Anti-Inflammatory Effects of Analogues of N-Acyl Homoserine Lactones on Eukaryotic Cells

Background: Since acyl-homoserine lactone (AHL) profiling has been described in the gut of healthy subjects and patients with inflammatory bowel disease (IBD), the potential effects of these molecules on host cells have raised interest in the medical community. In particular, natural AHLs such as the 3-oxo-C12-HSL exhibit anti-inflammatory properties. Our study aimed at finding stable 3-oxo-C12-HSL-derived analogues with improved anti-inflammatory effects on epithelial and immune cells. Methods: We first studied the stability and biological properties of the natural 3-oxo-C12-HSL on eukaryotic cells and a bacterial reporter strain. We then constructed and screened a library of 22 AHL-derived molecules. Anti-inflammatory effects were assessed by cytokine release in an epithelial cell model, Caco-2, and a murine macrophage cell line, RAW264.7, (respectively, IL-8 and IL-6) upon exposure to the molecule and after appropriate stimulation (respectively, TNF-α 50 ng/mL and IFN-γ 50 ng/mL, and LPS 10 ng/mL and IFN-γ 20 U/mL). Results: We found two molecules of interest with amplified anti-inflammatory effects on mammalian cells without bacterial-activating properties in the reporter strain. The molecules furthermore showed improved stability in biological medium compared to the native 3-oxo-C12-HSL. Conclusions: We provide new bio-inspired AHL analogues with strong anti-inflammatory properties that will need further study from a therapeutic perspective.

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In silico and in vitro Demonstration of Homoharrintonine Antagonism of RBD-ACE2 Binding and its Anti-inflammatory and anti-thrombogenic Properties in a 3D human vascular lung model

10.1101/2021.05.02.442384 ◽

2021 ◽

Author(s):

Shalini Saxena ◽

Kranti Meher ◽

Madhuri Rotella ◽

Subhramanyam Vangala ◽

Satish Chandran ◽

...

Keyword(s):

Molecular Docking ◽

Active Sites ◽

Cell Model ◽

Antiviral Drugs ◽

Lung Model ◽

Host Cells ◽

Spike Protein ◽

Prevention And Treatment ◽

Anti Inflammatory

Since 2019 the world has seen severe onslaught of SARS-CoV-2 viral pandemic. There is an urgent need for drugs that can be used to either prevent or treat the potentially fatal disease COVD-19. To this end, we screened FDA approved antiviral drugs which could be repurposed for COVID-19 through molecular docking approach in the various active sites of receptor binding domain (RBD). The RBD domain of SARS-CoV-2 spike protein is a promising drug target due to its pivotal role in viral-host attachment. Specifically, we focussed on identifying antiviral drugs which could a) block the entry of virus into host cells, b) demonstrate anti-inflammatory and/or anti-thrombogenic properties. Drugs which poses both properties could be useful for prevention and treatment of the disease. While we prioritized a few antiviral drugs based on molecular docking, corroboration with in vitro studies including a new 3D human vascular lung model strongly supported the potential of Homoharringtonine, a drug approved for chronic myeloid leukaemia to be repurposed for COVID-19. This natural product drug not only antagonized the biding of SARS-CoV-2 spike protein RBD binding to human angiotensin receptor 2 (ACE-2) protein but also demonstrated for the first time anti-thrombogenic and anti-leukocyte adhesive properties in a human cell model system. Overall, this work provides an important lead for development of rapid treatment of COVID-19 and also establishes a screening paradigm using molecular modelling and 3D human vascular lung model of disease to identify drugs with multiple desirable properties for prevention and treatment of COVID-19.

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Paraoxonases-2 and -3 Are Important Defense Enzymes againstPseudomonas aeruginosaVirulence Factors due to Their Anti-Oxidative and Anti-Inflammatory Properties

Journal of Lipids ◽

10.1155/2012/352857 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 15

Author(s):

Eva-Maria Schweikert ◽

Julianna Amort ◽

Petra Wilgenbus ◽

Ulrich Förstermann ◽

John F. Teiber ◽

...

