Brominated indoles from a marine mollusc inhibit inflammation in a murine model of acute lung injury.
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ABSTRACT:
SUBMITTER: Ahmad TB
PROVIDER: S-EPMC5658094 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Marine molluscs are rich in biologically active natural products that provide new potential sources of anti-inflammatory agents. Here we used bioassay guided fractionation of extracts from the muricid Dicathais orbita to identify brominated indoles with anti-inflammatory activity, based on the inhibition of nitric oxide (NO) and tumour necrosis factor ? (TNF?) in lipopolysaccharide (LPS) stimulated RAW264.7 macrophages and prostaglandin E2 (PGE2) in calcium ionophore-stimulated 3T3 ccl-92 fibroblasts. Muricid brominated indoles were then compared to a range of synthetic indoles to determine structure-activity relationships. Both hypobranchial gland and egg extracts inhibited the production of NO significantly with IC50 of 30.8 and 40 ?g/mL, respectively. The hypobranchial gland extract also inhibited the production of TNF? and PGE2 with IC50 of 43.03 µg/mL and 34.24 µg/mL, respectively. The purified mono-brominated indole and isatin compounds showed significant inhibitory activity against NO, TNF?, and PGE2, and were more active than dimer indoles and non-brominated isatin. The position of the bromine atom on the isatin benzene ring significantly affected the activity, with 5Br > 6Br > 7Br. The mode of action for the active hypobranchial gland extract, 6-bromoindole, and 6-bromoisatin was further tested by the assessment of the translocation of nuclear factor kappa B (NF?B) in LPS-stimulated RAW264.7 mouse macrophage. The extract (40 µg/mL) significantly inhibited the translocation of NF?B in the LPS-stimulated RAW264.7 macrophages by 48.2%, whereas 40 µg/mL of 6-bromoindole and 6-bromoistain caused a 60.7% and 63.7% reduction in NF?B, respectively. These results identify simple brominated indoles as useful anti-inflammatory drug leads and support the development of extracts from the Australian muricid D. orbita, as a new potential natural remedy for the treatment of inflammation.
| S-EPMC5450539 | biostudies-literature
Project description:Inflammation plays an important role in different chronic diseases. Brominated indoles derived from the Australian marine mollusk Dicathais orbita (D. orbita) are of interest for their anti-inflammatory properties. This study evaluates the binding mechanism and potentiality of several brominated indoles (tyrindoxyl sulfate, tyrindoleninone, 6-bromoisatin, and 6,6′-dibromoindirubin) against inflammatory mediators cyclooxygenases-1/2 (COX-1/2) using molecular docking, followed by molecular dynamics simulation, along with physicochemical, drug-likeness, pharmacokinetic (pk), and toxicokinetic (tk) properties. Molecular docking identified that these indole compounds are anchored, with the main amino acid residues, positioned in the binding pocket of the COX-1/2, required for selective inhibition. Moreover, the molecular dynamics simulation based on root mean square deviation (RMSD), radius of gyration (Rg), solvent accessible surface area (SASA), and root mean square fluctuation (RMSF) analyses showed that these natural brominated molecules transit rapidly to a progressive constant configuration during binding with COX-1/2 and seem to accomplish a consistent dynamic behavior by maintaining conformational stability and compactness. The results were comparable to the Food and Drug Administration (FDA)-approved selective COX inhibitor, aspirin. Furthermore, the free energy of binding for the compounds assessed by molecular mechanics–Poisson–Boltzmann surface area (MM–PBSA) confirmed the binding capacity of indoles towards COX-1/2, with suitable binding energy values except for the polar precursor tyrindoxyl sulfate (with COX-1). The physicochemical and drug-likeness analysis showed zero violations of Lipinski’s rule, and the compounds are predicted to have excellent pharmacokinetic profiles. These indoles are projected to be non-mutagenic and free from hepatotoxicity, with no inhibition of human ether-a-go–go gene (hERG) I inhibitors, and the oral acute toxicity LD50 in rats is predicted to be similar or lower than aspirin. Overall, this work has identified a plausible mechanism for selective COX inhibition by natural marine indoles as potential therapeutic candidates for the mitigation of inflammation.
