curcumin and Shock--Septic

Endotoxin-induced acute inflammatory diseases such as sepsis, mediated by excessive production of various proinflammatory cytokines, remain the leading cause of mortality in critically ill patients. Lipopolysaccharide (LPS), the characteristic endotoxin found in the outer membrane of Gram-negative bacteria, can induce the innate immunity system and through the myeloid differentiation protein 2 (MD2) and Toll-like receptor 4 (TLR4) complex, increase the production of inflammatory mediators. Our previous studies have found that a curcumin analog, L48H37 [1-ethyl-3,5-bis(3,4,5-trimethoxybenzylidene)piperidin-4-one], was able to inhibit LPS-induced inflammation, particularly tumor necrosis factor α and interleukin 6 production and gene expression in mouse macrophages. In this study, a series of biochemical experiments demonstrate L48H37 specifically targets MD2 and inhibits the interaction and signaling transduction of LPS-TLR4/MD2. L48H37 binds to the hydrophobic region of MD2 pocket and forms hydrogen bond interactions with Arg(90) and Tyr(102). Subsequently, L48H37 was shown to suppress LPS-induced mitogen-activated protein kinase phosphorylation and nuclear factor κB activation in macrophages; it also dose dependently inhibits the cytokine expression in macrophages and human peripheral blood mononuclear cells stimulated by LPS. In LPS-induced septic mice, both pretreatment and treatment with L48H37 significantly improved survival and protected lung injury. Taken together, this work identified a new MD2 specific inhibitor, L48H37, as a potential candidate in the treatment of sepsis.

Topics: Animals; Curcumin; Cytokines; Diarylheptanoids; Endotoxins; Humans; Lipopolysaccharides; Lymphocyte Antigen 96; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Primary Cell Culture; Protein Binding; Sepsis; Shock, Septic; Signal Transduction; Toll-Like Receptor 4; Transcription Factor RelA

The NLRP3 inflammasome responds to various pathogen-derived factors and danger-associated molecules, mediating IL-1β maturation, therefore is involved in multiple inflammatory diseases. Curcumin has been shown to possess strong anti-inflammatory activity, but the underlying mechanism is not fully understood. Here, we sought to investigate the role and mechanism of curcumin on the inhibition of mature IL-1β production via the regulation of NLRP3 inflammasome.. Curcumin dramatically inhibited the production of mature IL-1β in LPS-primed macrophages triggered by multiple NLRP3 inflammasome activators, and also reduced the level of cleaved caspase-1 as measured by western blot and ELISA. Curcumin prevented K(+) efflux, the common trigger for NLRP3 inflammasome activation, and attenuated lysosomes disruption and intracellular ROS formation as well. The inhibition of NLRP3 inflammasome by curcumin was in part mediated via the suppression of extracellular regulated protein kinases phosphorylation. Furthermore, administration of curcumin significantly reduced peritoneal IL-1β and HMGB-1 concentration induced by LPS and improved the survival of mice suffering from lethal endotoxic shock.. Curcumin potently inhibits the activation of NLRP3 inflammasome which may contribute to its anti-inflammatory activity. Our finding offers a mechanistic basis for the therapeutic potential of curcumin in septic shock and other NLRP3 inflammasome-driven diseases.

Topics: Animals; Anti-Inflammatory Agents; Caspase 1; Cells, Cultured; Curcumin; HMGB1 Protein; Inflammasomes; Interleukin-1beta; Lipopolysaccharides; Lysosomes; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Potassium; Reactive Oxygen Species; Shock, Septic

Curcumin is a natural active product that has various pharmacological activities such as anti-inflammatory effects. Here, we report the synthesis and evaluation of 34 monocarbonyl curcumin analogs as novel anti-inflammatory agents. Among the analogs, the symmetrical heterocyclic type displayed the strongest inhibition of lipopolysaccharide (LPS)-stimulated expression of pro-inflammatory cytokines in macrophages. Analogs S1-S5 and AS29 reduced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production in a dose-dependent manner and also displayed excellent stability and low cytotoxicity in vitro. In addition, analog S1 dose-dependently inhibited LPS-induced extracellular signal-regulated kinase (ERK) phosphorylation. Furthermore, analogs S1 and S4 displayed a significant protective effect on LPS-induced septic death in mouse models, with 40% and 50% survival rates, respectively. These data demonstrate that the heterocyclic monocarbonyl curcumin analogs have potential therapeutic effects in acute inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Products; Cell Line; Curcumin; Cytokines; Dose-Response Relationship, Drug; Drug Discovery; Humans; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Shock, Septic; Structure-Activity Relationship

Staphylococcus aureus initiates infections and produces virulence factors, including superantigens (SAgs), at mucosal surfaces. The SAg, Toxic Shock Syndrome Toxin-1 (TSST-1) induces cytokine secretion from epithelial cells, antigen presenting cells (APCs) and T lymphocytes, and causes toxic shock syndrome (TSS). This study investigated the mechanism of TSST-1-induced secretion of proinflammatory cytokines from human vaginal epithelial cells (HVECs) and determined if curcumin, an anti-inflammatory agent, could reduce TSST-1-mediated pathology in a rabbit vaginal model of TSS. TSST-1 caused a significant increase in NF-κB-dependent transcription in HVECs that was associated with increased expression of TNF- α, MIP-3α, IL-6 and IL-8. Curcumin, an antagonist of NF-κB-dependent transcription, inhibited IL-8 production from ex vivo porcine vaginal explants at nontoxic doses. In a rabbit model of TSS, co-administration of curcumin with TSST-1 intravaginally reduced lethality by 60% relative to 100% lethality in rabbits receiving TSST-1 alone. In addition, TNF-α was undetectable from serum or vaginal tissue of curcumin treated rabbits that survived. These data suggest that the inflammatory response induced at the mucosal surface by TSST-1 is NF-κB dependent. In addition, the ability of curcumin to prevent TSS in vivo by co-administration with TSST-1 intravaginally suggests that the vaginal mucosal proinflammatory response to TSST-1 is important in the progression of mTSS.

Topics: Animals; Bacterial Toxins; Cell Line, Transformed; Chemokines; Curcumin; Disease Models, Animal; Enterotoxins; Epithelial Cells; Female; Humans; In Vitro Techniques; Inflammation Mediators; Interleukin-8; Mucous Membrane; NF-kappa B; Protective Agents; Rabbits; Shock, Septic; Signal Transduction; Staphylococcus aureus; Superantigens; Sus scrofa; Vagina

The effect of curcumin on lipopolysaccharide/D: -galactosamine (LPS/GalN)-induced acute shock model of liver injury was examined in mice. The simultaneous administration of LPS (5-20 microg kg(-1), i.p.) and GalN (700 mg kg(-1), i.p.) markedly increased the serum tumor necrosis factor-alpha (TNF-alpha), glutamic oxaloacetic transaminase/glutamic pyruvic transaminase (GOT/GPT), and massive hepatic necrosis and inflammation, leading to 100% lethality. Pre-administration of curcumin (100 mg kg(-1), i.p.) 3 h before induction with LPS/GalN imparted a large extent of protection against acute elevation in serum TNF-alpha and serum GOT/GPT. Hepatic necrosis and lethality caused by LPS/GalN was also greatly reduced by curcumin treatment. The results demonstrated that curcumin could protect mice from LPS/GalN-induced hepatic injury and inflammation through blockading TNF-alpha production, eventually raising the survival rate of septic-shock-induced mice.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Curcumin; Disease Models, Animal; Female; Humans; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Shock, