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Innate immunity is present in all animals. In this review, we explore the main conserved mechanisms of recognition and innate immune responses among animals. In this sense, we discuss the receptors, critical for binding to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs); the downstream signaling proteins; and transcription factors that govern immune responses. We also highlight conserved inflammatory mediators that are induced after the recognition of DAMPs and PAMPs. At last, we discuss the mechanisms that are involved in the regulation and/or generation of reactive oxygen species (ROS), influencing immune responses, like heme-oxygenases (HOs).
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Imunidade Inata , Moléculas com Motivos Associados a Patógenos , Animais , Imunidade Inata/genética , Alérgenos , Fatores de Transcrição , Proteínas de TransporteRESUMO
Cancer is a process involving cell mutation, increased proliferation, invasion, and metastasis. Over the years, this condition has represented one of the most concerning health problems worldwide due to its significant morbidity and mortality. At present, the incidence of cancer continues to grow exponentially. Thus, it is imperative to open new avenues in cancer research to understand the molecular changes driving DNA transformation, cell-to-cell interaction derangements, and immune system surveillance decay. In this regard, evidence supports the relationship between chronic inflammation and cancer. In light of this, a group of bioactive lipids derived from polyunsaturated fatty acids (PUFAs) may have a position as novel anti-inflammatory molecules known as the specialized pro-resolving mediators (SPMs), a group of pro-resolutive inflammation agents that could improve the anti-tumor immunity. These molecules have the potential role of chemopreventive and therapeutic agents for various cancer types, and their effects have been documented in the scientific literature. Thus, this review objective centers around understanding the effect of SPMs on carcinogenesis and their potential therapeutic effect.
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Carcinogênese , Inflamação , Humanos , Comunicação Celular , Vigilância Imunológica , LipídeosRESUMO
INTRODUCTION: Gout arthritis (GA) is an intermittent inflammatory disease affecting approximately 10% of the worldwide population. Symptomatic phases (acute flares) are timely spaced by asymptomatic periods. During an acute attack, redness, joint swelling, limited movement, and excruciating pain are common symptoms. However, the current available therapies are not fully effective in reducing symptoms and offer numerous side effects. Therefore, unveiling new drug targets and effector molecules are required in developing novel GA therapeutics. AREAS COVERED: This review discusses the pathophysiological mechanisms of GA and explores potential pharmacological targets to ameliorate disease outcome. In addition, we listed promising pre-clinical studies demonstrating effector molecules with therapeutical potential. Among those, we emphasized the importance of natural products, including traditional Chinese medicine formulas and their multitarget mechanisms of action. EXPERT OPINION: In our search, we observed that there is a massive gap between pre-clinical and clinical knowledge. Only a minority (4.4%) of clinical trials aimed to intervene by applying natural products or current hot targets described herein. In this sense, we envisage four possibilities for GA therapeutics, which include the repurposing of existing therapies, ALX/FPR2 agonism for improvement in disease outcome, the use of multitarget drugs (e.g. natural products), and targeting the neuroinflammatory component of GA.
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Produtos Biológicos , Gota , Humanos , Gota/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêuticoRESUMO
Objective: Supervised exercise therapy (SET) is the first line treatment for intermittent claudication owing to peripheral arterial disease. Despite multiple randomized controlled trials proving the efficacy of SET, there are large differences in individual patient's responses. We used plasma metabolomics to identify potential metabolic influences on the individual response to SET. Methods: Primary metabolites, complex lipids, and lipid mediators were measured on plasma samples taken at before and after Gardner graded treadmill walking tests that were administered before and after 12 weeks of SET. We used an ensemble modeling approach to identify metabolites or changes in metabolites at specific time points that associated with interindividual variability in the functional response to SET. Specific time points analyzed included baseline metabolite levels before SET, dynamic metabolomics changes before SET, the difference in pre- and post-SET baseline metabolomics, and the difference (pre- and post-SET) of the dynamic (pre- and post-treadmill). Results: High levels of baseline anandamide levels pre- and post-SET were associated with a worse response to SET. Increased arachidonic acid (AA) and decreased levels of the AA precursor dihomo-γ-linolenic acid across SET were associated with a worse response to SET. Participants who were able to tolerate large increases in AA during acute exercise had longer, or better, walking times both before and after SET. Conclusions: We identified two pathways of relevance to individual response to SET that warrant further study: anandamide synthesis may activate endocannabinoid receptors, resulting in worse treadmill test performance. SET may train patients to withstand higher levels of AA, and inflammatory signaling, resulting in longer walking times. Clinical Relevance: This manuscript describes the use of metabolomic techniques to measure the interindividual effects of SET in patients with peripheral artery disease (PAD). We identified high levels of AEA are linked to CB1 signaling and activation of inflammatory pathways. This alters energy expenditure in myoblasts by decreasing glucose uptake and may induce an acquired skeletal muscle myopathy. SET may also help participants tolerate increased levels of AA and inflammation produced during exercise, resulting in longer walking times. This data will enhance understanding of the pathophysiology of PAD and the mechanism by which SET improves walking intolerance.
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Background: Oxidized lipid mediators such as eicosanoids play a central role in the inflammatory response associated with tuberculosis (TB) pathogenesis. Diabetes mellitus (DM) leads to marked changes in lipid mediators in persons with TB. However, the associations between diabetes-related changes in lipid mediators and clearance of M. tuberculosis (Mtb) among persons on anti-TB treatment (ATT) are unknown. Quantification of urinary eicosanoid metabolites can provide insights into the circulating lipid mediators involved in Mtb immune responses. Methods: We conducted a multi-site prospective observational study among adults with drug-sensitive pulmonary TB and controls without active TB; both groups had sub-groups with or without dysglycemia at baseline. Participants were enrolled from RePORT-Brazil (Salvador site) and RePORT-South Africa (Durban site) and stratified according to TB status and baseline glycated hemoglobin levels: a) TB-dysglycemia (n=69); b) TB-normoglycemia (n=64); c) non-TB/dysglycemia (n=31); d) non-TB/non-dysglycemia (n=29). We evaluated the following urinary eicosanoid metabolites: 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (major urinary metabolite of prostaglandin E2, PGE-M), tetranor-PGE1 (metabolite of PGE2, TN-E), 9α-hydroxy-11,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (metabolite of PGD2, PGD-M), 11-dehydro-thromboxane B2 (11dTxB2), 2,3-dinor-6-keto-PGF1α (prostaglandin I metabolite, PGI-M), and leukotriene E4 (LTE4). Comparisons between the study groups were performed at three time points: before ATT and 2 and 6 months after initiating therapy. Results: PGE-M and LTE4 values were consistently higher at all three time-points in the TB-dysglycemia group compared to the other groups (p<0.001). In addition, there was a significant decrease in PGI-M and LTE4 levels from baseline to month 6 in the TB-dysglycemia and TB-normoglycemia groups. Finally, TB-dysglycemia was independently associated with increased concentrations of PGD-M, PGI-M, and LTE4 at baseline in a multivariable model adjusting for age, sex, BMI, and study site. These associations were not affected by HIV status. Conclusion: The urinary eicosanoid metabolite profile was associated with TB-dysglycemia before and during ATT. These observations can help identify the mechanisms involved in the pathogenesis of TB-dysglycemia, and potential biomarkers of TB treatment outcomes, including among persons with dysglycemia.
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Mycobacterium tuberculosis , Tuberculose Pulmonar , Adulto , Dinoprostona , Eicosanoides , Humanos , África do Sul , Tuberculose Pulmonar/tratamento farmacológicoRESUMO
Type 1 diabetes mellitus (T1DM) is a chronic disease related to a persistent inflammatory process reaching the central nervous system, which leads to psychiatric comorbidities such as depression and anxiety. The search for new therapeutic agents effective in alleviating the psychiatric condition associated with T1DM becomes critical. Using an animal model of T1DM, we aimed to evaluate the effect of a specific specialized pro-resolving lipid mediator Resolvin D5 (RvD5), in preventing behaviors related to depression and anxiety, investigating its influence on inflammasome in interleukin (IL)-1ß in the hippocampus and prefrontal cortex. After experimental T1DM induction with streptozotocin (60 mg/kg, i.p.), these animals were treated for 23 days and randomly divided into 6 subgroups according to the treatment: vehicle (VEH), the antidepressant Fluoxetine (FLX; 10 mg/kg), the nonsteroidal anti-inflammatory Ibuprofen (IBU; 30 mg/kg) or Resolvin D5 (RvD5; 1 3, or 10 ng/animal). As a control group for the experimental-T1DM condition, a group of normoglycemic animals treated with VEH underwent the same behavioral tests: elevated plus maze, open field, and modified forced swimming tests. In the end, hippocampus and prefrontal cortex samples were processed to analyze the pro-inflammatory cytokine IL-1ß levels. Our data showed that RvD5 treatment prevented the more pronounced anxious-like and reduced the depressive-like behaviors of experimental-T1DM animals and significantly improved the plasma glucose levels. Additionally, RvD5 treatment prevented the increased level of pro-inflammatory cytokine IL-1ß in the hippocampus and prefrontal cortex of experimental-T1DM rats. To conclude, RvD5 presents a preventive therapeutic potential in impairing the development of the emotional complications resulting from T1DM. This potential may be related to its protective profile, as demonstrated in this study by its pro-resolutive action on neuroinflammation in the hippocampus and prefrontal cortex.
