On the Mechanism of Action of Anti-Inflammatory Activity of Hypericin: An In Silico Study Pointing to the Relevance of Janus Kinases Inhibition

St. John’s Wort (Hypericum perforatum L.) flowers are commonly used in ethnomedical preparations with promising outcomes to treat inflammation both per os and by topical application. However, the underlying molecular mechanisms need to be described toward a rational, evidence-based, and reproducible use. For this purpose, the aptitude of the prominent Hypericum metabolite hypericin was assessed, along with that of its main congeners, to behave as an inhibitor of janus kinase 1, a relevant enzyme in inflammatory response. It was used a molecular modeling approach relying on docking simulations, pharmacophoric modeling, and molecular dynamics to estimate the capability of molecules to interact and persist within the enzyme pocket. Our results highlighted the capability of hypericin, and some of its analogues and metabolites, to behave as ATP-competitive inhibitor providing: (i) a likely mechanistic elucidation of anti-inflammatory activity of H. perforatum extracts containing hypericin and related compounds; and (ii) a rational-based prioritization of H. perforatum components to further characterize their actual effectiveness as anti-inflammatory agents.

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Directed Search of Anti-inflammatory Agents Among (3HQuinazoline- 4-ylidene)hydrazides of N-protected Amino acids and their Heterocyclization Products

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry ◽

10.2174/1871523018666190115092215 ◽

2020 ◽

Vol 19 (1) ◽

pp. 61-73

Author(s):

Yulya Martynenko ◽

Oleksii Antypenko ◽

Inna Nosulenko ◽

Galina Berest ◽

Sergii Kovalenko

Keyword(s):

Amino Acids ◽

Molecular Mechanisms ◽

Diclofenac Sodium ◽

Inflammatory Activity ◽

Directed Search ◽

Reference Drug ◽

Aryl Amines ◽

Anti Inflammatory ◽

Sar Analysis ◽

Cox 1

Background: (Quinazoline-4-ylidene)hydrazides are valued intermediates in modern organic chemistry, as they are commonly used for the synthesis of substituted [1,2,4]triazolo[1,5-c]quinazolines. Objective: Unknown N-acyl-2-([1,2,4]triazolo[1,5-c]quinazoline-2-yl)-alkyl-(alkaryl-, aryl-) amines were synthesized and evaluated for anti-inflammatory potential. Methods: The peculiarities of the synthesized compounds structures were studied by IR-, NMR spectroscopy and chromatography-mass spectrometry and were discussed in detail. Probable molecular mechanisms of activity (inhibition of COX-1 and COX-2) were predicted due to molecular docking. Anti-inflammatory activity of synthesized compounds was determined by their ability to reduce the formalin-induced paw edema in rats. Diclofenac sodium was used as reference drug. Results: In this study, the synthesis of N-acetyl-(benzoyl)-2-([1,2,4]triazolo[1,5-c]quinazolinе- 2-yl)alkyl-(aralkyl-, aryl-)amines, using (3H-quinazoline-4-ylidene)hydrazides of Nprotected amino acids or 4-hydrazinoquinazoline and N-prorotected amino acids as starting compounds was developed. It was established that the reaction of (3H-quinazoline-4- ylidene)hydrazides of Boc-amino acids occurred with the formation of N-acetyl-substituted triazoloquinazolines. High anti-inflammatory activity was detected for unknown (3Hquinazoline- 4-ylidene)hydrazides Boc-amino acids (1.13-1.15) and N-acetyl-(benzoyl)-2- ([1,2,4]triazolo[1,5-c]quinazoline-2-yl-)aralkyl-(aryl-)amines (3.2, 3.3, 3.11, 3.12), using the experimental formalin test. Conclusion: The conducted SAR-analysis allowed to detect critical fragments. Namely, the Boc-aminoaralkyl-(aryl-)acid residue in (3H-quinazoline-4-ylidene)hydrazides (1.13- 1.15), benzyl and phenyl linker groups in N-acetyl-(benzoyl)-2-([1,2,4]triazolo[1,5- c]quinazoline-2-yl-)aralkyl-(aryl-) amines (3.2, 3.3, 3.11, 3.12) are believed to be substantial for anti-inflammatory activity.

