Melatonin as an Anti-Inflammatory Agent Modulating Inflammasome Activation

Inflammation may be defined as the innate response to harmful stimuli such as pathogens, injury, and metabolic stress; its ultimate function is to restore the physiological homeostatic state. The exact aetiology leading to the development of inflammation is not known, but a combination of genetic, epigenetic, and environmental factors seems to play an important role in the pathogenesis of many inflammation-related clinical conditions. Recent studies suggest that the pathogenesis of different inflammatory diseases also involves the inflammasomes, intracellular multiprotein complexes that mediate activation of inflammatory caspases thereby inducing the secretion of proinflammatory cytokines. Melatonin, an endogenous indoleamine, is considered an important multitasking molecule with fundamental clinical applications. It is involved in mood modulation, sexual behavior, vasomotor control, and immunomodulation and influences energy metabolism; moreover, it acts as an oncostatic and antiaging molecule. Melatonin is an important antioxidant and also a widespread anti-inflammatory molecule, modulating both pro- and anti-inflammatory cytokines in different pathophysiological conditions. This review, first, gives an overview concerning the growing importance of melatonin in the inflammatory-mediated pathological conditions and, then, focuses on its roles and its protective effects against the activation of the inflammasomes and, in particular, of the NLRP3 inflammasome.

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Techniques to Study Inflammasome Activation and Inhibition by Small Molecules

Molecules ◽

10.3390/molecules26061704 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1704

Author(s):

Diego Angosto-Bazarra ◽

Cristina Molina-López ◽

Alejandro Peñín-Franch ◽

Laura Hurtado-Navarro ◽

Pablo Pelegrín

Keyword(s):

Inflammatory Response ◽

Small Molecules ◽

Mechanism Of Action ◽

Inflammatory Diseases ◽

Inflammasome Activation ◽

Chronic Inflammatory Diseases ◽

Anti Inflammatory ◽

Inhibitory Molecules ◽

Inflammasome Inhibitors

Inflammasomes are immune cytosolic oligomers involved in the initiation and progression of multiple pathologies and diseases. The tight regulation of these immune sensors is necessary to control an optimal inflammatory response and recover organism homeostasis. Prolonged activation of inflammasomes result in the development of chronic inflammatory diseases, and the use of small drug-like inhibitory molecules are emerging as promising anti-inflammatory therapies. Different aspects have to be taken in consideration when designing inflammasome inhibitors. This review summarizes the different techniques that can be used to study the mechanism of action of potential inflammasome inhibitory molecules.

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A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction

Frontiers in Immunology ◽

10.3389/fimmu.2020.607564 ◽

2020 ◽

Vol 11 ◽

Author(s):

Chun-Hsien Wu ◽

Chin Heng Gan ◽

Lan-Hui Li ◽

Jen-Che Chang ◽

Shin-Tai Chen ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Membrane Integrity ◽

Mechanistic Study ◽

Autophagic Flux ◽

Inflammasome Activation ◽

Dependent Manner ◽

Inflammatory Agent ◽

Nlrp3 Inflammasome Activation ◽

Autophagy Induction ◽

Anti Inflammatory

Conjugated polyenes are a class of widely occurring natural products with various biological functions. We previously identified 4-hydroxy auxarconjugatin B (4-HAB) as anti‐inflammatory agent with an IC50 of ~20 µM. In this study, we synthesized a new anti‐inflammatory 4-HAB analogue, F240B, which has an IC50 of less than 1 µM. F240B dose-dependently induced autophagy by increasing autophagic flux, LC3 speck formation and acidic vesicular organelle formation. F240B inhibited NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome activation through autophagy induction. In a mechanistic study, F240B inhibited interleukin (IL)-1β (IL-1β) precursor expression, promoted degradation of NLRP3 and IL-1β, and reduced mitochondrial membrane integrity loss in an autophagy-dependent manner. Additionally, F240B inhibited apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and speck formation without affecting the interaction between NLRP3 and ASC or NIMA-related kinase 7 (NEK7) and double-stranded RNA-dependent kinase (PKR). Furthermore, F240B exerted in vivo anti-inflammatory activity by reducing the intraperitoneal influx of neutrophils and the levels of IL-1β, active caspase-1, IL-6 and monocyte chemoattractant protein-1 (MCP-1) in lavage fluids in a mouse model of uric acid crystal-induced peritonitis. In conclusion, F240B attenuated the NLRP3 inflammasome through autophagy induction and can be developed as an anti-inflammatory agent in the future.

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Update on the Role of Cannabinoid Receptors after Ischemic Stroke

Mediators of Inflammation ◽

10.1155/2012/824093 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 24

Author(s):

Luciano S. A. Capettini ◽

Silvia Q. Savergnini ◽

Rafaela F. da Silva ◽

Nikos Stergiopulos ◽

Robson A. S. Santos ◽

...

Keyword(s):

Ischemic Stroke ◽

Cannabinoid Receptors ◽

Inflammatory Diseases ◽

Receptor Activation ◽

Protective Effects ◽

Peripheral Tissues ◽

Transmembrane Receptors ◽

Anti Inflammatory

Cannabinoids are considered as key mediators in the pathophysiology of inflammatory diseases, including atherosclerosis. In particular, they have been shown to reduce the ischemic injury after acute cardiovascular events, such as acute myocardial infarction and ischemic stroke. These protective and anti-inflammatory properties on peripheral tissues and circulating inflammatory have been demonstrated to involve their binding with both selective cannabinoid type 1 (CB1) and type 2 (CB2) transmembrane receptors. On the other hands, the recent discoveries of novel different classes of cannabinoids and receptors have increased the complexity of this system in atherosclerosis. Although only preliminary data have been reported on the activities of novel cannabinoid receptors, several studies have already investigated the role ofCB1andCB2receptors in ischemic stroke. WhileCB1receptor activation has been shown to directly reduce atherosclerotic plaque inflammation, controversial data have been shown on neurotransmission and neuroprotection after stroke. Given its potent anti-inflammatory activities on circulating leukocytes, theCB2activation has been proven to produce protective effects against acute poststroke inflammation. In this paper, we will update evidence on different cannabinoid-triggered avenues to reduce inflammation and neuronal injury in acute ischemic stroke.

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Protective effects of ethyl pyruvate treatment on paraquat-intoxicated rats

Human & Experimental Toxicology ◽

10.1177/0960327108088976 ◽

2008 ◽

Vol 27 (1) ◽

pp. 49-54 ◽

Cited By ~ 25

Author(s):

JH Lee ◽

WY Kwon ◽

YH Jo ◽

GJ Suh ◽

YK Youn

Keyword(s):

Nitric Oxide ◽

Oxygen Radicals ◽

Ethyl Pyruvate ◽

Ischemia Reperfusion ◽

Oxygen Radical ◽

Protective Effects ◽

Inflammatory Agent ◽

Anti Inflammatory ◽

Inflammatory Action ◽

Liver Tissues

Although, numerous studies have attempted to reduce the oxygen radical injury induced by the antioxidants in paraquat intoxication, these antioxidant therapies have showed few survival benefits. Ethyl pyruvate (EP) may function as an effective scavenger of oxygen radicals, an anti-inflammatory agent and an energy source in many ischemia reperfusion models. The aim of this study was to evaluate the antioxidant and anti-inflammatory effects of EP on the lung and the liver tissues in paraquat-intoxicated rats. Rats were randomly given either a low (2 mg/kg i.p.) or high (40 mg/kg i.p.) EP dose, 30 min before or 1 h after paraquat (50 mg/kg i.p.) administration, and subsequently killed at 6 and 24 h. Glutathione (GSH) and malondialdehyde (MDA) levels of the lungs and the livers, and plasma nitric oxide (NO) concentrations were measured. Pretreatment of EP significantly decreased the MDA level in the lung and the liver tissues. EP also significantly decreased plasma NO concentrations at 6 h. EP pretreatment, however, failed to show significant change in GSH concentration. In post-treatment of EP, MDA levels in the lung tissue and plasma NO levels were significantly decreased. In conclusion, EP decreased the lipid peroxidation and seemed to exert an anti-inflammatory action in the paraquat intoxication rat model.

