Deficiency of circadian clock gene Bmal1 exacerbates noncanonical inflammasome-mediated pyroptosis and lethality via Rev-erbα-C/EBPβ-SAA1 axis.

Circadian arrhythmia has been linked to increased susceptibility to multiple inflammatory diseases, such as sepsis. However, it remains unclear how disruption of the circadian clock modulates molecular aspects of innate immune responses, including inflammasome signaling. Here, we examined the potential role of the circadian clock in inflammasome-mediated responses through myeloid-specific deletion of BMAL1, a master circadian clock regulator.

Intracellular NAD Depletion Confers a Priming Signal for NLRP3 Inflammasome Activation.

Nicotinamide adenine dinucleotide (NAD) is an important cofactor in many redox and non-redox NAD-consuming enzyme reactions. Intracellular NAD level steadily declines with age, but its role in the innate immune potential of myeloid cells remains elusive. In this study, we explored whether NAD depletion by FK866, a highly specific inhibitor of the NAD salvage pathway, can affect pattern recognition receptor-mediated responses in macrophages.

Neutrophils Facilitate Prolonged Inflammasome Response in the DAMP-Rich Inflammatory Milieu.

Aberrant inflammasome activation contributes to various chronic inflammatory diseases; however, pyroptosis of inflammasome-active cells promptly terminates local inflammasome response. Molecular mechanisms underlying prolonged inflammasome signaling thus require further elucidation. Here, we report that neutrophil-specific resistance to pyroptosis and NLRP3 desensitization can facilitate sustained inflammasome response and interleukin-1β secretion.

Zika Virus Impairs Host NLRP3-mediated Inflammasome Activation in an NS3-dependent Manner.

Zika virus (ZIKV) is a mosquito-borne flavivirus associated with severe neurological disorders including Guillain-Barré syndrome and microcephaly. The host innate immune responses against ZIKV infection are essential for protection; however, ZIKV has evolved strategies to evade and antagonize antiviral responses via its nonstructural (NS) proteins. Here, we demonstrated that ZIKV infection unexpectedly inhibits NLRP3-dependent inflammasome activation in bone marrow-derived macrophages and mixed glial cells from mouse brain.

Chemotherapeutic Agent Paclitaxel Mediates Priming of NLRP3 Inflammasome Activation.

Paclitaxel is a chemotherapeutic drug commonly used to treat different types of cancer. In addition to its antitumor effect, paclitaxel is also known to promote Toll-like receptor (TLR) 4-dependent inflammatory responses, which may lower its chemotherapeutic efficacy. However, it remains unclear whether paclitaxel is able to affect inflammasome signaling in myeloid or cancer cells.

Posttranslational Regulation of the NLR Family Pyrin Domain-Containing 3 Inflammasome.

The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multi-protein complex that can be activated by a variety of pathogen-associated molecular patterns or damage-associated molecular patterns. Inappropriate NLRP3 inflammasome activation can induce autoinflammatory, autoimmune, or metabolic disorders. Therefore, NLRP3 is an attractive target against NLRP3 inflammasome activation, and specific targeting of NLRP3 might be an intriguing approach to the development of drugs for the treatment of NLRP3 inflammasome-related diseases.

Inhibitory Effect and Mechanism of Extract Inflammasome Activation.

, Compositae, is considered a potential source of nutrition and is used as a traditional medicine in East Asian countries for centuries. Although several studies have shown its biological activities as an anti-inflammatory agent, there have been no reports on with regard to regulatory role in inflammasome activation. The purpose of this study was to investigate the inhibitory effects of extract (ALE) on NLRP3 inflammasome activation and explore the underlying mechanisms.

Actinidia arguta extract attenuates inflammasome activation: Potential involvement in NLRP3 ubiquitination.

Ethnopharmacological Relevance: Actinidia arguta (A. arguta) has been widely used in Asian countries as a traditional medicinal herb to treat inflammation-related diseases, such as gastritis, bronchitis, and arthritis.

Aim Of The Study: The inhibitory effect of A.

BOT-4-one attenuates NLRP3 inflammasome activation: NLRP3 alkylation leading to the regulation of its ATPase activity and ubiquitination.

The ATPase activity of NLRP3 has pivotal role in inflammasome activation and is recognized as a good target for the development of the NLRP3 inflammasome-specific inhibitor. However, signals in the vicinity of the ATPase activity of NLRP3 have not been fully elucidated. Here, we demonstrate NLRP3 inflammasome-specific action of a benzoxathiole derivative, BOT-4-one.

Protective effects of Cinnamomum cassia (Lamaceae) against gout and septic responses via attenuation of inflammasome activation in experimental models.

Ethnopharmacological Relevance: Cinnamomum cassia (C. cassia, Lauraceae family), commonly used for treating dyspepsia, gastritis, blood circulation, and inflammatory diseases is considered as one of the 50 fundamental herbs in traditional Chinese medicine.

Aim Of The Study: The anti-inflammatory action of an ethanol extract of C.

Juniperus rigida Sieb. extract inhibits inflammatory responses via attenuation of TRIF-dependent signaling and inflammasome activation.

Ethnopharmacological Relevance: Juniperus rigida Sieb. (J. rigida) is used for medicinal purposes in Asian countries to treat inflammation-related disorders, such as neuralgia, dropsy, and gout.

Cichorium intybus Linn. Extract Prevents Type 2 Diabetes Through Inhibition of NLRP3 Inflammasome Activation.

This study provides the scientific basis for the inhibitory effect of the aerial parts of Cichorium intybus Linn. (C. intybus) on the activation of the NLRP3 inflammasome in vitro and on high-fat diet (HFD)-induced type-2 diabetes (T2D).

Inhibition of glutamine utilization sensitizes lung cancer cells to apigenin-induced apoptosis resulting from metabolic and oxidative stress.

Recent studies have shown anticancer activity of apigenin by suppressing glucose transporter 1 (GLUT1) expression in cultured cancer cells; however, it is not clear whether apigenin can suppress glucose metabolism in lung cancer cells or sensitize them to inhibition of glutamine utilization-mediated apoptosis through metabolic and oxidative stress. We show that apigenin significantly decreases GLUT1 expression in mice. Furthermore, we demonstrate that apigenin induces growth retardation and apoptosis through metabolic and oxidative stress caused by suppression of glucose utilization in lung cancer cells.

Anti-inflammatory properties of Morus bombycis Koidzumi via inhibiting IFN-β signaling and NLRP3 inflammasome activation.

Ethnopharmacological Relevance: Morus bombycis Koidzumi (M. bombycis, Moraceae) has been used in Asian countries as a traditional medicine for the treatment of hypertension, diabetes, and inflammation-related disorders.

Aim Of Study: Although its anti-inflammatory actions have been partly documented, scientific evidence involving its molecular mechanisms related to inflammasome activation signaling pathways remains unknown.

Anti-Inflammatory Action of an Antimicrobial Model Peptide That Suppresses the TRIF-Dependent Signaling Pathway via Inhibition of Toll-Like Receptor 4 Endocytosis in Lipopolysaccharide-Stimulated Macrophages.

Antimicrobial peptides (AMPs), also called host defense peptides, particularly those with amphipathic helical structures, are emerging as target molecules for therapeutic development due to their immunomodulatory properties. Although the antimicrobial activity of AMPs is known to be exerted primarily by permeation of the bacterial membrane, the mechanism underlying its anti-inflammatory activity remains to be elucidated. We report potent anti-inflammatory activity of WALK11.

Anti-inflammatory effect of Impatiens textori Miq. extract via inhibition of NLRP3 inflammasome activation in in vitro and in vivo experimental models.

Ethnopharmacological Relevance: Impatiens textori Miq. (I. textori, Balsaminaceae) is a traditional medicinal herb used for centuries to treat several inflammatory related skin infections and allergic disorders in Asian countries.