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Diabetes Mellitus Tipo 1 , Animais , Ansiedade/tratamento farmacológico , Comportamento Animal , Citocinas , Depressão/tratamento farmacológico , Depressão/etiologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos , Hipocampo , RatosRESUMO
To become resistant, cancer cells need to activate and maintain molecular defense mechanisms that depend on an energy trade-off between resistance and essential functions. Metabolic reprogramming has been shown to fuel cell growth and contribute to cancer drug resistance. Recently, changes in lipid metabolism have emerged as an important driver of resistance to anticancer agents. In this review, we highlight the role of choline metabolism with a focus on the phosphatidylcholine cycle in the regulation of resistance to therapy. We analyze the contribution of phosphatidylcholine and its metabolites to intracellular processes of cancer cells, both as the major cell membrane constituents and source of energy. We further extended our discussion about the role of phosphatidylcholine-derived lipid mediators in cellular communication between cancer and immune cells within the tumor microenvironment, as well as their pivotal role in the immune regulation of therapeutic failure. Changes in phosphatidylcholine metabolism are part of an adaptive program activated in response to stress conditions that contribute to cancer therapy resistance and open therapeutic opportunities for treating drug-resistant cancers.
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Antineoplásicos , Neoplasias , Comunicação Celular , Humanos , Neoplasias/terapia , Fosfatidilcolinas , Microambiente TumoralRESUMO
The resolution of inflammation is an active process, guided by specialized pro-resolution lipid mediators (SPMs). These mediators originate from polyunsaturated fatty acids, such as omega-3. Sufficient evidence suggests that the beneficial effects attributed to omega-3 are, at least in part, the result of the immunomodulatory action of the SPMs, which act systemically by overcoming inflammation and repairing tissue damage, without suppressing the immune response. Recent studies suggest that an imbalance in the synthesis and/or activity of these compounds may be associated with the pathogenesis of several inflammatory conditions, such as inflammatory bowel disease (IBD). Thus, this review highlights the advances made in recent years with regard to the endo-genous synthesis and the biological role of lipoxins, resolvins, protectins, and maresins, as well as their precursors, in the regulation of inflammation; and provides an update on the participation of these mediators in the development and evolution of IBD and the therapeutic approaches that these immunomodulating substances are involved in this context.
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Lipokines are bioactive compounds, derived from adipose tissue depots, that control several molecular signaling pathways. Recently, 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), an oxylipin, has gained prominence in the scientific literature. An increase in circulating 12,13-diHOME has been associated with improved metabolic health, and the action of this molecule appears to be mediated by brown adipose tissue (BAT). Scientific evidence indicates that the increase in serum levels of 12,13-diHOME caused by stimuli such as physical exercise and exposure to cold may favor the absorption of fatty acids by brown adipose tissue and stimulate the browning process in white adipose tissue (WAT). Thus, strategies capable of increasing 12,13-diHOME levels may be promising for the prevention and treatment of obesity and metabolic diseases. This review explores the relationship of 12,13-diHOME with brown adipose tissue and its role in the metabolic health context, as well as the signaling pathways involved between 12,13-diHOME and BAT.