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Anti-Inflammatory Effects of Boldine and Reticuline Isolated from Litsea cubeba through JAK2/STAT3 and NF-κB Signaling Pathways

Planta Medica ◽

10.1055/s-0043-113447 ◽

2017 ◽

Vol 84 (01) ◽

pp. 20-25 ◽

Cited By ~ 15

Author(s):

Xinyao Yang ◽

Xiaoli Gao ◽

Yuan Cao ◽

Qiang Guo ◽

Shanshan Li ◽

...

Keyword(s):

Synergistic Effects ◽

Underlying Mechanism ◽

Janus Kinase ◽

Inflammatory Activity ◽

Intragastric Administration ◽

Litsea Cubeba ◽

Tnf Α ◽

Anti Inflammatory ◽

Rat Paw

AbstractThe anti-inflammatory effects of boldine and reticuline isolated from Litsea cubeba were evaluated by using xylene-induced ear edema and carrageenan-induced paw edema in mice and rats. Our results demonstrated that intragastric administration with boldine and reticuline significantly mitigated ear weight in mice and decreased paw volume in rats. A combination administration of boldine (0.5 mg/kg) + reticuline (0.25 mg/kg) resulted in a potentiated inhibition in these two models. In parallel, boldine or reticuline reduce the infiltration of neutrophil leukocytes in rat paw tissue, respectively, and the combination of the two groups performed a better anti-inflammatory activity as shown in histopathologies. Boldine, reticuline, and their combination notably inhibited mRNA expressions of TNF-α, and IL-6 and reduced the phosphorylation levels of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Beyond that, their combination also can reduce the phosphorylation levels of p65 and IκBα in the pathological tissues of animals, as observed by real-time PCR and western blot analyses, respectively. These findings indicate for the first time that boldine and reticuline have not only anti-inflammatory activity but also potential synergistic effects in vivo. The underlying mechanism may relate to the inhibition on the expression of pro-inflammatory cytokines, such as TNF-α and IL-6, which may be a consequence of JAK2/STAT3 and NF-κB pathway involvements. This study provides useful data for further exploration and application of boldine and reticuline as potential anti-inflammatory medicines.

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Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide

PeerJ ◽

10.7717/peerj.9533 ◽

2020 ◽

Vol 8 ◽

pp. e9533 ◽

Cited By ~ 1

Author(s):

Zhiyu Wang ◽

Yanfei Wang ◽

Prachi Vilekar ◽

Seung-Pil Yang ◽

Mayuri Gupta ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Small Molecule ◽