Anti-inflammatory effect of emodin via attenuation of NLRP3 inflammasome activation.

Emodin, an active constituent of oriental herbs, is widely used to treat allergy, inflammation, and other symptoms. This study provides the scientific basis for the anti-inflammasome effects of emodin on both in vitro and in vivo experimental models. Bone marrow-derived macrophages were used to study the effects of emodin on inflammasome activation by using inflammasome inducers such as ATP, nigericin, and silica crystals.

Anti-inflammatory effect of Streptochlorin via TRIF-dependent signaling pathways in cellular and mouse models.

Streptochlorin, a small compound derived from marine actinomycete, has been shown to have anti-angiogenic, anti-tumor, and anti-allergic activities. However, the anti-inflammatory effects and underlying mechanisms have not yet been reported. In the present study, we investigated the effect of streptochlorin on lipopolysaccharide (LPS)-induced inflammatory responses in vitro and in vivo.

Syneilesis palmata (Thunb.) Maxim. extract attenuates inflammatory responses via the regulation of TRIF-dependent signaling and inflammasome activation.

Ethnopharmacological Relevance: Syneilesis palmata (Thunb.) Maxim. (S.

A novel synthetic derivative of melatonin, 5-hydroxy-2'-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation.

Melatonin is substantially reported to possess anti-inflammatory properties. In the present study, we synthesized a novel melatonin derivative, 5-hydroxy-2'-isobutyl-streptochlorin (HIS), which displayed superior anti-inflammatory properties to its parent compound. Further, we explored its underlying mechanisms in cellular and experimental animal models.

Emodin attenuates A23187-induced mast cell degranulation and tumor necrosis factor-α secretion through protein kinase C and IκB kinase 2 signaling.

Mast cells are known to play a pivotal role in allergic diseases. Cross-linking of the high-affinity IgE receptor (FcεRI) is known to be one of the major causes that lead to degranulation and allergic inflammation. An increase in intracellular calcium (Ca(2+)) concentration also triggers degranulation, bypassing receptor activation.

Lysimachia clethroides Duby extract attenuates inflammatory response in Raw 264.7 macrophages stimulated with lipopolysaccharide and in acute lung injury mouse model.

Ethnopharmacological Relevance: Lysimachia clethroides Duby (LC) is a traditional medicinal herb used to treat edema, hepatitis and inflammatory diseases in China and other Asian countries. In this study, the anti-inflammatory effects of LC extract and the mechanisms underlying were explored in both in vitro cell lines and acute lung injury (ALI) animal model of inflammation in vivo.

Materials And Methods: Lipopolysaccharide (LPS)-stimulated Raw 264.

Streptochlorin suppresses allergic dermatitis and mast cell activation via regulation of Lyn/Fyn and Syk signaling pathways in cellular and mouse models.

Allergic diseases are chronic inflammatory conditions with specific immune and inflammatory mechanisms. Scientific interest in understanding the mechanisms and discovering novel agents for the prevention and treatment of allergic disease is increasing. Streptochlorin, a small compound derived from marine actinomycete possesses anti-angiogenic and anti-tumor activities.

Carpesium macrocephalum attenuates lipopolysaccharide-induced inflammation in macrophages by regulating the NF-κB/IκB-α, Akt, and STAT signaling pathways.

Carpesium macrocephalum (CM) Fr. et Sav. (Compositae) has been used in Chinese folk medicine as an analgesic, hemostatic, antipyretic, and to suppress inflammatory conditions.

Indole-3-carbinol inhibits LPS-induced inflammatory response by blocking TRIF-dependent signaling pathway in macrophages.

Indole-3-carbinol (I3C), a natural hydrolysis product of glucobrassicin, is a member of the Brassica family of vegetables and is known to have various anti-cancer activities. In the present study, we assessed in vitro and in vivo anti-inflammatory effects of I3C and its molecular mechanisms. I3C attenuated the production of pro-inflammatory mediators such as NO, IL-6, and IL-1β in LPS-induced Raw264.