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  1. Article ; Online: Editorial

    Letizia Crocetti / Mark T. Quinn / Agostino Cilibrizzi / Maria Paola Giovannoni

    Frontiers in Chemistry, Vol

    Serine protease inhibitors and their therapeutic applications

    2022  Volume 10

    Keywords serine proteases ; inhibitors ; drug design ; organic synthesis ; molecular modeling (MD) ; Chemistry ; QD1-999
    Language English
    Publishing date 2022-08-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Neutrophil Immunomodulatory Activity of Farnesene, a Component of Artemisia dracunculus Essential Oils

    Igor A. Schepetkin / Gulmira Özek / Temel Özek / Liliya N. Kirpotina / Andrei I. Khlebnikov / Robyn A. Klein / Mark T. Quinn

    Pharmaceuticals, Vol 15, Iss 642, p

    2022  Volume 642

    Abstract: Despite their reported therapeutic properties, not much is known about the immunomodulatory activity of essential oils present in Artemisia species. We isolated essential oils from the flowers and leaves of five Artemisia species: A. tridentata , A. ... ...

    Abstract Despite their reported therapeutic properties, not much is known about the immunomodulatory activity of essential oils present in Artemisia species. We isolated essential oils from the flowers and leaves of five Artemisia species: A. tridentata , A. ludoviciana , A. dracunculus , A. frigida , and A. cana . The chemical composition of the Artemisia essential oil samples had similarities and differences as compared to those previously reported in the literature. The main components of essential oils obtained from A. tridentata , A. ludoviciana , A. frigida , and A. cana were camphor (23.0–51.3%), 1,8-cineole (5.7–30.0%), camphene (1.6–7.7%), borneol (2.3–14.6%), artemisiole (1.2–7.5%), terpinen-4-ol (2.0–6.9%), α-pinene (0.8–3.9%), and santolinatriene (0.7–3.5%). Essential oils from A. dracunculus were enriched in methyl chavicol (38.8–42.9%), methyl eugenol (26.1–26.4%), terpinolene (5.5–8.8%), ( E / Z )-β-ocimene (7.3–16.0%), β-phellandrene (1.3–2.2%), p -cymen-8-ol (0.9–2.3%), and xanthoxylin (1.2–2.2%). A comparison across species also demonstrated that some compounds were present in only one Artemisia species. Although Artemisia essential oils were weak activators of human neutrophils, they were relatively more potent in inhibiting subsequent neutrophil Ca 2+ mobilization with N -formyl peptide receptor 1 (FPR1) agonist f MLF- and FPR2 agonist WKYMVM, with the most potent being essential oils from A. dracunculus . Further analysis of unique compounds found in A. dracunculus showed that farnesene, a compound with a similar hydrocarbon structure as lipoxin A 4 , inhibited Ca 2+ influx induced in human neutrophils by f MLF (IC 50 = 1.2 μM), WKYMVM (IC 50 = 1.4 μM), or interleukin 8 (IC 50 = 2.6 μM). Pretreatment with A. dracunculus essential oils and farnesene also inhibited human neutrophil chemotaxis induced by f MLF, suggesting these treatments down-regulated human neutrophil responses to inflammatory chemoattractants. Thus, our studies have identified farnesene as a potential anti-inflammatory modulator of ...
    Keywords anti-inflammatory ; Artemisia ; calcium flux ; chemotaxis ; essential oils ; farnesene ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
    Subject code 571
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Neutrophil Immunomodulatory Activity of (−)-Borneol, a Major Component of Essential Oils Extracted from Grindelia squarrosa

    Igor A. Schepetkin / Gulmira Özek / Temel Özek / Liliya N. Kirpotina / Andrei I. Khlebnikov / Mark T. Quinn

    Molecules, Vol 27, Iss 4897, p

    2022  Volume 4897

    Abstract: Grindelia squarrosa (Pursh) Dunal is used in traditional medicine for treating various diseases; however, little is known about the immunomodulatory activity of essential oils from this plant. Thus, we isolated essential oils from the flowers (GEO Fl ) ... ...

    Abstract Grindelia squarrosa (Pursh) Dunal is used in traditional medicine for treating various diseases; however, little is known about the immunomodulatory activity of essential oils from this plant. Thus, we isolated essential oils from the flowers (GEO Fl ) and leaves (GEO Lv ) of G. squarrosa and evaluated the chemical composition and innate immunomodulatory activity of these essential oils. Compositional analysis of these essential oils revealed that the main components were α-pinene (24.7 and 23.2% in GEO Fl and GEO Lv , respectively), limonene (10.0 and 14.7%), borneol (23.4 and 16.6%), p -cymen-8-ol (6.1 and 5.8%), β-pinene (4.0 and 3.8%), bornyl acetate (3.0 and 5.1%), trans -pinocarveol (4.2 and 3.7%), spathulenol (3.0 and 2.0%), myrtenol (2.5 and 1.7%), and terpinolene (1.7 and 2.0%). Enantiomer analysis showed that α-pinene, β-pinene, and borneol were present primarily as (−)-enantiomers (100% enantiomeric excess (ee) for (−)-α-pinene and (−)-borneol in both GEO Fl and GEO Lv

    82 and 78% ee for (−)-β-pinene in GEO Fl and GEO Lv ), while limonene was present primarily as the (+)-enantiomer (94 and 96 ee in GEO Fl and GEO Lv ). Grindelia essential oils activated human neutrophils, resulting in increased [Ca 2+ ] i (EC 50 = 22.3 µg/mL for GEO Fl and 19.4 µg/mL for GEO Lv ). In addition, one of the major enantiomeric components, (−)-borneol, activated human neutrophil [Ca 2+ ] i (EC 50 = 28.7 ± 2.6), whereas (+)-borneol was inactive. Since these treatments activated neutrophils, we also evaluated if they were able to down-regulate neutrophil responses to subsequent agonist activation and found that treatment with Grindelia essential oils inhibited activation of these cells by the N -formyl peptide receptor 1 (FPR1) agonist f MLF and the FPR2 agonist WKYMVM. Likewise, (−)-borneol inhibited FPR-agonist-induced Ca 2+ influx in neutrophils. Grindelia leaf and flower essential oils, as well as (−)-borneol, also inhibited f MLF-induced chemotaxis of human neutrophils (IC 50 = 4.1 ± 0.8 µg/mL, 5.0 ± 1.6 µg/mL, and 5.8 ...
    Keywords borneol ; calcium influx ; chemotaxis ; essential oils ; Grindelia squarrosa ; monoterpene ; Organic chemistry ; QD241-441
    Subject code 290
    Language English
    Publishing date 2022-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Alarmins and c-Jun N-Terminal Kinase (JNK) Signaling in Neuroinflammation

    Nina D. Anfinogenova / Mark T. Quinn / Igor A. Schepetkin / Dmitriy N. Atochin

    Cells, Vol 9, Iss 2350, p

    2020  Volume 2350

    Abstract: Neuroinflammation is involved in the progression or secondary injury of multiple brain conditions, including stroke and neurodegenerative diseases. Alarmins, also known as damage-associated molecular patterns, are released in the presence of ... ...

    Abstract Neuroinflammation is involved in the progression or secondary injury of multiple brain conditions, including stroke and neurodegenerative diseases. Alarmins, also known as damage-associated molecular patterns, are released in the presence of neuroinflammation and in the acute phase of ischemia. Defensins, cathelicidin, high-mobility group box protein 1, S100 proteins, heat shock proteins, nucleic acids, histones, nucleosomes, and monosodium urate microcrystals are thought to be alarmins. They are released from damaged or dying cells and activate the innate immune system by interacting with pattern recognition receptors. Being principal sterile inflammation triggering agents, alarmins are considered biomarkers and therapeutic targets. They are recognized by host cells and prime the innate immune system toward cell death and distress. In stroke, alarmins act as mediators initiating the inflammatory response after the release from the cellular components of the infarct core and penumbra. Increased c-Jun N-terminal kinase (JNK) phosphorylation may be involved in the mechanism of stress-induced release of alarmins. Putative crosstalk between the alarmin-associated pathways and JNK signaling seems to be inherently interwoven. This review outlines the role of alarmins/JNK-signaling in cerebral neurovascular inflammation and summarizes the complex response of cells to alarmins. Emerging anti-JNK and anti-alarmin drug treatment strategies are discussed.
    Keywords alarmin ; neuroinflammation ; Alzheimer’s disease ; microglia ; c-Jun N-terminal kinase ; high-mobility group box protein 1 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Volatile Composition, Antimicrobial Activity, and In Vitro Innate Immunomodulatory Activity of Echinacea purpurea (L.) Moench Essential Oils

