scholarly journals Gold Nanoparticles Modulate BCG-Induced Innate Immune Memory in Human Monocytes by Shifting the Memory Response towards Tolerance

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 284 ◽  
Author(s):  
Benjamin J. Swartzwelter ◽  
Francesco Barbero ◽  
Alessandro Verde ◽  
Maria Mangini ◽  
Marinella Pirozzi ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Inflammatory Diseases ◽  
Innate Immune ◽  
Secondary Response ◽  
Immune Memory ◽  
Inflammatory Factor ◽  
Memory Response ◽  
Lps Challenge ◽  
Anti Inflammatory

Innate immune memory is characterized by a modulation in the magnitude with which innate immune cells such as monocytes and macrophages respond to potential dangers, subsequent to previous exposure to the same or unrelated agents. In this study, we have examined the capacity of gold nanoparticles (AuNP), which are already in use for therapeutic and diagnostic purposes, to modulate the innate memory induced by bacterial agents. The induction of innate memory was achieved in vitro by exposing human primary monocytes to bacterial agents (lipopolysaccharide -LPS-, or live Bacille Calmette-Guérin -BCG) in the absence or presence of AuNP. After the primary activation, cells were allowed to return to a resting condition, and eventually re-challenged with LPS. The induction of memory was assessed by comparing the response to the LPS challenge of unprimed cells with that of cells primed with bacterial agents and AuNP. The response to LPS was measured as the production of inflammatory (TNFα, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra). While ineffective in directly inducing innate memory per se, and unable to influence LPS-induced tolerance memory, AuNP significantly affected the memory response of BCG-primed cells, by inhibiting the secondary response in terms of both inflammatory and anti-inflammatory factor production. The reprogramming of BCG-induced memory towards a tolerance type of reactivity may open promising perspectives for the use of AuNP in immunomodulatory approaches to autoimmune and chronic inflammatory diseases.

scholarly journals Personalised Profiling of Innate Immune Memory Induced by Nano-Imaging Particles in Human Monocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Giacomo Della Camera ◽  
Mariusz Madej ◽  
Anna Maria Ferretti ◽  
Rita La Spina ◽  
Yang Li ◽  
...  
Keyword(s):  
Iron Oxide ◽  
Primary Response ◽  
Innate Immune ◽  
Engineered Nanoparticles ◽  
Secondary Response ◽  
Immune Memory ◽  
Immune Reactivity ◽  
Iron Oxide Particles ◽  
Lps Challenge

Engineered nanoparticles used for medical purposes must meet stringent safety criteria, which include immunosafety, i.e., the inability to activate possibly detrimental immune/inflammatory effects. Even medical nanomaterials devoid of direct immunotoxic or inflammatory effects may have an impact on human health if able to modify innate memory, which is the ability to “prime” future immune responses towards a different, possibly more detrimental reactivity. Although innate memory is usually protective, anomalous innate memory responses may be at the basis of immune pathologies. In this study, we have examined the ability of two nanomaterials commonly used for diagnostic imaging purposes, gold and iron oxide nanoparticles, to induce or modulate innate memory, using an in vitro model based on human primary monocytes. Monocytes were exposed in culture to nanoparticles alone or together with the bacterial agent LPS (priming phase/primary response), then rested for six days (extinction phase), and eventually challenged with LPS (memory/secondary response). The memory response to the LPS challenge was measured as changes in the production of inflammatory (TNFα, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra), as compared to unprimed monocytes. The results show that both types of nanoparticles can have an effect in the induction of memory, with changes observed in the cytokine production. By comparing nanomaterials of different shapes (spherical vs. rod-shaped gold particles) and different size (17 vs. 22 nm diameter spherical iron oxide particles), it was evident that innate memory could be differentially induced and modulated depending on size, shape and chemical composition. However, the main finding was that the innate memory effect of the particles was strongly donor-dependent, with monocytes from each donor showing a distinct memory profile upon priming with the same particles, thereby making impossible to draw general conclusions on the particle effects. Thus, in order to predict the effect of imaging nanoparticles on the innate memory of patients, a personalised profiling would be required, able to take in consideration the peculiarities of the individual innate immune reactivity.

scholarly journals Innate Memory Reprogramming by Gold Nanoparticles Depends on the Microbial Agents That Induce Memory

