RESUMEN
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.
Asunto(s)
Ácidos Docosahexaenoicos , Eicosanoides , Humanos , Inflamación/tratamiento farmacológico , Mediadores de InflamaciónRESUMEN
Infections, including zoonoses, constitute a threat to human health due to the spread of resistant pathogens. These diseases generate an inflammatory response controlled by a resolving mechanism involving specialized membrane lipid-derived molecules called lipoxins, resolvins, maresins, and protectins. The production of some of these molecules can be triggered by aspirin or statins. Thus, it is proposed that modulation of the host response could be a useful therapeutic strategy, contributing to the management of resistance to antiparasitic agents or preventing drift to chronic, host-damaging courses. Therefore, the present work presents the state of the art on the use of statins or aspirin for the experimental management of parasitic infections such as Chagas disease, leishmaniasis, toxoplasmosis or malaria. The methodology used was a narrative review covering original articles from the last seven years, 38 of which met the inclusion criteria. Based on the publications consulted, modulation of the resolution of inflammation using statins may be feasible as an adjuvant in the therapy of parasitic diseases. However, there was no strong experimental evidence on the use of aspirin; therefore, further studies are needed to evaluate its role inflammation resolution process in infectious diseases.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Enfermedades Parasitarias , Animales , Humanos , Aspirina/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Ácidos Docosahexaenoicos/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/prevención & control , Enfermedades Parasitarias/tratamiento farmacológico , Enfermedades Parasitarias/prevención & controlRESUMEN
Inflammation plays a critical role in the response to and survival from injuries and/or infections. It occurs in two phases: initiation and resolution; however, when these events do not resolve and persist over time, the inflammatory response becomes chronic, prompting diseases that affect several systems and organs, such as the vasculature and the skin. Here, we reviewed inflammation that occurs in selected infectious and sterile pathologies. Thus, the immune processes induced by bacterial sepsis as well as T. cruzi and SARS-CoV-2 infections are shown. In addition, vaccine adjuvants as well as atherosclerosis are revised as examples of sterile-mediated inflammation. An example of the consequences of a lack of inflammation resolution is given through the revision of wound healing and chronic wounds. Then, we revised the resolution of the latter through advanced therapies represented by cell therapy and tissue engineering approaches, showing how they contribute to control chronic inflammation and therefore wound healing. Finally, new pharmacological insights into the management of chronic inflammation addressing the resolution of inflammation based on pro-resolving mediators, such as lipoxin, maresin, and resolvins, examining their biosynthesis, biological properties, and pharmacokinetic and pharmaceuticals limitations, are given. We conclude that resolution pharmacology and advanced therapies are promising tools to restore the inflammation homeostasis.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Lipoxinas , Ácidos Docosahexaenoicos/uso terapéutico , Humanos , Inflamación/patología , Mediadores de Inflamación/uso terapéutico , Preparaciones Farmacéuticas , SARS-CoV-2RESUMEN
PURPOSE: Clinically, it is challenging to manage diabetic patients with periodontitis. Biochemically, both involve a wide range of inflammatory/collagenolytic conditions which exacerbate each other in a "bi-directional manner." However, standard treatments for this type of periodontitis rely on reducing the bacterial burden and less on controlling hyper-inflammation/excessive-collagenolysis. Thus, there is a crucial need for new therapeutic strategies to modulate this excessive host response and to promote enhanced resolution of inflammation. The aim of the current study is to evaluate the impact of a novel chemically-modified curcumin 2.24 (CMC2.24) on host inflammatory response in diabetic rats. METHODS: Type I diabetes was induced by streptozotocin injection; periodontal breakdown then results as a complication of uncontrolled hyperglycemia. Non-diabetic rats served as controls. CMC2.24, or the vehicle-alone, was administered by oral gavage daily for 3 weeks to the diabetics. Micro-CT was used to analyze morphometric changes and quantify bone loss. MMPs were analyzed by gelatin zymography. Cell function was examined by cell migration assay, and cytokines and resolvins were measured by ELISA. RESULTS: In this severe inflammatory disease model, administration of the pleiotropic CMC2.24 was found to normalize the excessive accumulation and impaired chemotactic activity of macrophages in peritoneal exudates, significantly decrease MMP-9 and pro-inflammatory cytokines to near normal levels, and markedly increase resolvin D1 (RvD1) levels in the thioglycolate-elicited peritoneal exudates (tPE). Similar effects on MMPs and RvD1 were observed in the non-elicited resident peritoneal washes (rPW). Regarding clinical relevance, CMC2.24 significantly inhibited the loss of alveolar bone height, volume and mineral density (ie, diabetes-induced periodontitis and osteoporosis). CONCLUSION: In conclusion, treating hyperglycemic diabetic rats with CMC2.24 (a tri-ketonic phenylaminocarbonyl curcumin) promotes the resolution of local and systemic inflammation, reduces bone loss, in addition to suppressing collagenolytic MMPs and pro-inflammatory cytokines, suggesting a novel therapeutic strategy for treating periodontitis complicated by other chronic diseases.
RESUMEN
AIM: To investigate the presence of resolvins E1 (RvE1) and D2 (RvD2) in teeth with primary endodontic infections and apical periodontitis, and to assess the influence of calcium hydroxide medication [Ca(OH)2 ], in association with 2% chlorhexidine gel (2% CHX gel), and N-acetylcysteine (NAC) on the levels of RvE1 and RvD2 in periapical tissues. METHODOLOGY: Thirty-six single-rooted teeth with primary endodontic infections and apical periodontitis were selected and randomly divided into three groups according to the medication: [Ca(OH)2 ] + saline solution (SSL) [Ca(OH)2 + SSL group] (n = 12), Ca(OH)2 + 2% chlorhexidine gel [Ca(OH)2 + 2% CHX gel group] (n = 12) and NAC [NAC group] (n = 12). Samples were collected from the periapical interstitial fluid at two different sampling times: before (S1) and after 14 days of intracanal medications (S2). Resolvins were measured using the enzyme-linked immunosorbent assay. Data were analysed using paired t-test, Wilcoxon test and Kruskal-Wallis test, followed by Dunn's post hoc test; all statistical tests were performed at a significance level of 5%. RESULTS: RvE1 and RvD2 were detected in 100% of the samples (36/36) at S1 and S2. Ca(OH)2 medication did not increase the levels of RvE1 or RvD2 (both P > 0.05); however, NAC significantly increased the levels of RvE1 and RvD2 after 14 days of treatment (P < 0.05). CONCLUSIONS: RvE1 and RvD2 were detected in periapical tissues from teeth with root canal infections. Moreover, calcium hydroxide medication did not increase the levels of resolvins in apical periodontitis. In contrast, the use of NAC intracanal medication significantly increased the levels of RvE1 and RvD2 after 14 days of treatment.
Asunto(s)
Hidróxido de Calcio , Periodontitis Periapical , Acetilcisteína , Clorhexidina , Cavidad Pulpar , Humanos , Periodontitis Periapical/tratamiento farmacológico , Irrigantes del Conducto Radicular , Preparación del Conducto RadicularRESUMEN
High-fat diet (HFD)-fed mice show obesity with development of liver steatosis and a proinflammatory state without establishing an inflammatory reaction. The aim of this work was to assess the hypothesis that eicosapentaenoic acid (EPA) plus hydroxytyrosol (HT) supplementation prevents the inflammatory reaction through enhancement in the hepatic resolvin content in HFD-fed mice. Male C57BL/6J mice were fed an HFD or a control diet and supplemented with EPA (50 mg/kg/day) and HT (5 mg/kg/day) or their respective vehicles for 12 weeks. Measurements include liver levels of EPA, DHA and palmitate (gas chromatography), liver resolvins and triglyceride (TG) and serum aspartate transaminase (AST) (specific kits) and hepatic and serum inflammatory markers (quantitative polymerase chain reaction and enzyme-linked immunosorbent assay). Compared to CD, HFD induced body weight gain, liver steatosis and TG accumulation, with up-regulation of proinflammatory markers in the absence of histological inflammation or serum AST changes; these results were accompanied by higher hepatic levels of resolvins RvE1, RvE2, RvD1 and RvD2, with decreases in EPA and DHA contents. EPA+HT supplementation in HFD feeding synergistically reduced the steatosis score over individual treatments and increased the hepatic levels of EPA, DHA and resolvins, with attenuation of proinflammatory markers. Lack of progression of HFD-induced proinflammatory state into overt inflammation is associated with resolvin up-regulation, which is further increased by EPA+HT supplementation eliciting steatosis attenuation. These findings point to the importance of combined protocols in hepatoprotection due to the involvement of cross-talk mechanisms, which increase effectiveness and diminish dosages, avoiding undesirable effects.
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Dieta Alta en Grasa/efectos adversos , Ácido Eicosapentaenoico/farmacología , Hepatitis/dietoterapia , Hígado/efectos de los fármacos , Alcohol Feniletílico/análogos & derivados , Animales , Suplementos Dietéticos , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Ácidos Grasos/metabolismo , Hepatitis/etiología , Hepatitis/metabolismo , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Alcohol Feniletílico/farmacologíaRESUMEN
Sepsis is a big health problem and one of the most common causes of acute lung injury (ALI) leading to high mortality. Pro-resolving mediators play an important role in abrogating the inflammation and promoting tissue homeostasis restoration. ALI treatment is still a clinical health problem, so new therapies are needed. Here, we evaluated the effect of photobiomodulation treatment on the resolution process of ALI induced by lipopolysaccharide (LPS). Male Balb/c mice were submitted to LPS (ip) or vehicle and irradiated or not with light emitting diode (LED) 2 and 6 h after LPS or vehicle injection, and the parameters were investigated 3 and 7 days after the injections. Our results showed that after 3 days of LED treatment the blood and bronchoalveolar lavage (BAL) cells as well as interleukins (IL) including IL-6 and IL-17 were reduced. No differences were observed in the bone marrow cells, tracheal reactivity, and lipoxin A4 and resolvin E2. Indeed, after 7 days of LED treatment the bone marrow cells, lymphocytes, and lipoxin A4 were increased, while IL-6, IL-17, and IL-10 were decreased. No differences were observed in the blood cells and tracheal reactivity. Thus, our results showed that LED treatment attenuated ALI induced by sepsis by modulating the cell mobilization from their reserve compartments. In addition, we also showed later effects of the LED up to 7 days after the treatment. This study proposes photobiomodulation as therapeutic adjuvant to treat ALI.
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Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/radioterapia , Inflamación/radioterapia , Terapia por Luz de Baja Intensidad , Sepsis/complicaciones , Animales , Médula Ósea/patología , Médula Ósea/efectos de la radiación , Lavado Broncoalveolar , Movimiento Celular/efectos de la radiación , Colinérgicos/farmacología , Citocinas/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Inflamación/patología , Lipopolisacáridos , Lipoxinas/metabolismo , Pulmón/patología , Pulmón/efectos de la radiación , Masculino , Ratones Endogámicos BALB C , Contracción Muscular/efectos de la radiación , Músculo Liso/fisiopatología , Músculo Liso/efectos de la radiaciónRESUMEN
Pathogenic trypanosomatids (Trypanosoma cruzi, Trypanosoma brucei, and Leishmania spp.) are protozoan parasites that cause neglected diseases affecting millions of people in Africa, Asia, and the Americas. In the process of infection, trypanosomatids evade and survive the immune system attack, which can lead to a chronic inflammatory state that induces cumulative damage, often killing the host in the long term. The immune mediators involved in this process are not entirely understood. Most of the research on the immunologic control of protozoan infections has been focused on acute inflammation. Nevertheless, when this process is not terminated adequately, permanent damage to the inflamed tissue may ensue. Recently, a second process, called resolution of inflammation, has been proposed to be a pivotal process in the control of parasite burden and establishment of chronic infection. Resolution of inflammation is an active process that promotes the normal function of injured or infected tissues. Several mediators are involved in this process, including eicosanoid-derived lipids, cytokines such as transforming growth factor (TGF)-ß and interleukin (IL)-10, and other proteins such as Annexin-V. For example, during T. cruzi infection, pro-resolving lipids such as 15-epi-lipoxin-A4 and Resolvin D1 have been associated with a decrease in the inflammatory changes observed in experimental chronic heart disease, reducing inflammation and fibrosis, and increasing host survival. Furthermore, Resolvin D1 modulates the immune response in cells of patients with Chagas disease. In Leishmania spp. infections, pro-resolving mediators such as Annexin-V, lipoxins, and Resolvin D1 are related to the modulation of cutaneous manifestation of the disease. However, these mediators seem to have different roles in visceral or cutaneous leishmaniasis. Finally, although T. brucei infections are less well studied in terms of their relationship with inflammation, it has been found that arachidonic acid-derived lipids act as key regulators of the host immune response and parasite burden. Also, cytokines such as IL-10 and TGF-ß may be related to increased infection. Knowledge about the inflammation resolution process is necessary to understand the host-parasite interplay, but it also offers an interesting opportunity to improve the current therapies, aiming to reduce the detrimental state induced by chronic protozoan infections.
RESUMEN
Inflammatory bowel diseases are chronic diseases divided into two major forms, ulcerative colitis and Crohn's disease, which are both associated with a chronic inflammatory condition of the gastrointestinal tract. Recent studies have shown that the resolution of inflammatory conditions is a biosynthetically active process where new pro-resolution lipid mediators derived from omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), such as E- and D-series resolvins, protectins, and macrophage mediator in resolving inflammation (maresins), have potent anti-inflammatory activity and serve as specialised mediators that play an important role in the resolution of inflammation. Recent studies have also shown the role of resolvins in referred hyperalgesia associated with different inflammatory processes, such as the visceral pain caused by inflammatory bowel disease. There are many reports describing the principal effects of EPA- and DHA-derived mediators in experimental models of inflammatory bowel diseases. This review focuses on the recent studies on the important role played by pro-resolution lipid mediators in controlling the inflammatory process associated with inflammatory bowel diseases.
Asunto(s)
Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Enfermedades Inflamatorias del Intestino/metabolismo , Animales , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/fisiopatología , Nocicepción , Dolor Visceral/complicacionesRESUMEN
This study investigated whether the spinal or systemic treatment with the lipid resolution mediators resolvin D1 (RvD1), aspirin-triggered resolvin D1 (AT-RvD1) and resolvin D2 (RvD2) might interfere with behavioral and neurochemical changes in the mouse fibromyalgia-like model induced by reserpine. Acute administration of AT-RvD1 and RvD2 produced a significant inhibition of mechanical allodynia and thermal sensitization in reserpine-treated mice, whereas RvD1 was devoid of effects. A similar antinociceptive effect was obtained by acutely treating animals with the reference drug pregabalin. Noteworthy, the repeated administration of AT-RvD1 and RvD2 also prevented the depressive-like behavior in reserpine-treated animals, according to assessment of immobility time, although the chronic administration of pregabalin failed to affect this parameter. The induction of fibromyalgia by reserpine triggered a marked decrease of dopamine and serotonin (5-HT) levels, as examined in total brain, spinal cord, cortex and thalamus. Reserpine also elicited a reduction of glutamate levels in total brain, and a significant increase in the spinal cord and thalamus. Chronic treatment with RvD2 prevented 5-HT reduction in total brain, and reversed the glutamate increases in total brain and spinal cord. Otherwise, AT-RvD1 led to a recovery of dopamine levels in cortex, and 5-HT in thalamus, whilst it diminished brain glutamate contents. Concerning pregabalin, this drug prevented dopamine reduction in total brain, and inhibited glutamate increase in brain and spinal cord of reserpine-treated animals. Our data provide novel evidence, showing the ability of D-series resolvins AT-RvD1, and mainly RvD2, in reducing painful and depressive symptoms allied to fibromyalgia in mice.
Asunto(s)
Analgésicos/farmacología , Antidepresivos/farmacología , Ácidos Docosahexaenoicos/farmacología , Fibromialgia/tratamiento farmacológico , Fibromialgia/fisiopatología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Depresión/tratamiento farmacológico , Depresión/fisiopatología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Ácido Glutámico/metabolismo , Calor , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Masculino , Ratones , Dolor Nociceptivo/tratamiento farmacológico , Dolor Nociceptivo/fisiopatología , Pregabalina , Serotonina/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiopatología , Tacto , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
A inflamação é uma resposta de defesa do organismo ao trauma ou a infecções por microorganismos. Na fase de término da inflamação e retorno à homeostase ocorrem mecanismos de regulação chamados de resolução onde há alternância de prostaglandinas pró-inflamatórias e leucotrienos a mediadores pró-resolução, produzidos a partir de ácidos graxos poliinsaturados ω3 (ácido eicosapentanóico e ácido docosapentanóico). A dieta interfere na composição de ácidos graxos das membranas celulares que serão metabolizados em compostos ativos chamados de resolvinas, protectinas e maresinas. Como as doenças inflamatórias têm papel importante na saúde pública o estudo destas substâncias e o delineamento de seus efeitos podem trazer novos horizontes no tratamento das doenças inflamatórias, com redução de custos e minimização de efeitos colaterais.
Inflammation is a defensive response to the trauma, infections or injury to the organism. When inflammation is ending occurs a program for active regulation called the resolution. This is accompanied by a class of lipid mediators where there is alternation of pro-inflammatory prostaglandins and leukotrienes to proresolution mediators, produced from 3 polyunsaturated fatty acids (eicosapentaenoic and docosapentanoicacid). The diet interferes the fatty acid composition of cell membranes that will be metabolized to active compounds called resolvins, protectins and maresins. The inflammatory diseases have an important rolein public health, so the study of these substances and delineation of their effects can bring new horizons in the treatment of inflammatory diseases, reducing costs and minimizing side effects.