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Tecido Adiposo Marrom/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Ácidos Oleicos/metabolismo , Tecido Adiposo Branco/metabolismo , Humanos , Terapia de Alvo Molecular , Ácidos Oleicos/sangue , Ácidos Oleicos/farmacologia , Oxilipinas/metabolismoRESUMO
Pooled evidence conveys the association between polyunsaturated fatty acids and infectious disease. SARS-CoV-2, an enveloped mRNA virus, was also reported to interact with polyunsaturated fatty acids. The present review explores the possible mode of action, immunology, and consequences of these polyunsaturated fatty acids during the viral infection. Polyunsaturated fatty acids control protein complex formation in lipid rafts associated with the function of two SARS-CoV-2 entry gateways: angiotensin-converting enzyme-2 and cellular protease transmembrane protease serine-2. Therefore, the viral entry can be mitigated by modulating polyunsaturated fatty acids contents in the body. α-Linolenic acid is the precursor of two clinically important eicosanoids eicosapentaenoic acid and docosahexaenoic acid, the members of ω-3 fats. Resolvins, protectins, and maresins derived from docosahexaenoic acid suppress inflammation and augment phagocytosis that lessens microbial loads. Prostaglandins of 3 series, leukotrienes of 5 series, and thromboxane A3 from eicosapentaenoic acid exhibit anti-inflammatory, vasodilatory, and platelet anti-aggregatory effects that may also contribute to the control of pre-existing pulmonary and cardiac diseases. In contrast, ω-6 linoleic acid-derived arachidonic acid increases the prostaglandin G2, lipoxins A4 and B4, and thromboxane A2. These cytokines are pro-inflammatory and enhance the immune response but aggravate the COVID-19 severity. Therefore, the rational intake of ω-3-enriched foods or supplements might lessen the complications in COVID-19 and might be a preventive measure.
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Phospholipases A2s (PLA2s) constitute one of the major protein groups present in the venoms of viperid and crotalid snakes. Snake venom PLA2s (svPLA2s) exhibit a remarkable functional diversity, as they have been described to induce a myriad of toxic effects. Local inflammation is an important characteristic of snakebite envenomation inflicted by viperid and crotalid species and diverse svPLA2s have been studied for their proinflammatory properties. Moreover, based on their molecular, structural, and functional properties, the viperid svPLA2s are classified into the group IIA secreted PLA2s, which encompasses mammalian inflammatory sPLA2s. Thus, research on svPLA2s has attained paramount importance for better understanding the role of this class of enzymes in snake envenomation and the participation of GIIA sPLA2s in pathophysiological conditions and for the development of new therapeutic agents. In this review, we highlight studies that have identified the inflammatory activities of svPLA2s, in particular, those from Bothrops genus snakes, which are major medically important snakes in Latin America, and we describe recent advances in our collective understanding of the mechanisms underlying their inflammatory effects. We also discuss studies that dissect the action of these venom enzymes in inflammatory cells focusing on molecular mechanisms and signaling pathways involved in the biosynthesis of lipid mediators and lipid accumulation in immunocompetent cells.
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Venenos de Crotalídeos/enzimologia , Venenos de Crotalídeos/toxicidade , Inflamação , Fosfolipases A2/toxicidade , Animais , Bothrops , Humanos , Mediadores da Inflamação , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/imunologia , Transdução de SinaisRESUMO
Chronic pain (CP) is a severe clinical entity with devastating physical and emotional consequences for patients, which can occur in a myriad of diseases. Often, conventional treatment approaches appear to be insufficient for its management. Moreover, considering the adverse effects of traditional analgesic treatments, specialized pro-resolving lipid mediators (SPMs) have emerged as a promising alternative for CP. These include various bioactive molecules such as resolvins, maresins, and protectins, derived from ω-3 polyunsaturated fatty acids (PUFAs); and lipoxins, produced from ω-6 PUFAs. Indeed, SPMs have been demonstrated to play a central role in the regulation and resolution of the inflammation associated with CP. Furthermore, these molecules can modulate neuroinflammation and thus inhibit central and peripheral sensitizations, as well as long-term potentiation, via immunomodulation and regulation of nociceptor activity and neuronal pathways. In this context, preclinical and clinical studies have evidenced that the use of SPMs is beneficial in CP-related disorders, including rheumatic diseases, migraine, neuropathies, and others. This review integrates current preclinical and clinical knowledge on the role of SPMs as a potential therapeutic tool for the management of patients with CP.