2021 ◽  
Vol 12 ◽  
Author(s):  
Benjamin J. Swartzwelter ◽  
Sara Michelini ◽  
Tobias Frauenlob ◽  
Francesco Barbero ◽  
Alessandro Verde ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Inflammatory Cytokine ◽  
Primary Response ◽  
Engineered Nanoparticles ◽  
Immune Memory ◽  
Secondary Memory ◽  
Memory Response ◽  
Anti Inflammatory ◽  
Induced Tolerance ◽  
Microbial Agents

Innate immune memory, the ability of innate cells to react in a more protective way to secondary challenges, is induced by exposure to infectious and other exogeous and endogenous agents. Engineered nanoparticles are particulate exogenous agents that, as such, could trigger an inflammatory reaction in monocytes and macrophages and could therefore be also able to induce innate memory. Here, we have evaluated the capacity of engineered gold nanoparticles (AuNPs) to induce a memory response or to modulate the memory responses induced by microbial agents. Microbial agents used were in soluble vs. particulate form (MDP and the gram-positive bacteria Staphylococcus aureus; β-glucan and the β-glucan-producing fungi C. albicans), and as whole microrganisms that were either killed (S. aureus, C. albicans) or viable (the gram-negative bacteria Helicobacter pylori). The memory response was assessed in vitro, by exposing human primary monocytes from 2-7 individual donors to microbial agents with or without AuNPs (primary response), then resting them for 6 days to allow return to baseline, and eventually challenging them with LPS (secondary memory response). Primary and memory responses were tested as production of the innate/inflammatory cytokine TNFα and other inflammatory and anti-inflammatory factors. While inactive on the response induced by soluble microbial stimuli (muramyl dipeptide -MDP-, β-glucan), AuNPs partially reduced the primary response induced by whole microorganisms. AuNPs were also unable to directly induce a memory response but could modulate stimulus-induced memory in a circumscribed fashion, limited to some agents and some cytokines. Thus, the MDP-induced tolerance in terms of TNFα production was further exacerbated by co-priming with AuNPs, resulting in a less inflammatory memory response. Conversely, the H. pylori-induced tolerance was downregulated by AuNPs only relative to the anti-inflammatory cytokine IL-10, which would lead to an overall more inflammatory memory response. These effects of AuNPs may depend on a differential interaction/association between the reactive particle surfaces and the microbial components and agents, which may lead to a change in the exposure profiles. As a general observation, however, the donor-to-donor variability in memory response profiles and reactivity to AuNPs was substantial, suggesting that innate memory depends on the individual history of exposures.

scholarly journals Systemic administration of β-glucan induces immune training in microglia

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Yang Heng ◽  
Xiaoming Zhang ◽  
Malte Borggrewe ◽  
Hilmar R. J. van Weering ◽  
Maaike L. Brummer ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Morphological Changes ◽  
Innate Immune ◽  
Cytokine Gene Expression ◽  
Immune Memory ◽  
Lps Challenge ◽  
Lps Preconditioning ◽  
Gene Expression Levels

Abstract Background An innate immune memory response can manifest in two ways: immune training and immune tolerance, which refers to an enhanced or suppressed immune response to a second challenge, respectively. Exposing monocytes to moderate-to-high amounts of bacterial lipopolysaccharide (LPS) induces immune tolerance, whereas fungal β-glucan (BG) induces immune training. In microglia, it has been shown that different LPS inocula in vivo can induce either immune training or tolerance. Few studies focused on impact of BG on microglia and were only performed in vitro. The aim of the current study was to determine whether BG activates and induces immune memory in microglia upon peripheral administration in vivo. Methods Two experimental designs were used. In the acute design, mice received an intraperitoneal (i.p.) injection with PBS, 1 mg/kg LPS or 20 mg/kg BG and were terminated after 3 h, 1 or 2 days. In the preconditioning design, animals were first challenged i.p. with PBS, 1 mg/kg LPS or 20 mg/kg BG. After 2, 7 or 14 days, mice received a second injection with PBS or 1 mg/kg LPS and were sacrificed 3 h later. Microglia were isolated by fluorescence-activated cell sorting, and cytokine gene expression levels were determined. In addition, a self-developed program was used to analyze microglia morphological changes. Cytokine concentrations in serum were determined by a cytokine array. Results Microglia exhibited a classical inflammatory response to LPS, showing significant upregulation of Tnf, Il6, Il1β, Ccl2, Ccl3 and Csf1 expression, three h after injection, and obvious morphological changes 1 and 2 days after injection. With an interval of 2 days between two challenges, both BG and LPS induced immune training in microglia. The training effect of LPS changed into immune tolerance after a 7-day interval between 2 LPS challenges. Preconditioning with BG and LPS resulted in increased morphological changes in microglia in response to a systemic LPS challenge compared to naïve microglia. Conclusions Our results demonstrate that preconditioning with BG and LPS both induced immune training of microglia at two days after the first challenge. However, with an interval of 7 days between the first and second challenge, LPS-preconditioning resulted in immune tolerance in microglia.

scholarly journals Systemic administration of β-glucan induces immune training in microglia

2020 ◽  
Author(s):  
Yang Heng ◽  
Xiaoming Zhang ◽  
Malte Borggrewe ◽  
Hilmar R.J. van Weering ◽  
Maaike L. Brummer ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Morphological Changes ◽  
Innate Immune ◽  
Cytokine Gene Expression ◽  
Immune Memory ◽  
Lps Challenge ◽  
Lps Preconditioning ◽  
Gene Expression Levels

Abstract BackgroundAn innate immune memory response can manifest in two ways: immune training and immune tolerance, which refers to an enhanced or suppressed immune response to a second challenge, respectively. Exposing monocytes to moderate-to-high amounts of bacterial lipopolysaccharide (LPS) induces immune tolerance, whereas fungal β-glucan (BG) induces immune training. In microglia, it has been shown that different LPS inocula in vivo can induce either immune training or tolerance. Few studies focused on impact of BG on microglia and were only performed in vitro. The aim of the current study was to determine whether BG activates and induces immune memory in microglia upon peripheral administration in vivo.MethodsTwo experimental designs were used. In the acute design, mice received an intraperitoneal (i.p.) injection with PBS, 1 mg/kg LPS or 20 mg/kg BG and were terminated after 3 h, 1 or 2 days. In the preconditioning design, animals were first challenged i.p. with PBS, 1 mg/kg LPS or 20 mg/kg BG. After 2, 7 or 14 days, mice received a second injection with PBS or 1 mg/kg LPS and were sacrificed 3 h later. Microglia were isolated by fluorescence-activated cell sorting, and cytokine gene expression levels were determined. In addition, a self-developed program was used to analyze microglia morphological changes. Cytokine concentrations in serum were determined by a cytokine array.ResultsMicroglia exhibited a classical inflammatory response to LPS, showing significant upregulation of Tnf, Il6, Il1β, Ccl2, Ccl3 and Csf1 expression, three h after injection, and obvious morphological changes 1 and 2 days after injection. With an interval of 2 days between two challenges, both BG and LPS induced immune training in microglia. The training effect of LPS changed into immune tolerance after a 7-day interval between 2 LPS challenges. Preconditioning with BG and LPS resulted in increased morphological changes in microglia in response to a systemic LPS challenge compared to naïve microglia.ConclusionsOur results demonstrate that preconditioning with BG and LPS both induced immune training of microglia at two days after the first challenge. However, with an interval of 7 days between the first and second challenge, LPS-preconditioning resulted in immune tolerance in microglia.

scholarly journals PSIII-38 Butyric acid and derivatives: In vitro anti-inflammatory effects tested in porcine alveolar macrophages

2020 ◽  
Vol 98 (Supplement_4) ◽  
pp. 370-370
Author(s):  
Lauren L Kovanda ◽  
Monika Hejna ◽  
Yanhong Liu
Keyword(s):  
Organic Acid ◽  
Butyric Acid ◽  
Sodium Butyrate ◽  
Alveolar Macrophages ◽  
Block Design ◽  
Lps Challenge ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Challenge Group

