The anti-inflammatory activity of 2-iminothiazolidines: evidence for macrophage repolarization

Mohr, Eduarda Talita Bramorski; Lubschinski, Tainá Larissa; Rosa, Júlia Salvan da; Vieira, Guilherme Nicácio; Felisberto, Mariano; Romualdo, Robson Ruan; Ferreira, Misael; Sá, Marcus M.; Dalmarco, Eduardo Monguilhott

doi:10.1007/s10787-022-01084-x

Cited by 6 publications

(6 citation statements)

References 46 publications

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“…This finding reinforces the affirmation that 1,4‐DHP derivatives exert their anti‐inflammatory effects by changing the macrophage phenotype, Choe et al demonstrated that murine macrophages stimulated with LPS and pretreated with nifedipine led to a significant increase in mRNA expression of Arg‐1, Ym‐1, FIZZ1, and TGF‐β, characteristic markers of polarization of M2‐type macrophages [14]. Our results show, in addition to the decrease in the levels of cytokines characteristic of M1 responses, an increase in the phagocytic activity of the macrophages, as well as an increase in the production of the anti‐inflammatory cytokine IL‐10, which is characteristic of the M2 phenotype [37, 38].…”

Section: Discussionsupporting

confidence: 91%

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Evaluation of the anti‐inflammatory effect of 1,4‐dihydropyridine derivatives

Facchin,

Lubschinski,

Moon

et al. 2023

Fundamemntal Clinical Pharma

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IntroductionInflammation is a physiological event that protects the organism against different factors that lead to loss of tissue homeostasis. Dihydropyridine (DHP) derivatives are heterocyclic compounds known for their different biological activities, including anti‐inflammatory activities.ObjectiveTo evaluate the anti‐inflammatory activity of 1,4‐dihydropyridine (1,4‐DHP) derivatives using anti‐inflammatory models in vitro, in RAW264.7 cells induced by lipopolysaccharide (LPS) and in vivo using the acute lung injury (ALI) model in mice.ResultsFifteen compounds derived from 1,4‐DHP were tested in RAW264.7 cells for their cytotoxic effect and cell viability. Thereafter, only the six compounds that showed the highest cell viability were tested for the production or inhibition of the pro‐inflammatory cytokine interleukin 6 (IL‐6). The best compound (compound 4) was tested for its anti‐inflammatory effects in vitro and in vivo, showing inhibition of nitric oxide (NO), pro‐inflammatory cytokines, increased phagocytic activity, and an increase in IL‐10 in vitro. In in vivo tests, compound 4 also reduces the levels of NO, myeloperoxidase (MPO) activity, leukocyte migration, and exudation, as well as reducing the levels of tumor necrosis factor‐alpha (TNF‐α) and IL‐6 and preventing the loss in the lung architecture.ConclusionThis compound showed important anti‐inflammatory activity, with a significant ability to reduce the production of pro‐inflammatory mediators and increase the phagocytic activity of macrophages and anti‐inflammatory mediator secretion (IL‐10). These findings led us to hypothesize that this compound can repolarize the macrophage response to an anti‐inflammatory profile (M2). Moreover, it was also able to maintain its anti‐inflammatory activity in vivo experiments.

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Section: Discussionsupporting

confidence: 91%

“…Our results show, in addition to the decrease in the levels of cytokines characteristic of M1 responses, an increase in the phagocytic activity of the macrophages, as well as an increase in the production of the antiinflammatory cytokine IL-10, which is characteristic of the M2 phenotype [37,38].…”

Section: Groupmentioning

confidence: 55%

Evaluation of the anti‐inflammatory effect of 1,4‐dihydropyridine derivatives

Facchin,

Lubschinski,

Moon

et al. 2023

Fundamemntal Clinical Pharma

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“…EGFR is a driver of tumorigenesis, and the development of anticancer drugs targeting this pathway helps to reduce PD‐L1 expression to reduce tumor immune escape, but the generation of cancer cell resistance during this process is also a difficulty for this therapeutic tool 33,34 . TNFα and NF‐κB mediate the expression of two cytokines, and the expression of two inflammatory cytokines is important for the induction of anti‐inflammatory M2 macrophage polarization, which was also consistent with the results of the C1 subtype possessing higher macrophage infiltration as shown in the present study 35–37 . The relatively up‐regulated Trail pathway in the C4 subtype mediates tumor necrosis factor‐associated apoptotic ligand, which was found to rapidly induce exogenous apoptosis in tumors in related studies, being delivered in a membrane‐bound manner through extracellular vesicles, which can overcome drug resistance of tumor and exhibit great clinical value 38 .…”

Section: Discussionsupporting

confidence: 90%

“…33,34 TNFα and NF-κB mediate the expression of two cytokines, and the expression of two inflammatory cytokines is important for the induction of anti-inflammatory M2 macrophage polarization, which was also consistent with the results of the C1 subtype possessing higher macrophage infiltration as shown in the present study. [35][36][37] The relatively up-regulated Trail pathway in the C4 subtype mediates tumor necrosis factor-associated apoptotic ligand, which was found to rapidly induce exogenous apoptosis in tumors in related studies, being delivered in a membrane-bound manner through extracellular vesicles, which can overcome drug resistance of tumor and exhibit great clinical value. 38 This suggests that the differences in pathways between C1 and C4 groups are closely related to the immune regulation and drug sensitivity of patients.…”

Section: Discussionmentioning

confidence: 99%

Identification of prognostic biomarkers for cervical cancer based on programmed cell death‐related genes and assessment of their immune profile and response to drug therapy