    Noura S. Dosoky / Liliya N. Kirpotina / Igor A. Schepetkin / Andrei I. Khlebnikov / Brent L. Lisonbee / Jeffrey L. Black / Hillary Woolf / Trever L. Thurgood / Brittany L. Graf / Prabodh Satyal / Mark T. Quinn

    Molecules, Vol 28, Iss 21, p

    2023  Volume 7330

    Abstract: Echinacea purpurea (L.) Moench is a medicinal plant commonly used for the treatment of upper respiratory tract infections, the common cold, sore throat, migraine, colic, stomach cramps, and toothaches and the promotion of wound healing. Based on the ... ...

    Abstract Echinacea purpurea (L.) Moench is a medicinal plant commonly used for the treatment of upper respiratory tract infections, the common cold, sore throat, migraine, colic, stomach cramps, and toothaches and the promotion of wound healing. Based on the known pharmacological properties of essential oils (EOs), we hypothesized that E. purpurea EOs may contribute to these medicinal properties. In this work, EOs from the flowers of E. purpurea were steam-distilled and analyzed by gas chromatography–mass spectrometry (GC–MS), GC with flame-ionization detection (GC–FID), and chiral GC–MS. The EOs were also evaluated for in vitro antimicrobial and innate immunomodulatory activity. About 87 compounds were identified in five samples of the steam-distilled E. purpurea EO. The major components of the E. purpurea EO were germacrene D (42.0 ± 4.61%), α-phellandrene (10.09 ± 1.59%), β-caryophyllene (5.75 ± 1.72%), γ-curcumene (5.03 ± 1.96%), α-pinene (4.44 ± 1.78%), δ-cadinene (3.31 ± 0.61%), and β-pinene (2.43 ± 0.98%). Eleven chiral compounds were identified in the E. purpurea EO, including α-pinene, sabinene, β-pinene, α-phellandrene, limonene, β-phellandrene, α-copaene, β-elemene, β-caryophyllene, germacrene D, and δ-cadinene. Analysis of E. purpurea EO antimicrobial activity showed that they inhibited the growth of several bacterial species, although the EO did not seem to be effective for Staphylococcus aureus . The E. purpurea EO and its major components induced intracellular calcium mobilization in human neutrophils. Additionally, pretreatment of human neutrophils with the E. purpurea EO or (+)-δ-cadinene suppressed agonist-induced neutrophil calcium mobilization and chemotaxis. Moreover, pharmacophore mapping studies predicted two potential MAPK targets for (+)-δ-cadinene. Our results are consistent with previous reports on the innate immunomodulatory activities of β-caryophyllene, α-phellandrene, and germacrene D. Thus, this study identified δ-cadinene as a novel neutrophil agonist and suggests that δ-cadinene may ...
    Keywords Echinacea purpurea ; purple coneflower ; essential oil ; antimicrobial activity ; (+)-δ-cadinene ; calcium flux ; Organic chemistry ; QD241-441
    Subject code 571
    Language English
    Publishing date 2023-10-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Novel Tryptanthrin Derivatives with Selectivity as c –Jun N–Terminal Kinase (JNK) 3 Inhibitors

    Igor A. Schepetkin / Oleksander S. Karpenko / Anastasia R. Kovrizhina / Liliya N. Kirpotina / Andrei I. Khlebnikov / Stepan I. Chekal / Alevtyna V. Radudik / Maryna O. Shybinska / Mark T. Quinn

    Molecules, Vol 28, Iss 4806, p

    2023  Volume 4806

    Abstract: The c -Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that regulate many physiological processes, including cell proliferation and differentiation, cell survival, and inflammation. Because of emerging data suggesting that JNK3 may ... ...