Abstract The aim of this experiment was to examine the anti-inflammatory effects of butyric acid, sodium butyrate, monobutyrin and tributyrin using porcine alveolar macrophages (PAMs). PAMs were isolated from the bronchial lavage of 6 piglets at 6 weeks of age, and then seeded at 106 cells/mL in 24-well plates. After 24 h incubation, cells were treated with different treatments in a randomized complete block design with 10 replicates. The treatments were in a factorial arrangement with 2 doses of lipopolysaccharide (LPS, 0 or 1 μg/mL) and 5 levels of organic acid (0, 0.5, 1, 2, 4 mM for butyric acid and tributyrin and 0, 1, 2, 4, 8 mM for sodium butyrate and monobutyrin). Supernatants were collected after another 24 h incubation and analyzed for tumor necrosis factor alpha (TNF-α). Cell viability was also tested by the MTT assay. Data were analyzed using the MIXED procedure of SAS. No cytotoxic effect was observed in LPS challenge and each organic acid with the percentage of live cells was more than 76% in comparison to the sham control. Sodium butyrate at 2 and 4 mM dose exhibited (P < 0.01) a stimulatory effect on cell proliferation. LPS challenge remarkably stimulated (P < 0.0001) TNF-α secretion from PAMs. In the non-challenge group, butyric acid, monobutyrin, and tributyrin linearly reduced TNF-α production from PAMs, whereas 2 mM sodium butyrate tended to increase (P = 0.056) TNF-α secretion from PAMs. In the LPS challenge group, all tested organic acid dose-dependently reduced (P < 0.001) TNF-α production from LPS-challenged PAMs, with the strongest inhibiting effect observed at the highest dose. Results indicated that butyric acid and its derivatives that were tested in the current experiment all had strong anti-inflammatory activities in vitro.

Advances in Anti-inflammatory Activity, Mechanism and Therapeutic Application of Ursolic Acid

2021 ◽  
Vol 21 ◽  
Author(s):  
Mingzhu Luan ◽  
Huiyun Wang ◽  
Jiazhen Wang ◽  
Xiaofan Zhang ◽  
Fenglan Zhao ◽  
...  
Keyword(s):  
Ursolic Acid ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Inflammatory Activity ◽  
Inflammatory Factors ◽  
Inflammatory Stimuli ◽  
Bowel Diseases ◽  
Anti Inflammatory

: In vivo and in vitro studies reveal that ursolic acid (UA) is able to counteract endogenous and exogenous inflammatory stimuli, and has favorable anti-inflammatory effects. The anti-inflammatory mechanisms mainly include decreasing the release of histamine in mast cells, suppressing the activities of lipoxygenase, cyclooxygenase and phospholipase, and reducing the production of nitric oxide and reactive oxygen species, blocking the activation of signal pathway, down-regulating the expression of inflammatory factors, and inhibiting the activities of elastase and complement. These mechanisms can open up new avenues for the scientific community to develop or improve novel therapeutic approaches to tackle inflammatory diseases such as arthritis, atherosclerosis, neuroinflammation, liver diseases, kidney diseases, diabetes, dermatitis, bowel diseases, cancer. The anti-inflammatory activity, the anti-inflammatory mechanism of ursolic acid and its therapeutic applications are reviewed in this paper.

scholarly journals Protective Effect of Phillyrin on Lethal LPS-Induced Neutrophil Inflammation in Zebrafish

2017 ◽  
Vol 43 (5) ◽  
pp. 2074-2087 ◽  
Author(s):  
Liling Yang ◽  
Xiangjun Zhou ◽  
Weijuan Huang ◽  
Qin Fang ◽  
Jianlan Hu ◽  
...  
Keyword(s):  
Signalling Pathway ◽  
Dependent Manner ◽  
Zebrafish Model ◽  
Lps Challenge ◽  
Cell Counts ◽  
Tnf Α ◽  
Forsythia Suspensa ◽  
Anti Inflammatory

Background/Aims: Forsythia suspensa Vahl. (Oleaceae) fruits are widely used in traditional Chinese medicine to treat pneumonia, typhoid, dysentery, ulcers and oedema. Antibacterial and anti-inflammatory activities have been reported for phillyrin (PHN), the main ingredient in Forsythia suspensa Vahl fruits, in vitro. However, the underlying mechanisms in vivo remain poorly defined. In this study, we discovered that PHN exerted potent anti-inflammatory effects in lethal LPS-induced neutrophil inflammation by suppressing the MyD88-dependent signalling pathway in zebrafish. Methods: LPS-yolk microinjection was used to induce a lethal LPS-infected zebrafish model. The effect of PHN on the survival of zebrafish challenged with lethal LPS was evaluated using survival analysis. The effect of PHN on neutrophil inflammation grading in vivo was assessed by tracking neutrophils with a transgenic line. The effects of PHN on neutrophil production and migration were analysed by SB+ cell counts during consecutive hours after modelling. Additionally, key cytokines and members of the MyD88 signalling pathway that are involved in inflammatory response were detected using quantitative RT-PCR. To assess gene expression changes during consecutive hours after modelling, the IL-1β, IL-6, TNF-α, MyD88, TRIF, ERK1/2, JNK, IκBa and NF-κB expression levels were measured. Results: PHN could protect zebrafish against a lethal LPS challenge in a dose-dependent manner, as indicated by decreased neutrophil infltration, reduced tissue necrosis and increased survival rates. Up-regulated IL-1β, IL-6 and TNF-α expression also showed the same tendencies of depression by PHN. Critically, PHN significantly inhibited the LPS-induced activation of MyD88, IκBa, and NF-κB but did not affect the expression of ERK1/2 MAPKs or JNK MAPKs in LPS-stimulated zebrafish. Additionally, PHN regulated the MyD88/IκBα/NF-κB signalling pathway by controlling IκBα, IL-1β, IL-6, and TNF-α expression. Conclusion: This study provides a rationale for the clinical application of PHN as an anti-inflammatory agent.

Ulinastatin Activated The ERK5/Mer Signaling Pathway To Promote Macrophage Efferocytosis And Ameliorate Lung Inflammation

2021 ◽  
Author(s):  
Jinju Li ◽  
Rongge Shao ◽  
Qiuwen Xie ◽  
XueKe Du
Keyword(s):  
Lung Injury ◽  
Signaling Pathway ◽  
Lung Inflammation ◽  
Raw264.7 Cells ◽  
Inflammatory Factors ◽  
Inflammatory Factor ◽  
Dependent Manner ◽  
Anti Inflammatory

Abstract Purpose:Ulinastatin (UTI) is an endogenous protease inhibitor with potent anti-inflammatory, antioxidant and organ protective effects. The inhibitor has been reported to ameliorate inflammatory lung injury but precise mechanisms remain unclear. Methods: An in vivo model of lung injury has been constructed by intratracheal infusion of lipopolysaccharide (LPS). The number of neutrophils and the phagocytosis of apoptotic neutrophils were observed by Diff- Quick method. Lung injury was observed by HE staining .BALF cells were counted by hemocytometer and concentrations of protein plus inflammatory factors were measured with a BCA test kit. During in vitro experiments, RAW264.7 cells were pretreated with UTI (1000 and 5000U/ mL), stained with CellTrackerTM Green B0DIPYTM and HL60 cells added with UV-induced apoptosis and PKH26 Red staining. The expression of ERK5\Mer related proteins was detected by western blot and immunofluorescence.Results: An in vivo model of lung injury has been constructed by intratracheal infusion of lipopolysaccharide (LPS). UTI treatment enhanced the phagocytotic effect of mouse alveolar macrophages on neutrophils, alleviated lung lesions, decreased the pro-inflammatory factor and total protein content of BALF and increased levels of anti-inflammatory factors. in vitro experiments ，UTI enhanced the phagocytosis of apoptotic bodies by RAW264.7 cells in a dose-dependent manner. Increased expression levels of ERK5 and Mer by UTI were shown by Western blotting and immunofluorescence.Conclusions: UTI mediated the activation of the ERK5/Mer signaling pathway, enhanced phagocytosis of neutrophils by macrophages and improved lung inflammation. The current study indicates potential new clinical approaches for accelerating the recovery from lung inflammation.

scholarly journals In Vitro Anti-Inflammatory and In Vivo Antiarthritic Activities of Aqueous and Ethanolic Extracts of Dissotis thollonii Cogn. (Melastomataceae) in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Stephanie Flore Djuichou Nguemnang ◽  
Eric Gonzal Tsafack ◽  
Marius Mbiantcha ◽  
Ateufack Gilbert ◽  
Albert Donatien Atsamo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Denaturation ◽  
Inflammatory Diseases ◽  
Ros Production ◽  
Zymosan A ◽  
Ethanolic Extracts ◽  
Anti Inflammatory ◽  
Promising Source