Feng,

Wang,

Zhang

et al. 2023

The Journal of Gene Medicine

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BackgroundProgrammed cell death (PCD) has been widely investigated in various human diseases. The present study aimed to identify a novel PCD‐related genetic signature in cervical squamous cell carcinoma (CESC) to provide clues for survival, immunotherapy and drug sensitization prediction.MethodsSingle‐sample gene set enrichment analysis (ssGSEA) was used to quantify the PCD score and assess the distribution of PCD in clinicopathological characteristics in The Cancer Genome Atlas (TCGA)‐CESC samples. Then, the ConsensusClusterPlus method was used to identify molecular subtypes in the TCGA‐CESC database. Genomic mutation analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment, as well as tumor microenvironment (TME) infiltration analysis, were performed for each molecular subtype group. Finally, a prognostic model by Uni‐Cox and least absolute shrinkage and selection operator‐Cox analysis was established based on differentially expressed genes from molecular subtypes. ESTIMATE (i.e. Estimation of STromal and Immune cells in MAlignantTumours using Expression data) and ssGSEA were performed to assess the correlation between the model and TME. Drug sensitization prediction was carried out with the oncoPredict package.ResultsPreliminary analysis indicated that PCD had a potential association clinical characteristics of the TCGA‐CESC cohort, and PCD‐related genes mutated in 289 (70.59%) CESC patients. Next, four groups of CESC molecular typing were clustered based on 63 significantly prognostic PCD‐related genes. Among four subtypes, C1 group displayed the worst prognosis combined with over expressed PCD genes and enriched cell cycle‐related pathways. C4 group exhibited the best prognosis accompanied with high degree of immune infiltration. Finally, a five‐gene (SERPINE1, TNF, CA9, CX3CL1 and JAK3) prognostic model was constructed. Patients in the high‐risk group displayed unfavorable survival. Immune infiltration analysis found that the low‐risk group had significantly higher levels of immune cell infiltration such as T cells, Macrophages_M1, relative to the high‐risk group, and were significantly enriched in apoptosis‐associated pathways, which predicted a higher level of immunity. Drug sensitivity correlation analysis revealed that the high‐risk group was resistant to conventional chemotherapeutic drugs and sensitive to the Food and Drug Administration‐approved drugs BI.2536_1086 and SCH772984_1564.ConclusionsIn the present study, we first found that PCD‐related gene expression patterns were correlated with clinical features of CESC patients, which predicts the feasibility of subsequent mining of prognostic features based on these genes. The five‐PCD‐associated‐gene prognostic model showed good assessment ability in predicting patient prognosis, immune response and drug‐sensitive response, and provided guidance for the elucidation of the mechanism by which PCD affects CESC, as well as for the clinical targeting of drugs.

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“…NO production was measured indirectly through the Griess reaction [22]. In this test, the IC 50 of each compound tested was determined, i.e., the concentration of the compound capable of inhibiting 50% of the nitric oxide metabolites when compared with the inflamed group (negative control) [23,24].…”

Section: Cell Viability (Cytotoxicity Testmentioning

confidence: 99%

Interference in Macrophage Balance (M1/M2): The Mechanism of Action Responsible for the Anti-Inflammatory Effect of a Fluorophenyl-Substituted Imidazole

Salvan da Rosa,

Bramorski Mohr,

Lubschinski

et al. 2024

Mediators of Inflammation

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Traditionally, the treatment of inflammatory conditions has focused on the inhibition of inflammatory mediator production; however, many conditions are refractory to this classical approach. Recently, an alternative has been presented by researchers to solve this problem: The immunomodulation of cells closely related to inflammation. Hence, macrophages, a critical key in both innate and acquired immunity, have been presented as an alternative target for the development of new medicines. In this work, we tested the fluorophenyl-imidazole for its anti-inflammatory activity and possible immunomodulatory effect on RAW 264.7 macrophages. We also evaluated the anti-inflammatory effect of the compound, and the macrophage repolarization to M2 was confirmed by the ability of the compound to reduce the M1 markers TNF-α, IL-6, MCP-1, IL-12p70, IFN-γ, and TLR4, the high levels of p65 phosphorylated, iNOS and COX-2 mRNA expression, and the fact that the compound was not able to induce the production of M1 markers when used in macrophages without lipopolysaccharide (LPS) stimulation. Moreover, fluorophenyl-imidazole had the ability to increase the M2 markers IL-4, IL-13, CD206, apoptosis and phagocytosis levels, arginase-1, and FIZZ-1 mRNA expression before LPS stimulation. Similarly, it was also able to induce the production of these same M2 markers in macrophages without being induced with LPS. These results reinforce the affirmation that the fluorophenyl-imidazole has an important anti-inflammatory effect and demonstrates that this effect is due to immunomodulatory activity, having the ability to trigger a repolarization of macrophages from M1 to M2a. These facts suggest that this molecule could be used as an alternative scaffold for the development of a new medicine to treat inflammatory conditions, where the anti-inflammatory and proregenerative properties of M2a macrophages are desired.

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The anti-inflammatory activity of 2-iminothiazolidines: evidence for macrophage repolarization

Cited by 6 publications

References 46 publications

Evaluation of the anti‐inflammatory effect of 1,4‐dihydropyridine derivatives

Evaluation of the anti‐inflammatory effect of 1,4‐dihydropyridine derivatives

Identification of prognostic biomarkers for cervical cancer based on programmed cell death‐related genes and assessment of their immune profile and response to drug therapy

Interference in Macrophage Balance (M1/M2): The Mechanism of Action Responsible for the Anti-Inflammatory Effect of a Fluorophenyl-Substituted Imidazole

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