Keyword(s):

Oxidative Stress ◽

Defense Mechanism ◽

Homoserine Lactone ◽

Host Cells ◽

Defense System ◽

Innate Defense ◽

Redox Active ◽

Intracellular Ca ◽

Anti Inflammatory ◽

Underlying Mechanisms

The pathogenPseudomonas aeruginosacauses serious damage in immunocompromised patients by secretion of various virulence factors, among them the quorum sensing N-(3-oxododecanoyl)-L-homoserine lactone (3OC12) and the redox-active pyocyanin (PCN). Paraoxonase-2 (PON2) may protect againstP. aeruginosainfections, as it efficiently inactivates 3OC12 and diminishes PCN-induced oxidative stress. This defense could be circumvented because 3OC12 mediates intracellular Ca2+-rise in host cells, which causes rapid inactivation and degradation of PON2. Importantly, we recently found that the PON2 paralogue PON3 prevents mitochondrial radical formation. Here we investigated its role as additional potential defense mechanism againstP. aeruginosainfections. Our studies demonstrate that PON3 diminished PCN-induced oxidative stress. Moreover, it showed clear anti-inflammatory potential by protecting against NF-κB activation and IL-8 release. The latter similarly applied to PON2. Furthermore, we observed a Ca2+-mediated inactivation and degradation of PON3, again in accordance with previous findings for PON2. Our results suggest that the anti-oxidative and anti-inflammatory functions of PON2 and PON3 are an important part of our innate defense system againstP. aeruginosainfections. Furthermore, we conclude thatP. aeruginosacircumvents PON3 protection by the same pathway as for PON2. This may help identifying underlying mechanisms in order to sustain the protection afforded by these enzymes.

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Metal Chelating, Inhibitory DNA Damage, and Anti-Inflammatory Activities of Phenolics from Rambutan (Nephelium lappaceum) Peel and the Quantifications of Geraniin and Corilagin

Molecules ◽

10.3390/molecules23092263 ◽

2018 ◽

Vol 23 (9) ◽

pp. 2263 ◽

Cited By ~ 9

Author(s):

Yujing Li ◽

Zhaojie Li ◽

Hu Hou ◽

Yongliang Zhuang ◽

Liping Sun

Keyword(s):

Dna Damage ◽

Cell Model ◽

Biological Properties ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Dependent Manner ◽

Protective Effects ◽

Metal Chelating ◽

Study Results ◽

Anti Inflammatory

Whereas the preparation and biological properties of rambutan peel phenolics (RPP) were explored in our previous studies, the metal chelating, inhibitory DNA damage, and anti-inflammatory activities of RPP were evaluated and the important phenolics of RPP quantified in this study. Results showed that RPP had high Fe2+ and Cu2+-chelating activities with EC50 of 0.80 mg/mL and 0.13 mg/mL, respectively. RPP effectively decreased the production of hydroxyl radical with IC50 of 62.4 μg/mL. The protective effects of RPP against AAPH-induced DNA damage were also explored. RPP efficiently inhibited peroxyl radical-induced plasmid DNA strand breakage. The anti-inflammatory effects of RPP were determined using a lipopolysaccharide (LPS)-induced RAW 264.7 cell model. RPP significantly inhibited the production of nitric oxide (NO) and controlled the levels of inducible NO synthase mRNA in LPS-induced RAW 264.7 cells. The inhibitory activity increased in a dose-dependent manner. The above bioactivity of RPP was associated with its phenolic content and phenolic profiles. Furthermore, the contents of geraniin and corilagin in RPP were determined by an ultra-high performance liquid chromatography coupled with triple quadruple mass spectrometry (UPLC-QQQ-MS), showing 140.02 and 7.87 mg/g extract dry weight. Thus, RPP has potential applications as a novel nutraceutical and functional food in health promotion.

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Tangeretin Inhibits Oxidative Stress and Inflammation via Upregulating Nrf-2 Signaling Pathway in Collagen-Induced Arthritic Rats

Pharmacology ◽

10.1159/000501163 ◽

2019 ◽

Vol 104 (3-4) ◽

pp. 187-195 ◽

Cited By ~ 7

Author(s):