Inflammatory Activity ◽

Health Concern ◽

Docking Simulations ◽

Tnf Α ◽

Anti Inflammatory ◽

Novel Coronavirus ◽

Pro Inflammatory Cytokines

The novel coronavirus SARS-CoV-2 has become a global health concern. The morbidity and mortality of the potentially lethal infection caused by this virus arise from the initial viral infection and the subsequent host inflammatory response. The latter may lead to excessive release of pro-inflammatory cytokines, IL-6 and IL-8, as well as TNF-α ultimately culminating in hypercytokinemia (“cytokine storm”). To address this immuno-inflammatory pathogenesis, multiple clinical trials have been proposed to evaluate anti-inflammatory biologic therapies targeting specific cytokines. However, despite the obvious clinical utility of such biologics, their specific applicability to COVID-19 has multiple drawbacks, including they target only one of the multiple cytokines involved in COVID-19’s immunopathy. Therefore, we set out to identify a small molecule with broad-spectrum anti-inflammatory mechanism of action targeting multiple cytokines of innate immunity. In this study, a library of small molecules endogenous to the human body was assembled, subjected to in silico molecular docking simulations and a focused in vitro screen to identify anti-pro-inflammatory activity via interleukin inhibition. This has enabled us to identify the loop diuretic furosemide as a candidate molecule. To pre-clinically evaluate furosemide as a putative COVID-19 therapeutic, we studied its anti-inflammatory activity on RAW264.7, THP-1 and SIM-A9 cell lines stimulated by lipopolysaccharide (LPS). Upon treatment with furosemide, LPS-induced production of pro-inflammatory cytokines was reduced, indicating that furosemide suppresses the M1 polarization, including IL-6 and TNF-α release. In addition, we found that furosemide promotes the production of anti-inflammatory cytokine products (IL-1RA, arginase), indicating M2 polarization. Accordingly, we conclude that furosemide is a reasonably potent inhibitor of IL-6 and TNF-α that is also safe, inexpensive and well-studied. Our pre-clinical data suggest that it may be a candidate for repurposing as an inhaled therapy against COVID-19.

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) and Spike (S) Proteins Antagonize Host Type I Interferon Response

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.766922 ◽

2021 ◽

Vol 11 ◽

Author(s):

Qi Zhang ◽

Zhiqiang Chen ◽

Chenxiao Huang ◽

Jiuyuan Sun ◽

Minfei Xue ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Type I Interferon ◽

Typical Feature ◽

Janus Kinase ◽

Interferon Response ◽

Type I ◽

Downstream Signaling ◽

Janus Kinase 1

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide and has infected more than 250 million people. A typical feature of COVID-19 is the lack of type I interferon (IFN-I)-mediated antiviral immunity in patients. However, the detailed molecular mechanisms by which SARS-CoV-2 evades the IFN-I-mediated antiviral response remain elusive. Here, we performed a comprehensive screening and identified a set of SARS-CoV-2 proteins that antagonize the IFN-I response. Subsequently, we characterized the mechanisms of two viral proteins antagonize IFN-I production and downstream signaling. SARS-CoV-2 membrane protein binds to importin karyopherin subunit alpha-6 (KPNA6) to inhibit interferon regulatory factor 3(IRF3) nuclear translocation. Further, the spike protein interacts with signal transducer and activator of transcription 1 (STAT1) to block its association with Janus kinase 1 (JAK1). This study increases our understanding of SARS-CoV-2 pathogenesis and suggests novel therapeutic targets for the treatment of COVID-19.

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Fucoidan Isolated from Saccharina japonica Inhibits LPS-Induced Inflammation in Macrophages via Blocking NF-κB, MAPK and JAK-STAT Pathways

Marine Drugs ◽

10.3390/md18060328 ◽

2020 ◽

Vol 18 (6) ◽

pp. 328 ◽

Cited By ~ 4

Author(s):

Jing Ye ◽

Donghui Chen ◽

Zhicheng Ye ◽

Yayan Huang ◽

Na Zhang ◽

...

Keyword(s):

High Performance ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Biological Activities ◽

Saccharina Japonica ◽

Janus Kinase ◽

Mitogen Activated Protein Kinase ◽

Resonance Spectroscopy ◽

Mechanism Study ◽

Anti Inflammatory

Fucoidan has been reported to have a variety of biological activities. However, different algae species, extraction methods, harvesting seasons, and growth regions lead to the structural variation of fucoidan, which would affect the bioactivities of fucoidan. To date, the anti-inflammatory properties and the underlying mechanism of fucoidan from brown alga Saccharina japonica (S. japonica) remain limited. The aims of the present study were to investigate the structure, the anti-inflammatory properties, and the potential molecular mechanisms of fucoidan isolated from S. japonica (SF6) against lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. SF6 was characterized using high performance liquid gel permeation chromatography (HPGPC), Fourier transform infrared spectroscopy (FTIR), and nuclear magnetic resonance spectroscopy (NMR), and observed to be rich in fucose, galactose, and sulfate. Additionally, results showed that SF6 remarkably inhibited LPS-induced production of various inflammatory mediators and pro-inflammation cytokines, including nitric oxide (NO), NO synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-β (IL-β), and interleukin-6 (IL-6). A mechanism study showed that SF6 could effectively inhibit inflammatory responses through blocking LPS-induced inflammation pathways, including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase (JAK)-2 and signal transducer and activator of transcription (STAT)-1/3 pathways. These results suggested that SF6 has the potential to be developed as an anti-inflammatory agent applied in functional food.