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Dor Crônica/metabolismo , Dor Crônica/terapia , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Mediadores da Inflamação/metabolismo , Manejo da Dor , Animais , HumanosRESUMO
Systemic increased inflammatory mediators' levels are a hallmark in a plethora of pathological conditions, including thrombotic diseases as the envenomation by Bothrops lanceolatus snake. Multiple organ infarctions, which are not prevented by anticoagulant therapy, are the main cause of death on this envenomation. However, the potential mechanisms involved in these systemic reactions are underexplored. This study aimed to explore the potential systemic events which could contribute to thrombotic reactions on the envenomation by B. lanceolatus in an ex vivo human whole-blood model. B. lanceolatus venom elicited an inflammatory reaction, which was characterized by a strong complement activation, since we detected high C3a, C4a and C5a anaphylatoxins levels. Besides, the venom promoted soluble Terminal Complement Complex (sTCC) assembly. Complement activation was accompanied by intense lipid mediators' release, which included LTB4, PGE2 and TXB2. In addition, in the blood exposed to B. lanceolatus venom, we detected IL-1ß, IL-6 and TNF-α interleukins production. Chemokines, including CCL2, CCL5 and CXCL8 were upregulated in the venom presence. These outcomes show that B. lanceolatus venom causes a strong inflammatory reaction in the blood favoring a potential setting to thrombi formation. Thus, inhibiting inflammatory mediators or their receptors may help in the envenomed patients' management.
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Bothrops , Venenos de Crotalídeos/toxicidade , Mediadores da Inflamação/metabolismo , Inflamação/etiologia , Animais , Humanos , Inflamação/patologia , Mediadores da Inflamação/sangue , Trombose/etiologia , Trombose/patologiaRESUMO
Phospholipases A2s (PLA2s) constitute one of the major protein groups present in the venoms of viperid and crotalid snakes. Snake venom PLA2s (svPLA2s) exhibit a remarkable functional diversity, as they have been described to induce a myriad of toxic effects. Local inflammation is an important characteristic of snakebite envenomation inflicted by viperid and crotalid species and diverse svPLA2s have been studied for their proinflammatory properties. Moreover, based on their molecular, structural, and functional properties, the viperid svPLA2s are classified into the group IIA secreted PLA2s, which encompasses mammalian inflammatory sPLA2s. Thus, research on svPLA2s has attained paramount importance for better understanding the role of this class of enzymes in snake envenomation and the participation of GIIA sPLA2s in pathophysiological conditions and for the development of new therapeutic agents. In this review, we highlight studies that have identified the inflammatory activities of svPLA2s, in particular, those from Bothrops genus snakes, which are major medically important snakes in Latin America, and we describe recent advances in our collective understanding of the mechanisms underlying their inflammatory effects. We also discuss studies that dissect the action of these venom enzymes in inflammatory cells focusing on molecular mechanisms and signaling pathways involved in the biosynthesis of lipid mediators and lipid accumulation in immunocompetent cells.
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Systemic increased inflammatory mediators’ levels are a hallmark in a plethora of pathological conditions, including thrombotic diseases as the envenomation by Bothrops lanceolatus snake. Multiple organ infarctions, which are not prevented by anticoagulant therapy, are the main cause of death on this envenomation. However, the potential mechanisms involved in these systemic reactions are underexplored. This study aimed to explore the potential systemic events which could contribute to thrombotic reactions on the envenomation by B. lanceolatus in an ex vivo human whole-blood model. B. lanceolatus venom elicited an inflammatory reaction, which was characterized by a strong complement activation, since we detected high C3a, C4a and C5a anaphylatoxins levels. Besides, the venom promoted soluble Terminal Complement Complex (sTCC) assembly. Complement activation was accompanied by intense lipid mediators’ release, which included LTB4, PGE2 and TXB2. In addition, in the blood exposed to B. lanceolatus venom, we detected IL-1β, IL-6 and TNF-α interleukins production. Chemokines, including CCL2, CCL5 and CXCL8 were upregulated in the venom presence. These outcomes show that B. lanceolatus venom causes a strong inflammatory reaction in the blood favoring a potential setting to thrombi formation. Thus, inhibiting inflammatory mediators or their receptors may help in the envenomed patients’ management.