| S-EPMC8587571 | biostudies-literature
Project description:With advances in supportive therapy in the last two decades, mortality rates from ALI/ARDS have improved somewhat, but remain around 30 to 40% with significant morbidity in survivors. Several promising treatments are in various stages of evaluation, but many have failed to prove beneficial in large randomized clinical trials (RCT). The first definitive step forward in ALI therapeutics occurred recently as a result of a large RCT demonstrating a mortality decrease from 40 to 31% with the use of low-volume ventilation strategies. From this, it is clear that the opportunity for successful intervention in ALI exists. However, therapeutic advances remain frustrated by the lack of complete understanding of ALI pathophysiology. This stresses the importance of integrating basic and clinical research of the molecular pathogenesis of this disease. The conclusions of a recent National Heart, Lung, and Blood Institute (NHLBI) Working Group on ALI support this type of research as a priority for future investigations of ALI. One of the areas of research given priority by this ALI Working Group is the issue of ALI severity progression and the role of cells of innate immunity in this process. Currently, the processes that determine which ALI patients progress to ARDS and which do not are unclear. As with many phenotype differences, there is most likely a genetic component involved. The basis for this has been demonstrated. For example, a surfactant protein B (SP-B) polymorphism appears to increase a patient’s risk of developing ALI from pneumonia. Additionally, a polymorphism in the promoter region of the gene for interleukin-6 (IL-6) has been associated with a poor prognosis in patients with ARDS. Understanding the intracellular processes of these genes and the cells expressing them in ALI progression could lead to the identification of molecular markers of ALI severity and eventually to the development of targeted therapies. An examination of genetically uniform animals will provide a clearer insight into the interaction between immune cells in ALI progression as well as guide future human experiments. Keywords: Time Series Design, ALI - acute lung injury, ARDS - acute respiratory distress syndrome, CLP - cecal ligation and puncture
2008-02-02 | GSE10343 | GEO
Project description:Although the accumulation of amyloidogenic proteins in neuroinflammatory conditions is generally considered pathologic, in a murine model of multiple sclerosis, amyloid-forming fibrils, comprised of hexapeptides, are anti-inflammatory. Whether these molecules modulate systemic inflammatory conditions remains unknown. We hypothesized that an amylin hexapeptide that forms fibrils can attenuate the systemic inflammatory response in a murine model of sepsis. To test this hypothesis, mice were pre-treated with either vehicle or amylin hexapeptide (20 ?g) at 12 hours and 6 hours prior to intraperitoneal (i.p.) lipopolysaccharide (LPS, 20 mg/kg) administration. Illness severity and survival were monitored every 6 hours for 3 days. Levels of pro- (IL-6, TNF-?, IFN-?) and anti-inflammatory (IL-10) cytokines were measured via ELISA at 1, 3, 6, 12, and 24 hours after LPS (i.p.). As a metric of lung injury, pulmonary artery endothelial cell (PAEC) barrier function was tested 24 hours after LPS administration by comparing lung wet-to-dry ratios, Evan's blue dye (EBD) extravasation, lung histology and caspase-3 activity. Compared to controls, pretreatment with amylin hexapeptide significantly reduced mortality (p<0.05 at 72 h), illness severity (p<0.05), and pro-inflammatory cytokine levels, while IL-10 levels were elevated (p<0.05). Amylin pretreatment attenuated LPS-induced lung injury, as demonstrated by decreased lung water and caspase-3 activity (p<0.05, versus PBS). Hence, in a murine model of systemic inflammation, pretreatment with amylin hexapeptide reduced mortality, disease severity, and preserved lung barrier function. Amylin hexapeptide may represent a novel therapeutic tool to mitigate sepsis severity and lung injury.
| S-EPMC6039005 | biostudies-literature
Project description:IntroductionAcute respiratory distress syndrome (ARDS) is a severe form of acute lung injury (ALI) resulting in life-threatening hypoxaemia. Although ARDS can be caused by a variety of pathogens or major trauma, it is best known as the major cause of mortality in COVID-19 patients. Since ARDS is often associated with dysregulated inflammatory immune responses, immunomodulatory approaches represent a possible treatment option. The objective of this study was to evaluate the therapeutic potential of interleukin (IL)-1 blockade using Anakinra in a mouse model of lipopolysaccharide (LPS)-induced ALI.MethodsWe evaluated the effects of a daily subcutaneous Anakinra treatment in a mouse model of LPS-induced ALI. We monitored body weight to assess the general health status of the mice. Two days after ALI induction, we evaluated the inflammatory cytokine MIP-2 as well as protein levels in bronchoalveolar lavage (BAL) fluids. Two and nine days after ALI induction, we evaluated infiltrating leukocytes in BAL fluid and lung tissue.ResultsAnakinra treatment reduced ALI-induced weight loss compared to nontreated groups. At Day 2, Anakinra treatment reduced levels of MIP-2 and protein in BAL fluids and reduced frequencies of NK cells and neutrophils in the lung tissue. Nine days after ALI induction, Anakinra treated mice displayed reduced levels of neutrophils and alveolar macrophages in BAL fluids.ConclusionsIL-1 blockade using Anakinra reduced classical hallmarks of inflammation in a mouse model of ALI. Our data support ongoing and future research on the evaluation of Anakinra as a potential treatment option in ARDS.
| S-EPMC8767508 | biostudies-literature
Project description:Molecules that simultaneously inhibit independent or co-dependent proinflammatory pathways may have advantages over conventional monotherapeutics. OmCI is a bifunctional protein derived from blood-feeding ticks that specifically prevents complement (C)-mediated C5 activation and also sequesters leukotriene B4 (LTB4) within an internal binding pocket. Here, we examined the effect of LTB4 binding on OmCI structure and function and investigated the relative importance of C-mediated C5 activation and LTB4 in a mouse model of immune complex-induced acute lung injury (IC-ALI). We describe two crystal structures of bacterially expressed OmCI: one binding a C16 fatty acid and the other binding LTB4 (C20). We show that the C5 and LTB4 binding activities of the molecule are independent of each other and that OmCI is a potent inhibitor of experimental IC-ALI, equally dependent on both C5 inhibition and LTB4 binding for full activity. The data highlight the importance of LTB4 in IC-ALI and activation of C5 by the complement pathway C5 convertase rather than by non-C proteases. The findings suggest that dual inhibition of C5 and LTB4 may be useful for treatment of human immune complex-dependent diseases.
| S-EPMC3696655 | biostudies-literature
Project description:The benefits of emollients for eczematous dermatitis and psoriasis have been thought to be due to the improvements in epidermal function, including epidermal permeability barrier, stratum corneum hydration, and stratum corneum pH. We determined here whether emollient can direct inhibit cutaneous inflammation. Ear inflammation was induced by topical application of either 12-O-tetradecanoylphorbol-13-acetate (TPA) or 1-fluoro-2,4-dinitrofluorobenzene (DNFB). Either 1% hydrocortisone cream or the novel emollient was applied to the right ear of the mice 45 min and 2 hours after TPA or DNFB application. The untreated left ear served as untreated controls. Both ear weight and ear thickness were measured 24 hours after TPA and DNFB application. Topical applications of either hydrocortisone cream or emollient significantly decreased both ear thickness and ear weight in comparison to untreated controls. In DNFB model, hydrocortisone significantly lowered expression levels of mRNA for IL-1α, IL-1β, and TNFα, while the emollient markedly decreased expression levels of IL-1α and TNFα mRNA. In TPA model, both hydrocortisone and emollient significantly decreased expression levels of IL-1α, IL-1β, IL-6, and TNFα mRNA. In parallel, inflammatory infiltration was also reduced by topical applications of either hydrocortisone or emollient. These results demonstrate that this novel emollient can directly inhibit cutaneous inflammation in murine models of both acute irritant contact dermatitis and acute allergic contact dermatitis. However, whether this emollient could also alleviate eczematous dermatitis in humans remains to be explored.
| S-EPMC8057889 | biostudies-literature
Project description:Acute lung injury (ALI) is characterized by exuberant proinflammatory responses and mitochondrial dysfunction. However, the link between mitochondrial dysfunction and inflammation in ALI is not well understood. In this report, we demonstrate a critical role for the mitochondrial NAD+-dependent deacetylase, sirtuin-3 (SIRT3), in regulating macrophage mitochondrial bioenergetics, ROS formation, and proinflammatory responses. We found that SIRT3 expression was significantly diminished in lungs of mice subjected to LPS-induced ALI. SIRT3-deficient mice (SIRT3-/-) develop more severe ALI compared with wild-type controls (SIRT3+/+). Macrophages obtained from SIRT3-/- mice show significant alterations in mitochondrial bioenergetic and redox homeostasis, in association with a proinflammatory phenotype characterized by NLRP3 inflammasome activation. The SIRT3 activator viniferin restored macrophage bioenergetic function in LPS-treated macrophages. Viniferin also reduced NLRP3 activation and the production of proinflammatory cytokines, effects that were absent in SIRT3-/- macrophages. In-vivo administration of viniferin reduced production of inflammatory mediators TNF-α, MIP-2, IL-6, IL-1β, and HMGB1, and diminished neutrophil influx and severity of endotoxin-mediated ALI; this protective effect of vinferin was abolished in SIRT3-/- mice. Taken together, our results show that the induction/activation of SIRT3 may serve as a new therapeutic strategy in ALI by modulating cellular bioenergetics, controlling inflammatory responses, and reducing the severity of lung injury.
| S-EPMC6485358 | biostudies-literature
Project description:Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-induced ALI. Because of a growing body of literature demonstrating important pathophysiologic differences between ALI caused by different etiologies, we hypothesized that TF on myeloid cells may have distinct contributions to airspace inflammation and permeability between direct and indirect causes of ALI. To test this, we compared mice lacking TF on myeloid cells (TF(∆mye), LysM.Cre(+/-)TF(flox/flox)) to littermate controls during direct (bacterial pneumonia, ventilator-induced ALI, bleomycin-induced ALI) and indirect ALI (systemic LPS, cecal ligation and puncture). ALI was quantified by weight loss, bronchoalveolar lavage (BAL) inflammatory cell number, cytokine concentration, protein concentration, and BAL procoagulant activity. There was no significant contribution of TF on myeloid cells in multiple models of experimental ALI, leading to the conclusion that TF in myeloid cells is not a major contributor to experimental ALI.
| S-EPMC4770302 | biostudies-other
Project description:BackgroundBreakdown of the alveolo-capillary wall is pathognomonic for Acute Lung Injury (ALI). Angiopoietins, vascular-specific growth factors, are linked to endothelial barrier dysfunction, and elevated Angiopoietin-2 (ANG2) levels are associated with poor outcome of ALI patients. Specialized immune cells, referred to as 'TIE2-expressing monocytes and macrophages' (TEM), were shown to specifically respond to ANG2 binding. However, their involvement in acute inflammatory processes is so far completely undescribed. Thus, our aim was to assess the dynamics of TEMs in a murine model of ALI.ResultsIntratracheal instillation of LPS induced a robust pulmonary pro-inflammatory response with endothelial barrier dysfunction and significantly enhanced ANG2 expression. The percentage number of TEMs, assessed by FACS analysis, was more than trebled compared to controls, with TEM count in lungs reaching more than 40% of all macrophages. Such distinct dynamic was absent in all other analyzed compartments (alveolar space, spleen, blood). Incubation of the monocytic cell line THP-1 with LPS or TNF-α resulted in a dose-dependent, significant upregulation of TIE2, suggesting that not recruitment from extra-pulmonary compartments but TIE2 upregulation in resident macrophages accounts for increased lung TEM frequencies.ConclusionsFor the first time, our data provide evidence that the activity of TEMs changes at sites of acute inflammation.
| S-EPMC6001122 | biostudies-literature