    Abstract The c -Jun N-terminal kinase (JNK) family includes three proteins (JNK1-3) that regulate many physiological processes, including cell proliferation and differentiation, cell survival, and inflammation. Because of emerging data suggesting that JNK3 may play an important role in neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease, as well as cancer pathogenesis, we sought to identify JNK inhibitors with increased selectivity for JNK3. A panel of 26 novel tryptanthrin-6-oxime analogs was synthesized and evaluated for JNK1-3 binding (K d ) and inhibition of cellular inflammatory responses. Compounds 4d (8-methoxyindolo[2,1- b ]quinazolin-6,12-dione oxime) and 4e (8-phenylindolo[2,1- b ]quinazolin-6,12-dione oxime) had high selectivity for JNK3 versus JNK1 and JNK2 and inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) transcriptional activity in THP-1Blue cells and interleukin-6 (IL-6) production by MonoMac-6 monocytic cells in the low micromolar range. Likewise, compounds 4d , 4e , and pan-JNK inhibitor 4h (9-methylindolo[2,1- b ]quinazolin-6,12-dione oxime) decreased LPS-induced c -Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. Molecular modeling suggested modes of binding interaction of these compounds in the JNK3 catalytic site that were in agreement with the experimental data on JNK3 binding. Our results demonstrate the potential for developing anti-inflammatory drugs based on these nitrogen-containing heterocyclic systems with selectivity for JNK3.
    Keywords anti-inflammatory ; c -Jun N-terminal kinase ; molecular docking ; nuclear factor-κB ; oxime ; selective kinase inhibitor ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Chemical Composition and Immunomodulatory Activity of Essential Oils from Rhododendron albiflorum

    Igor A. Schepetkin / Gulmira Özek / Temel Özek / Liliya N. Kirpotina / Andrei I. Khlebnikov / Mark T. Quinn

    Molecules, Vol 26, Iss 3652, p

    2021  Volume 3652

    Abstract: Rhododendron (Ericaceae) extracts contain flavonoids, chromones, terpenoids, steroids, and essential oils and are used in traditional ethnobotanical medicine. However, little is known about the immunomodulatory activity of essential oils isolated from ... ...

    Abstract Rhododendron (Ericaceae) extracts contain flavonoids, chromones, terpenoids, steroids, and essential oils and are used in traditional ethnobotanical medicine. However, little is known about the immunomodulatory activity of essential oils isolated from these plants. Thus, we isolated essential oils from the flowers and leaves of R. albiflorum (cascade azalea) and analyzed their chemical composition and innate immunomodulatory activity. Compositional analysis of flower (REO Fl ) versus leaf (REO Lv ) essential oils revealed significant differences. REO Fl was comprised mainly of monoterpenes (92%), whereas sesquiterpenes were found in relatively low amounts. In contrast, REO Lv was primarily composed of sesquiterpenes (90.9%), with a small number of monoterpenes. REO Lv and its primary sesquiterpenes (viridiflorol, spathulenol, curzerene, and germacrone) induced intracellular Ca 2+ mobilization in human neutrophils, C20 microglial cells, and HL60 cells transfected with N -formyl peptide receptor 1 (FPR1) or FPR2. On the other hand, pretreatment with these essential oils or component compounds inhibited agonist-induced Ca 2+ mobilization and chemotaxis in human neutrophils and agonist-induced Ca 2+ mobilization in microglial cells and FPR-transfected HL60 cells, indicating that the direct effect of these compounds on [Ca 2+ ] i desensitized the cells to subsequent agonist activation. Reverse pharmacophore mapping suggested several potential kinase targets for these compounds; however, these targets were not supported by kinase binding assays. Our results provide a cellular and molecular basis to explain at least part of the beneficial immunotherapeutic properties of the R. albiflorum essential oils and suggest that essential oils from leaves of this plant may be effective in modulating some innate immune responses, possibly by inhibition of neutrophil migration.
    Keywords Rhododendron albiflorum ; essential oil ; calcium flux ; neutrophil ; chemotaxis ; sesquiterpene ; Organic chemistry ; QD241-441
    Subject code 571
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Neutrophil Immunomodulatory Activity of Natural Organosulfur Compounds

    Igor A. Schepetkin / Liliya N. Kirpotina / Andrei I. Khlebnikov / Narayanaganesh Balasubramanian / Mark T. Quinn

    Molecules, Vol 24, Iss 9, p

    2019  Volume 1809

    Abstract: Organosulfur compounds are bioactive components of garlic essential oil (EO), mustard oil, Ferula EOs, asafoetida, and other plant and food extracts. Traditionally, garlic ( Allium sativum ) is used to boost the immune system; however, the mechanisms ... ...