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Bitis arietans is a snake of medical importance, as it is responsible for more accidents in humans and domestic animals than all other African snakes put together. The accidents are characterized by local and systemic alterations, such as inflammation, cardiovascular and hemostatic disturbances, which can lead victims to death or permanent disability. However, little is known about the envenomation mechanism, especially regarding the inflammatory response, which is related to severe clinical conditions triggered by the venom. Therefore, the aim of the present study was to evaluate the inflammatory response related to the B. arietans envenomation using a peritonitis mice model. By pharmacological interventions and use of mice genetically deficient of the 5-lipoxygenase enzyme (5-LO-/-) or platelet-activating factor (PAF) receptor (PAFR-/- the participation of eicosanoids and PAF in this response was also investigated. The obtained results demonstrated that the venom induces an in vivo inflammatory response, characterized by an early increased vascular permeability, followed by an accumulation of polymorphonuclear (PMN) cells in the peritoneal cavity, accompanied by the production of the eicosanoids LTB4, LTC4, TXB2 and PGE2, as well as the local and systemic production of IL-6 and MCP-1. These inflammatory events were attenuated by the pre-treatment with anti-inflammatory drugs that interfere in lipid mediators' functions. However, 5-LO-/- mice did not show a reduction of inflammatory response induced by the venom, while PAFR-/- mice showed a reduction in both the PMN leukocytes number and the local and systemic production of IL-6 and MCP-1. This study demonstrated that the Bitis arietans venom contains toxins that trigger an inflammatory process, which is partially dependent on lipid mediators, and may contribute to the envenomation pathology.
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Mediadores da Inflamação/metabolismo , Leucotrienos/metabolismo , Neutrófilos/metabolismo , Peritonite/metabolismo , Prostaglandinas/metabolismo , Mordeduras de Serpentes/metabolismo , Venenos de Víboras/metabolismo , Viperidae/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/metabolismo , Permeabilidade Capilar , Modelos Animais de Doenças , Feminino , Metabolismo dos Lipídeos , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Peritonite/tratamento farmacológico , Peritonite/imunologia , Glicoproteínas da Membrana de Plaquetas/genética , Glicoproteínas da Membrana de Plaquetas/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Mordeduras de Serpentes/tratamento farmacológico , Mordeduras de Serpentes/imunologiaRESUMO
Signaling lipid mediators released from 5 lipoxygenase (5LO) pathways influence both bone and muscle cells, interfering in their proliferation and differentiation capacities. A major limitation to studying inflammatory signaling pathways in bone and muscle healing is the inadequacy of available animal models. We developed a surgical injury model in the vastus lateralis (VL) muscle and femur in 129/SvEv littermates mice to study simultaneous musculoskeletal (MSK) healing in male and female, young (3 months) and aged (18 months) WT mice compared to mice lacking 5LO (5LOKO). MSK defects were surgically created using a 1-mm punch device in the VA muscle followed by a 0.5-mm round defect in the femur. After days 7 and 14 post-surgery, the specimens were removed for microtomography (microCT), histopathology, and immunohistochemistry analyses. In addition, non-injured control skeletal muscles along with femur and L5 vertebrae were analyzed. Bones were microCT phenotyped, revealing that aged female WT mice presented reduced BV/TV and trabecular parameters compared to aged males and aged female 5LOKO mice. Skeletal muscles underwent a customized targeted lipidomics investigation for profiling and quantification of lipid signaling mediators (LMs), evidencing age, and gender related-differences in aged female 5LOKO mice compared to matched WT. Histological analysis revealed a suitable bone-healing process with osteoid deposition at day 7 post-surgery, followed by woven bone at day 14 post-surgery, observed in all young mice. Aged WT females displayed increased inflammatory response at day 7 post-surgery, delayed bone matrix maturation, and increased TRAP immunolabeling at day 14 post-surgery compared to 5LOKO females. Skeletal muscles of aged animals showed higher levels of inflammation in comparison to young controls at day 14 post-surgery; however, inflammatory process was attenuated in aged 5LOKO mice compared to aged WT. In conclusion, this new model shows that MSK healing is influenced by age, gender, and the 5LO pathway, which might serve as a potential target to investigate therapeutic interventions and age-related MSK diseases. Our new model is suitable for bone-muscle crosstalk studies.