Xing Li ◽

Peigen Xie ◽

Yu Hou ◽

Shudong Chen ◽

Peiheng He ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathway ◽

Chinese Herb ◽

Biological Properties ◽

Therapeutic Effects ◽

Protective Effects ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Ifn Γ ◽

Anti Inflammatory

Background/Aims: Tangeretin (TAN), a major phytochemical in tangerine peels and an important Chinese herb, has multiple biological properties, especially antioxidative and anti-inflammatory effects. However, the mechanisms remain unclear. Based on these findings, the aim of the present study was to assess the antioxidant and anti-inflammatory properties of TAN in bovine type II collagen-induced arthritis rats. Methods: TAN (50 mg/kg) was given orally once daily for 14 days. The effects of treatment were evaluated by biochemical assay (articular elastase, myeloperoxidase, end products of lipid peroxidation [MDA], antioxidant enzyme, such as superoxide dismutase, catalase, glutathione), nitric oxide, and inflammatory cytokines (interleukin-1β [IL-1β], IL-10, tumor necrosis factor-alpha [TNF-α], interferon-γ [IFN-γ], and prostaglandin E2 [PGE2]). The protective effects of TAN against rheumatoid arthritis (RA) were evident from the decrease in arthritis scoring. Furthermore, the Nrf-2 signaling pathway was assessed to illustrate the molecular mechanism. Results: TAN had therapeutic effects on RA by decreasing the oxidative stress damage and regulating inflammatory cytokine expression, including suppression of the accumulation of MDA products, decreasing the IL-1β, TNF-α, IFN-γ, and PGE2 levels, enhancing the IL-10 and the activity of antioxidant enzymes, which was through upregulating Nrf-2 signaling pathway. Conclusion: TAN might have potential as a therapeutic agent for the treatment of RA.

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The TIR-domain containing effectors BtpA and BtpB from Brucella abortus block energy metabolism

10.1101/703330 ◽

2019 ◽

Cited By ~ 1

Author(s):

Julia María Coronas-Serna ◽

Arthur Louche ◽

María Rodríguez-Escudero ◽

Morgane Roussin ◽

Paul R.C. Imbert ◽

...

Keyword(s):

Energy Metabolism ◽

Mammalian Cells ◽

Molecular Mechanisms ◽

Cell Model ◽

Interleukin 1 ◽

Effector Proteins ◽

Host Cells ◽

Yeast Cells ◽

Tir Domain ◽

Tir Domains

ABSTRACTBrucella species are facultative intracellular Gram-negative bacteria relevant to animal and human health. Their ability to establish an intracellular niche and subvert host cell pathways to their advantage depends on the delivery of bacterial effector proteins through a type IV secretion system. Brucella Toll/Interleukin-1 Receptor (TIR)-domain-containing proteins BtpA (also known as TcpB) and BtpB are among such effectors. Although divergent in primary sequence, they interfere with Toll-like receptor (TLR) signaling to inhibit the innate immune responses. However, the molecular mechanisms implicated still remain unclear. To gain insight into the functions of BtpA and BtpB, we expressed them in the budding yeast Saccharomyces cerevisiae as a eukaryotic cell model. We found that both effectors were cytotoxic and that their respective TIR domains were necessary and sufficient for yeast growth inhibition. Growth arrest was concomitant with actin depolymerization, endocytic block and a general decrease in kinase activity in the cell, suggesting a failure in energetic metabolism. Indeed, levels of ATP and NAD+ were low in yeast cells expressing BtpA and BtpB TIR domains, consistent with the recently described enzymatic activity of some TIR domains as NAD+ hydrolases. In human epithelial cells, both BtpA and BtpB expression reduced intracellular total NAD levels. In infected cells, both BtpA and BtpB contributed to reduction of total NAD, indicating that their NAD+ hydrolase functions are active intracellularly during infection. Overall, combining the yeast model together with mammalian cells and infection studies our results show that BtpA and BtpB modulate energy metabolism in host cells through NAD+ hydrolysis, assigning a novel role for these TIR domain-containing effectors in Brucella pathogenesis.

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Antagonistic and Immunomodulant Effects of Two Probiotic Strains of Lactobacillus on Clinical Strains of Helicobacter pylori

Galen Medical Journal ◽

10.31661/gmj.v9i0.1794 ◽

2020 ◽

Vol 9 ◽

pp. 1794

Author(s):

Somayyeh Taghizadeh ◽

Tahereh Falsafi ◽

Rouha Kasra Kermanshahi ◽

Reihaneh Ramezani

Keyword(s):