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Treatment with Peanut Sprout Root Extract Alleviates Inflammation in a Lipopolysaccharide-Stimulated Mouse Macrophage Cell Line by Inhibiting the MAPK Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms20235907 ◽

2019 ◽

Vol 20 (23) ◽

pp. 5907 ◽

Cited By ~ 1

Author(s):

Yun Mi Lee ◽

Eunjung Son ◽

Dong-Seon Kim

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Mapk Signaling ◽

Significant Inhibition ◽

Inflammatory Activity ◽

No Production ◽

Root Extract ◽

Tnf Α ◽

Anti Inflammatory ◽

Dose Dependent

Inflammation is a key response of the immune system to infection but aberrant inflammatory activity can lead to tissue damage and inflammatory diseases. Increasing evidence suggests that peanut sprout root extract (PSRE) has anti-inflammatory activity, and the aim of this study is therefore to investigate the effects of PSRE on the inflammatory response and the molecular mechanisms underpinning this effect in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Using a combination of cell viability, ELISA, and nitric oxide (NO) assays, together with Western blotting, we showed that PSRE effectively inhibited NO production in LPS-stimulated cells and significantly reduced the expression of pro-inflammatory cytokines, including IL-6, IL-1β, and PGE2, at a dose of 200 µg/mL of PSRE, whereas TNF-α expression tended to decrease under PSRE treatment. We also confirmed a dose-dependent and significant inhibition of iNOS and COX-2 protein expression. In addition, PSRE treatment induced anti-inflammatory effects by inhibiting the phosphorylation of MAPKs (ERK, JNK, and p38) and NF-κB activation. Our results indicate that the anti-inflammatory properties of PSRE may result from inhibition of the MAPK pathways, which are known promoters of cytokine secretion.

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Dietary Cameroonian Plants Exhibit Anti-Inflammatory Activity in Human Gastric Epithelial Cells

Nutrients ◽

10.3390/nu12123787 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3787

Author(s):

Achille Parfait Atchan Nwakiban ◽

Marco Fumagalli ◽

Stefano Piazza ◽

Andrea Magnavacca ◽

Giulia Martinelli ◽

...

Keyword(s):

Epithelial Cells ◽

Molecular Mechanisms ◽

Biological Activities ◽

Antioxidant Properties ◽

Inflammatory Activity ◽

Ros Generation ◽

Gastric Epithelial Cells ◽

Free System ◽

Tetrapleura Tetraptera ◽

Anti Inflammatory

In Cameroon, local plants are traditionally used as remedies for a variety of ailments. In this regard, several papers report health benefits of Cameroonian spices, which include antioxidant and anti-microbial properties, whereas gastric anti-inflammatory activities have never been previously considered. The present study investigates the antioxidant and anti-inflammatory activities of hydro-alcoholic extracts of eleven Cameroonian spices in gastric epithelial cells (AGS and GES-1 cells). The extracts showed antioxidant properties in a cell-free system and reduced H2O2-induced ROS generation in gastric epithelial cells. After preliminary screening on TNFα-induced NF-κB driven transcription, six extracts from Xylopia parviflora, Xylopia aethiopica, Tetrapleura tetraptera, Dichrostachys glomerata, Aframomum melegueta, and Aframomum citratum were selected for further studies focusing on the anti-inflammatory activity. The extracts reduced the expression of some NF-κB-dependent pro-inflammatory mediators strictly involved in the gastric inflammatory process, such as IL-8, IL-6, and enzymes such as PTGS2 (COX-2), without affecting PTGS1 (COX-1). In conclusion, the selected extracts decreased pro-inflammatory markers by inhibiting the NF-κB signaling in gastric cells, justifying, in part, the traditional use of these spices. Other molecular mechanisms cannot be excluded, and further studies are needed to better clarify their biological activities at the gastric level.