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Araquidonato 5-Lipoxigenase/fisiologia , Doenças Ósseas/terapia , Osso e Ossos/lesões , Modelos Anatômicos , Músculo Esquelético/lesões , Doenças Musculares/terapia , Cicatrização , Fatores Etários , Animais , Doenças Ósseas/etiologia , Doenças Ósseas/patologia , Osso e Ossos/patologia , Osso e Ossos/cirurgia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/cirurgia , Doenças Musculares/etiologia , Doenças Musculares/patologia , Fatores SexuaisRESUMO
Oxylipins are oxidized compounds of polyunsaturated fatty acids that play important roles in the body. Recently, metabololipidomic-based studies using advanced mass spectrometry have measured the oxylipins generated during acute and chronic physical exercise and described the related physiological effects. The objective of this systematic review was to provide a panel of the primary exercise-related oxylipins and their respective functions in healthy individuals. Searches were performed in five databases (Cochrane, PubMed, Science Direct, Scopus and Web of Science) using combinations of the Medical Subject Headings (MeSH) terms: "Humans", "Exercise", "Physical Activity", "Sports", "Oxylipins", and "Lipid Mediators". An adapted scoring system created in a previous study from our group was used to rate the quality of the studies. Nine studies were included after examining 1749 documents. Seven studies focused on the acute effect of physical exercise while two studies determined the effects of exercise training on the oxylipin profile. Numerous oxylipins are mobilized during intensive and prolonged exercise, with most related to the inflammatory process, immune function, tissue repair, cardiovascular and renal functions, and oxidative stress.
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Excessive exposure to UV, especially UVB, is the most important risk factor for skin cancer and premature skin aging. The identification of the specialized pro-resolving lipid mediators (SPMs) challenged the preexisting paradigm of how inflammation ends. Rather than a passive process, the resolution of inflammation relies on the active production of SPMs, such as Lipoxins (Lx), Maresins, protectins, and Resolvins. LXA4 is an SPM that exerts its action through ALX/FPR2 receptor. Stable ALX/FPR2 agonists are required because SPMs can be quickly metabolized within tissues near the site of formation. BML-111 is a commercially available synthetic ALX/FPR2 receptor agonist with analgesic, antioxidant, and anti-inflammatory properties. Based on that, we aimed to determine the effect of BML-111 in a model of UVB-induced skin inflammation in hairless mice. We demonstrated that BML-111 ameliorates the signs of UVB-induced skin inflammation by reducing neutrophil recruitment and mast cell activation. Reduction of these cells by BML-111 led to lower number of sunburn cells formation, decrease in epidermal thickness, collagen degradation, cytokine production (TNF-α, IL-1ß, IL-6, TGF, and IL-10), and oxidative stress (observed by an increase in total antioxidant capacity and Nrf2 signaling pathway), indicating that BML-111 might be a promising drug to treat skin disorders.
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Dermatite/prevenção & controle , Ácidos Heptanoicos/administração & dosagem , Protetores contra Radiação/administração & dosagem , Receptores de Lipoxinas/antagonistas & inibidores , Animais , Antígenos CD59/metabolismo , Dermatite/etiologia , Dermatite/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Relação Dose-Resposta a Droga , Ácidos Heptanoicos/farmacologia , Lipoxinas/metabolismo , Camundongos , Camundongos Pelados , Protetores contra Radiação/farmacologia , Raios Ultravioleta/efeitos adversosRESUMO
Poorly controlled diabetes mellitus leads to several comorbidities, including susceptibility to infections. Hyperglycemia increases phagocyte responsiveness, however immune cells from people with diabetes show inadequate antimicrobial functions. We and others have shown that aberrant production of leukotriene B4 (LTB4) is detrimental to host defense in models of bacterial infection. Here, we will unveil the consequences of high glucose in the outcome of Leishmania braziliensis skin infection in people with diabetes and determine the role of LTB4 in human phagocytes. We show that diabetes leads to higher systemic levels of LTB4, IL-6 and TNF-α in cutaneous leishmaniasis. Only LTB4 correlated with blood glucose levels and healing time in diabetes comorbidity. Skin lesions of people with leishmaniasis and diabetes exhibit increased neutrophil and amastigote numbers. Monocyte-derived macrophages from these individuals showed higher L. braziliensis loads, reduced production of Reactive Oxygen Species and unbalanced LTB4/PGE2 ratio. Our data reveal a systemic inflammation driven by diabetes comorbidity in opposition to a local reduced capacity to resolve L. braziliensis infection and a worse disease outcome.