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Inhibitory Role of Berberine, an Isoquinoline Alkaloid, on NLRP3 Inflammasome Activation for the Treatment of Inflammatory Diseases

Molecules ◽

10.3390/molecules26206238 ◽

2021 ◽

Vol 26 (20) ◽

pp. 6238

Author(s):

Paromita Sarbadhikary ◽

Blassan P. George ◽

Heidi Abrahamse

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammatory Diseases ◽

In Vivo Studies ◽

Inflammasome Activation ◽

Inflammatory Disorders ◽

Nlrp3 Inflammasome Activation ◽

Anti Inflammatory

The pyrin domain-containing multiprotein complex NLRP3 inflammasome, consisting of the NLRP3 protein, ASC adaptor, and procaspase-1, plays a vital role in the pathophysiology of several inflammatory disorders, including neurological and metabolic disorders, chronic inflammatory diseases, and cancer. Several phytochemicals act as promising anti-inflammatory agents and are usually regarded to have potential applications as complementary or alternative therapeutic agents against chronic inflammatory disorders. Various in vitro and in vivo studies have reported the anti-inflammatory role of berberine (BRB), an organic heteropentacyclic phytochemical and natural isoquinoline, in inhibiting NLRP3 inflammasome-dependent inflammation against many disorders. This review summarizes the mechanism and regulation of NLRP3 inflammasome activation and its involvement in inflammatory diseases, and discusses the current scientific evidence on the repressive role of BRB on NLRP3 inflammasome pathways along with the possible mechanism(s) and their potential in counteracting various inflammatory diseases.

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Protective effects of berberine as a natural antioxidant and anti-inflammatory agent against nephrotoxicity induced by cyclophosphamide in mice

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-021-02182-3 ◽

2022 ◽

Author(s):

Mohammad Amin Mombeini ◽

Hadi Kalantar ◽

Elahe Sadeghi ◽

Mehdi Goudarzi ◽

Hamidreza Khalili ◽

...

Keyword(s):

Natural Antioxidant ◽

Protective Effects ◽

Inflammatory Agent ◽

Anti Inflammatory

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Sinapic Acid Controls Inflammation by Suppressing NLRP3 Inflammasome Activation

Cells ◽

10.3390/cells10092327 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2327

Author(s):

Eun Hye Lee ◽

Jin Hak Shin ◽

Seon Sook Kim ◽

Su Ryeon Seo

Keyword(s):

Cinnamic Acid ◽

Nlrp3 Inflammasome ◽

Inflammatory Diseases ◽

Endotoxic Shock ◽

Sinapic Acid ◽

Inflammasome Activation ◽

Cinnamic Acid Derivative ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation ◽

Anti Inflammatory

A natural phenolic acid compound, sinapic acid (SA), is a cinnamic acid derivative that contains 3,5-dimethoxyl and 4-hydroxyl substitutions in the phenyl ring of cinnamic acid. SA is present in various orally edible natural herbs and cereals and is reported to have antioxidant, antitumor, anti-inflammatory, antibacterial, and neuroprotective activities. Although the anti-inflammatory function of SA has been reported, the effect of SA on the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome has not been explored. In the present study, to elucidate the anti-inflammatory mechanism of SA, we examined whether SA modulates the NLRP3 inflammasome. We found that SA blocked caspase-1 activation and IL-1β secretion by inhibiting NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs). Apoptosis-associated speck-like protein containing CARD (ASC) pyroptosome formation was consistently blocked by SA treatment. SA specifically inhibited NLRP3 activation but not the NLRC4 or AIM2 inflammasomes. In addition, SA had no significant effect on the priming phase of the NLRP3 inflammasome, such as pro-IL-1β and NLRP3 inflammasome expression levels. Moreover, we found that SA attenuated IL-1β secretion in LPS-induced systemic inflammation in mice and reduced lethality from endotoxic shock. Our findings suggest that the natural compound SA has potential therapeutic value for the suppression of NLRP3 inflammasome-associated inflammatory diseases.