    Abstract Organosulfur compounds are bioactive components of garlic essential oil (EO), mustard oil, Ferula EOs, asafoetida, and other plant and food extracts. Traditionally, garlic ( Allium sativum ) is used to boost the immune system; however, the mechanisms involved in the putative immunomodulatory effects of garlic are unknown. We investigated the effects of garlic EO and 22 organosulfur compounds on human neutrophil responses. Garlic EO, allyl propyl disulfide, dipropyl disulfide, diallyl disulfide, and allyl isothiocyanate (AITC) directly activated Ca 2+ flux in neutrophils, with the most potent being AITC. Although 1,3-dithiane did not activate neutrophil Ca 2+ flux, this minor constituent of garlic EO stimulated neutrophil reactive oxygen species (ROS) production. In contrast, a close analog (1,4-dithiane) was unable to activate neutrophil ROS production. Although 1,3-dithiane-1-oxide also stimulated neutrophil ROS production, only traces of this oxidation product were generated after a 5 h treatment of HL60 cells with 1,3-dithiane. Evaluation of several phosphatidylinositol-3 kinase (PI3K) inhibitors with different subtype specificities (A-66, TGX 221, AS605240, and PI 3065) showed that the PI3K p110δ inhibitor PI 3065 was the most potent inhibitor of 1,3-dithiane-induced neutrophil ROS production. Furthermore, 1,3-dithiane enhanced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), glycogen synthase kinase 3 α/β (GSK-3α/β), and cAMP response element binding (CREB) protein in differentiated neutrophil-like HL60 cells. Density functional theory (DFT) calculations confirmed the reactivity of 1,3-dithiane vs. 1,4-dithiane, based on the frontier molecular orbital analysis. Our results demonstrate that certain organosulfur compounds can activate neutrophil functional activity and may serve as biological response modifiers by augmenting phagocyte functions.
    Keywords organosulfur compounds ; phosphatidylinositol-3 kinase ; reactive oxygen species ; 1,3-dithiane ; neutrophil ; immunomodulation ; Organic chemistry ; QD241-441
    Subject code 571
    Language English
    Publishing date 2019-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Immunomodulatory Activity of Polysaccharides Isolated from Saussurea salicifolia L. and Saussurea frolovii Ledeb

    Igor A. Schepetkin / Marina G. Danilets / Anastasia A. Ligacheva / Evgenia S. Trofimova / Natalia S. Selivanova / Evgenii Yu. Sherstoboev / Sergei V. Krivoshchekov / Ekaterina I. Gulina / Konstantin S. Brazovskii / Liliya N. Kirpotina / Mark T. Quinn / Mikhail V. Belousov

    Molecules, Vol 28, Iss 6655, p

    2023  Volume 6655

    Abstract: The genus Saussurea has been used in the preparation of therapies for a number of medical problems, yet not much is known about the therapeutic high-molecular-weight compounds present in extracts from these plants. Since polysaccharides are important in ... ...