Dissotis thollonii Cogn. (Melastomataceae) is a tropical plant widely used in traditional Cameroonian medicine to relieve and treat many pathologies. It is widespread in the western region where it is used to treat typhoid fever, gastrointestinal disorders, and inflammatory diseases. The purpose of this study is to scientifically demonstrate the anti-inflammatory and antiarthritic properties of the aqueous and ethanolic extracts of the leaves of Dissotis thollonii. The anti-inflammatory properties were evaluated in vitro by inhibition tests for cyclooxygenase, 5-lipoxygenase, protein denaturation, extracellular ROS production, and cell proliferation; while antiarthritic properties were evaluated in vivo in rats using the zymosan A-induced monoarthritis test and the CFA-induced polyarthritis model. This study shows that aqueous and ethanolic extracts at a concentration of 1000 μg/ml inhibit the activity of cyclooxygenase (47.07% and 63.36%) and 5-lipoxygenase (66.79% and 77.7%) and protein denaturation (42.51% and 44.44%). Similarly, both extracts inhibited extracellular ROS production (IC50 = 5.74 μg/ml and 2.96 μg/ml for polymorphonuclear leukocytes, 7.47 μg/ml and 3.28 μg ml for peritoneal macrophages of mouse) and cell proliferation (IC50 = 16.89 μg/ml and 3.29 μg/ml). At a dose of 500 mg/kg, aqueous and ethanolic extracts significantly reduce edema induced by zymosan A (69.30% and 81.80%) and CFA (71.85% and 79.03%). At the same dose, both extracts decreased sensitivity to mechanical hyperalgesia with 69.00% and 70.35% inhibition, respectively. Systemic and histological analyzes show that both extracts maintain the studied parameters very close to normal and greatly restored the normal architecture of the joint in animals. Dissotis thollonii would therefore be a very promising source for the treatment of inflammatory diseases.

scholarly journals Betulinic Acid-Azaprostanoid Hybrids: Synthesis and Pharmacological Evaluation as Anti-inflammatory Agents

2020 ◽  
Vol 19 (3) ◽  
pp. 254-267
Author(s):  
Tatyana S. Khlebnicova ◽  
Yuri A. Piven ◽  
Fedor A. Lakhvich ◽  
Iryna V. Sorokina ◽  
Tatiana S. Frolova ◽  
...  
Keyword(s):  
Cell Lines ◽  
Betulinic Acid ◽  
Inflammatory Diseases ◽  
Toxic Agent ◽  
Analgesic Effects ◽  
Low Toxic ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Background: Prevention and treatment of chronic inflammatory diseases require effective and low-toxic medicines. Molecular hybridization is an effective strategy to enhance the biological activity of new compounds. Triterpenoid scaffolds are in the focus of attention owing to their anti-inflammatory, antiviral, antiproliferative, and immunomodulatory activities. Heteroprostanoids have different pleiotropic effects in acute and chronic inflammatory processes. Objective: The study aimed to develop structurally new and low toxic anti-inflammatory agents via hybridization of betulinic acid with azaprostanoic acids. Methods: A series of betulinic acid-azaprostanoid hybrids was synthesized. The synthetic pathway included the transformation of betulin via Jones' oxidation into betulonic acid, reductive amination of the latter and coupling obtained by 3β-amino-3-deoxybetulinic acid with the 7- or 13-azaprostanoic acids and their homo analogues. The hybrids 1-9 were investigated in vivo on histamine-, formalin- and concanavalin A-induced mouse paw edema models and two models of pain - the acetic acid-induced abdominal writhing and the hotplate test. The hybrids were in vitro evaluated for cytotoxic activity on cancer (MCF7, U- 87 MG) and non-cancer humane cell lines. Results: In the immunogenic inflammation model, the substances showed a pronounced anti-inflammatory effect, which was comparable to that of indomethacin. In the models of the exudative inflammation, none of the compounds displayed a statistically significant effect. The hybrids produced weak or moderate analgesic effects. All the agents revealed low cytotoxicity on human immortalized fibroblasts and cancer cell lines compared with 3β- amino-3-deoxybetulinic acid and doxorubicin. Conclusion: The results indicate that the principal anti-inflammatory effect of hybrids is substantially provided with the triterpenoid scaffold and in some cases with the azaprostanoid scaffold, but the latter makes a significant contribution to reducing the toxicity of hybrids. Hybrid 1 is of interest as a potent low toxic agent against immune-mediated inflammation.

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