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Action of the 4-Nitro-2-phenoximethanesulphonanilide (Nimesulide) on neutrophil chemotaxis and superoxide production

Sao Paulo Medical Journal ◽

10.1590/s1516-31801994000100003 ◽

1994 ◽

Vol 112 (1) ◽

pp. 489-494 ◽

Cited By ~ 2

Author(s):

Susana Beatriz Veríssimo de Mello ◽

leda Maria Magalhães Laurindo ◽

Wilson Cossermelli

Keyword(s):

Inflammatory Response ◽

Peripheral Blood ◽

Superoxide Anion ◽

Healthy Subjects ◽

Inflammatory Diseases ◽

Neutrophil Function ◽

Neutrophil Chemotaxis ◽

Inflammatory Agent ◽

Blood Neutrophils ◽

Anti Inflammatory

4-nitro-2-phenoximethanesulphonanilide (nimesulide) is a nonsteroidal anti-inflammatory agent that has been employed in the treatment of inflammatory diseases because of its specific actions on the inflammatory response mechanisms caused by injury. The objectives of this paper were to determine the action of this agent on two notable neutrophil functions, chemotaxis and production of the superoxide anion. These two functions were studied after the neutrophils were pre-incubated with three different concentrations of 4-nitro-2-phenoximethanesulphonanilide (0.1; 0.3 and 0.5 mN). The results obtained herein demonstrated that 4-nitro-2-phenoximethanesulphonanilide-exposed peripheral blood neutrophils from healthy subjects produced significantly less superoxide when challenged by phorbol-mirystate acetate (PMA at 50 ng/ml) or formy-methionil-leucyl-phenilalanine (FMLP 10 -7 M) and opsonizided zymozan (1 mg/ml). Additionally, the agent was equally effective in reducing the PMN chemotoaxis when challenged by C5a factor (2% zimozan activated solution), FMLP 10 -9 M and leukotrien (3. 10 -7 M). The results obtained suggest that in addition to its interference in the metabolism of the aracdonic acid, the 4-nitro-2 phenoximethanesulphonanilide may interfere in a more direct fashion with the neutrophil function. This specific action may contribute to its anti-inflammatory activity.

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Protective Effects of Astragaloside IV against LPS-Induced Endometritis in Mice through Inhibiting Activation of the NF-κB, p38 and JNK Signaling Pathways

Molecules ◽

10.3390/molecules24020373 ◽

2019 ◽

Vol 24 (2) ◽

pp. 373 ◽

Cited By ~ 8

Author(s):

Fengge Wang ◽

Shuxiong Chen ◽

Liang Deng ◽

Lu Chen ◽

Yuwen Huang ◽

...

Keyword(s):

Signaling Pathways ◽

Inflammatory Diseases ◽

Signal Pathways ◽

Protective Effects ◽

Astragaloside Iv ◽

Active Components ◽

Jnk Signaling ◽

Tnf Α ◽

Anti Inflammatory ◽

New Evidence

Endometritis, inflammation of the endometrium, is a common reproductive obstacle disease that can lead to infertility in female animals. Astragaloside IV (AS IV), one of the major and active components of the Astragalus membranaceus (Fisch.) Bunge, is known for its anti-inflammatory effects. In the present study, the effects and mechanisms of AS IV on lipopolysaccharide (LPS)-induced endometritis were investigated using a mouse model. Female mice were prepared with AS IV (0.01 mg/g) by gavage for six days before being stimulated with LPS. The results showed that the histopathological changes, levels of inflammatory cytokines (IL-1β and TNF-α), concentration of NO, and myeloperoxidase (MPO) activity in LPS-induced uteri were attenuated significantly by pretreatment with AS IV. Furthermore, LPS-induced activations of NF-κB, p38, and JNK signal pathways were suppressed by pretreatment with AS IV. In conclusion, the data provided new evidence that AS IV effectively attenuates LPS-induced endometritis through inhibition of TLR4-mediated NF-κB, p38, and JNK signaling pathways, implying that AS IV might become a promising potential anti-inflammatory agent for endometritis and other inflammatory diseases.

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