogenous protective pathways might be associated with PE etiopathogenesis. Resolution of inflammation is an active process coordinated by mediators from diverse nature that regulate key cellular events to restore tissue homeostasis. Inadequate or insufficient resolution of inflammation is believed to play an important role in the development of chronic inflammatory diseases, like PE. In this narrative review, we discuss possible pro-resolution pathways that might be compromised in PE women, which could be targets to novel therapeutic strategies in this disease.