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Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling

Science Signaling ◽

10.1126/scisignal.aaf8566 ◽

2016 ◽

Vol 9 (453) ◽

pp. ra109-ra109 ◽

Cited By ~ 42

Author(s):

C. Rutherford ◽

C. Speirs ◽

J. J. L. Williams ◽

M.-A. Ewart ◽

S. J. Mancini ◽

...

Keyword(s):

Protein Kinase ◽

Janus Kinase ◽

Inflammatory Signaling ◽

Janus Kinase 1 ◽

Anti Inflammatory ◽

Energy Sensing ◽

Amp Activated Protein Kinase

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Molecular modelling, Synthesis and Evaluation of Flavone and Flavanone Scaffolds as Anti-inflammatory Agents

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry ◽

10.2174/1871523019666200102112017 ◽

2020 ◽

Vol 19 ◽

Author(s):

Natarajan Kiruthiga ◽

Manikandan Alagumuthu ◽

Chellappa Selvinthanuja ◽

Kulandaivel Srinivasan ◽

Thangavel Sivakumar

Keyword(s):

Inflammatory Diseases ◽

In Vitro Models ◽

Cyclooxygenase 2 ◽

Inflammatory Activity ◽

Spectroscopic Techniques ◽

Binding Interaction ◽

Docking Simulations ◽

Ic50 Values ◽

Anti Inflammatory

Objective: The objective of the study was to develop new Cyclooxygenase-2 inhibitors as anti-inflammatory agents from synthetic route. Method: The 2-phenyl-4H-chromen-4-one and 2-phenyl-2,3-dihydro-4H-chromen-one hybrids were synthesised and characterised by using UV, IR, 1H-NMR, and mass spectrometry. An attempt was made for consolidated the lead flavones and flavanones scaffolds by determining ADME/T properties. Molecular docking simulations were performed by using Autodock.4. for understanding the binding interaction over the targeted enzyme Cyclooxygenase-2. The titled compounds were evaluated for various in-vitro models for antioxidant and anti-inflammatory activities and based upon the IC50 values, the selected compounds were screened for invivo anti-inflammatory activity by both acute and chronic models. Results: The twenty compounds of titled compounds were synthesised and elucidated their structure for confirmation of their functional groups by various spectroscopic techniques. Among the synthesized compounds, in flavone derivatives such as HFc (7-hydroxy-3-(4-methoxy phenyl)-4H-chromen-4-one), HFd (2-(2,4-di methoxy-phenyl)-7-hydroxy-4H-chromen-4-one) and HFe (7-hydroxy-2-(thiophen-2-yl)-4H-chromen-4-one) were produced higher potency. As like, flavanone derivatives HFAc (7-hydroxy-2-(4-hydroxy-3-methoxy phenyl)-2,3-dihydro-4H-chromen-4-one), HFAb (7-hydroxy-2-(4-methoxy phenyl)-2,3-dihydro-4H-chromen-4-one) and HFAd (7-hydroxy-2-(thiophen-2-yl)-2,3-dihydro-4H-chromen-4-one) showed significant anti-inflammatory activity compared to the standard COX-2 inhibitors. Conclusions: The flavone and flavanone scaffolds were posses their excellent inhibitory action over the Cyclooxygenase-2 and acts as a potential anti-inflammatory agents. The results of computational studies were also significantly correlated and conclude that those naturally mimicking flavonoid analogues were tremendous candidates for fighting against the inflammatory diseases in drug discovery.

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