Helicobacter Pylori ◽

Cell Model ◽

Host Cells ◽

Macrophage Cell ◽

Cell Free Supernatant ◽

Probiotic Strains ◽

Ifn Γ ◽

Probiotic Lactobacilli ◽

H Pylori

Background: The present study aimed to evaluate the in vitro and in situ antagonistic effects of Lactobacillus probiotic strains on clinical strains of Helicobacter pylori . Also to investigate their immunomodulation effects on a macrophage cell model. Materials and Methods: Anti-microbial effects of probiotic lactobacilli against H. pylori was assessed using the well and disk diffusion methods. Effects of lactobacilli probiotics strains, as well as their cell-free supernatant on adhesion of H. pylori to MKN-45 gastric epithelial cells, were examined in their presence and absence. Immunomodulation effects of probiotic lactobacilli were performed using the U937 macrophage cell model. Incubation of host cells with probiotics and their cell-free supernatants with cultured host cells was performed in different optimized conditions. The supernatant of host cells cultured in their presence and absence was used for cytokines measurement. Results: Two probiotics‏, Lactobacillus acidophilus ATCC4356, and Lactobacillus rhamnosus PTCC1607, could inhibit the growth of clinical H. pylori in vitro. They could also inhibit attachment of H. pylori to MKN-45 cells. Cell-free supernatant of L. acidophilus had a stimulating effect on the production of Interferon-gamma (IFN-γ) by U937 cells. Conclusion: The present study demonstrates that, L. acidophilus ATCC4356 and L. rhamnosus PTCC1607 probiotic strains can inhibit the growth of clinical H. pylori in vitro. Treatment of U937 with alive H. pylori plus cell-free supernatant of L. acidophilus, have a significantly higher capacity to stimulate IFN-γ production than H. pylori alone. So, the metabolite (s) of this probiotic may have an immunomodulatory effect in immune response versus H. pylori. [GMJ.2020;9:e1794]

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Pseudomonas aeruginosa Autoinducer Enters and Functions in Mammalian Cells

Journal of Bacteriology ◽

10.1128/jb.186.8.2281-2287.2004 ◽

2004 ◽

Vol 186 (8) ◽

pp. 2281-2287 ◽

Cited By ~ 63

Author(s):

Simon C. Williams ◽

Erin K. Patterson ◽

Nancy L. Carty ◽

John A. Griswold ◽

Abdul N. Hamood ◽

...

Keyword(s):

Gene Expression ◽

Pseudomonas Aeruginosa ◽

Transcription Factors ◽

Nuclear Localization ◽

Mammalian Cells ◽

Homoserine Lactone ◽

Host Cells ◽

Human Pathogens ◽

Coding Region ◽

Binding Domains

ABSTRACT Quorum sensing (QS) is a cell density-dependent signaling mechanism used by many bacteria to control gene expression. Several recent reports indicate that the signaling molecules (autoinducers) that mediate QS in Pseudomonas aeruginosa may also modulate gene expression in host cells; however, the mechanisms are largely unknown. Here we show that two P. aeruginosa autoinducers, N-3-oxododecanoyl-homoserine lactone and N-butyryl-homoserine lactone, can both enter eukaryotic cells and activate artificial chimeric transcription factors based on their cognate transcriptional activators, LasR and RhlR, respectively. The autoinducers promoted nuclear localization of chimeric proteins containing the full LasR or RhlR coding region, and the LasR-based proteins were capable of activating transcription of a LasR-dependent luciferase gene. Responsiveness to autoinducer required the N-terminal autoinducer-binding domains of LasR and RhlR. Truncated proteins consisting of only the C-terminal helix-turn-helix DNA-binding domains of both proteins attached to a nuclear localization signal efficiently translocated to the nucleus in the absence of autoinducer, and truncated LasR-based proteins functioned as constitutively active transcription factors. Chimeric LasR proteins were only activated by their cognate autoinducer ligand and not by N-butyryl-l-homoserine lactone. These data provide evidence that autoinducer molecules from human pathogens can enter mammalian cells and suggest that autoinducers may influence gene expression in host cells by interacting with and activating as-yet-unidentified endogenous proteins.

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Diverse chemical and biological potentials of various pyridazine and pyridazinone derivatives

10.31221/osf.io/n5xvt ◽

2019 ◽

Author(s):

Chem Int

Keyword(s):

Heterocyclic Compounds ◽

Biological Activities ◽

Wide Spectrum ◽

Biological Properties ◽

Industrial Chemical ◽

Anti Inflammatory ◽

Pyridazinone Derivatives

A series of heterocyclic compounds incorporating pyridazine moiety were for diverse biological activities. Pyridazines and pyridazinones derivatives showed wide spectrum of biological activities such as vasodialator, cardiotonic, anticonvulsant, antihypertensive, antimicrobial, anti-inflammatory, analgesic, anti-feedant, herbicidal, and various other biological, agrochemical and industrial chemical activities. The results illustrated that the synthesized pyridazine/pyridazine compounds have diverse and significant biological activities. Mechanistic insights into the biological properties of pyridazinone derivatives and various synthetic techniques used for their synthesis are also described.