    Abstract The genus Saussurea has been used in the preparation of therapies for a number of medical problems, yet not much is known about the therapeutic high-molecular-weight compounds present in extracts from these plants. Since polysaccharides are important in immune modulation, we investigated the chemical composition and immunomodulatory activity of Saussurea salicifolia L. and Saussurea frolovii Ledeb polysaccharides. Water-soluble polysaccharides from the aerial parts of these plants were extracted using water at pHs of 2 and 6 and subsequently precipitated in ethanol to obtain fractions SSP2 and SSP6 from S. salicifolia and fractions SSF2 and SSF6 from S. frolovii . The molecular weights of fractions SSP2, SSP6, SFP2, and SFP6 were estimated to be 143.7, 113.2, 75.3, and 64.3 kDa, respectively. The polysaccharides from S. frolovii contained xylose (67.1–71.7%) and glucose (28.3–32.9%), whereas the polysaccharides from S. frolovii contained xylose (63.1–76.7%), glucose (11.8–19.2%), galactose (4.7–8.3%), and rhamnose (6.8–9.4%). Fractions SSP2, SSP6, and SFP2 stimulated nitric oxide (NO) production by murine macrophages, and NO production induced by SSP2, SSP6, and SFP2 was not inhibited by polymyxin B treatment of the fractions, whereaspolymyxin B treatment diminished the effects of SFP6, suggesting that SFP6 could contain lipopolysaccharide (LPS). The LPS-free fractions SSP2, SSP6, and SFP2 had potent immunomodulatory activity, induced NO production, and activated transcription factors NF-κB/AP-1 in human monocytic THP-1 cells and cytokine production by human MonoMac-6 monocytic cells, including interleukin (IL)-1α, IL-1β, IL-6, granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-γ, monocyte chemotactic protein 1 (MCP-1), and tumor necrosis factor (TNF). These data suggest that at least part of the beneficial therapeutic effects reported for water extracts of the Saussurea species are due to the modulation of leukocyte functions by polysaccharides.
    Keywords plant polysaccharide ; Saussurea ; macrophage ; nitric oxide ; cytokine ; polymyxin B ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2023-09-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Pyridazinones and Structurally Related Derivatives with Anti-Inflammatory Activity

    Niccolo Cantini / Igor A. Schepetkin / Nadezhda V. Danilenko / Andrei I. Khlebnikov / Letizia Crocetti / Maria Paola Giovannoni / Liliya N. Kirpotina / Mark T. Quinn

    Molecules, Vol 27, Iss 3749, p

    2022  Volume 3749

    Abstract: Persistent inflammation contributes to a number of diseases; therefore, control of the inflammatory response is an important therapeutic goal. In an effort to identify novel anti-inflammatory compounds, we screened a library of pyridazinones and ... ...

    Abstract Persistent inflammation contributes to a number of diseases; therefore, control of the inflammatory response is an important therapeutic goal. In an effort to identify novel anti-inflammatory compounds, we screened a library of pyridazinones and structurally related derivatives that were used previously to identify N-formyl peptide receptor (FPR) agonists. Screening of the compounds for their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor κB (NF-κB) transcriptional activity in human THP1-Blue monocytic cells identified 48 compounds with anti-inflammatory activity. Interestingly, 34 compounds were FPR agonists, whereas 14 inhibitors of LPS-induced NF-κB activity were not FPR agonists, indicating that they inhibited different signaling pathways. Further analysis of the most potent inhibitors showed that they also inhibited LPS-induced production of interleukin 6 (IL-6) by human MonoMac-6 monocytic cells, again verifying their anti-inflammatory properties. Structure–activity relationship (SAR) classification models based on atom pair descriptors and physicochemical ADME parameters were developed to achieve better insight into the relationships between chemical structures of the compounds and their biological activities, and we found that there was little correlation between FPR agonist activity and inhibition of LPS-induced NF-κB activity. Indeed, Cmpd43, a well-known pyrazolone-based FPR agonist, as well as FPR1 and FPR2 peptide agonists had no effect on the LPS-induced NF-κB activity in THP1-Blue cells. Thus, some FPR agonists reported to have anti-inflammatory activity may actually mediate their effects through FPR-independent pathways, as it is suggested by our results with this series of compounds. This could explain how treatment with some agonists known to be inflammatory (i.e., FPR1 agonists) could result in anti-inflammatory effects. Further research is clearly needed to define the molecular targets of pyridazinones and structurally related compounds with anti-inflammatory activity and ...
    Keywords anti-inflammatory ; pyridazinone ; N-formyl peptide receptor ; nuclear factor-κB ; monocyte/macrophage ; binary classification tree ; Organic chemistry ; QD241-441
    Subject code 540 ; 500
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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