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The Molecular Diversity Scope of Urazole in the Synthesis of Organic Compounds

Current Organic Synthesis ◽

10.2174/1570179416666190925162215 ◽

2019 ◽

Vol 16 (7) ◽

pp. 953-967 ◽

Cited By ~ 1

Author(s):

Ghodsi M. Ziarani ◽

Fatemeh Mohajer ◽

Razieh Moradi ◽

Parisa Mofatehnia

Keyword(s):

Biological Activities ◽

Biological Properties ◽

Biologically Active ◽

Microtubule Assembly ◽

Heterocyclic Molecules ◽

Biological Perspective ◽

Highly Active ◽

Anti Inflammatory ◽

High Yields ◽

Short Time

Background: As a matter of fact, nitrogen as a hetero atom among other atoms has had an important role in active biological compounds. Since heterocyclic molecules with nitrogen are highly demanded due to biological properties, 4-phenylurazole as a compound containing nitrogen might be important in the multicomponent reaction used in agrochemicals, and pharmaceuticals. Considering the case of fused derivatives “pyrazolourazoles” which are highly applicable because of their application for analgesic, antibacterial, anti-inflammatory and antidiabetic activities as HSP-72 induction inhibitors (I and III) and novel microtubule assembly inhibitors. It should be mentioned that spiro-pyrazole also has biological activities like cytotoxic, antimicrobial, anticonvulsant, antifungal, anticancer, anti-inflammatory, and cardiotonic activities. Objective: Urazole has been used in many heterocyclic compounds which are valuable in organic syntheses. This review disclosed the advances in the use of urazole as the starting material in the synthesis of various biologically active molecules from 2006 to 2019. Conclusion: Compounds of urazole (1,2,4-triazolidine-3,5-dione) are the most important molecules which are highly active from the biological perspective in the pharmaceuticals as well as polymers. In summary, many protocols for preparations of the urazole derivatives from various substrates in multi-component reactions have been reported from different aromatic and aliphatic groups which have had carbonyl groups in their structures. It is noted that several catalysts have been synthesized to afford applicable molecules with urazole scaffolds. In some papers, being environmentally friendly, short time reactions and high yields are highlighted in the protocols. There is a room to synthesize new catalysts and perform new reactions by manipulating urazole to produce biologically active compounds, even producing chiral urazole component as many groups of chiral urazole compounds are important from biological perspective.

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Helenalin: An Anti-Inflammatory and Anti-Neoplastic Agent: A Review

Current Bioactive Compounds ◽

10.2174/1573407216666191226121004 ◽

2020 ◽

Vol 16 (8) ◽

pp. 1134-1146

Author(s):

Priyanka Kriplani ◽

Kumar Guarve ◽

Uttam S. Baghel

Keyword(s):

Rheumatoid Arthritis ◽

Adverse Effects ◽

Chronic Conditions ◽

Review Article ◽

Google Scholar ◽

Medical Community ◽

Inflammatory Agent ◽

Skin Cancers ◽

Medicinal Properties ◽

Anti Inflammatory

Objective: Helenalin is a natural anti-inflammatory agent that is proving its efficacy to treat various medical conditions. Though many plants are proving their effectiveness but their mechanisms are still not well understood. The objective of the review is to summarize various mechanisms of helenalin to treat inflammatory disorders and cancers, adverse effects, and avenues of further research. Methods: Structured research was carried out including Pub med, Science direct Medline, Research Gate and Google Scholar to find all articles published on helenalin. Various keywords used were “helenalin”, “Arnica”, “cancer”, “anti-inflammatory”, “cardiovascular”, “IBD”, “pharmacokinetics” etc. The aim of the review was to find out the problem prevailing in the data published to date which will help the researchers to investigate the molecule clinically. Results: Seventy articles are included in the review. Helenalin is found to cure chronic conditions like rheumatoid arthritis, ulcers and malignancies like stomach, colon, breast, larynx, lung and skin cancers via multiple mechanisms. These diseases do not proceed via a unilateral pathway. So, it can be a useful molecule to treat numerous diseases. Conclusion: This review article will help us to systemically analyze the wealth of information concerning the medicinal properties of helenalin and to recognize the gaps which have vetoed its pervasive application in the medical community.

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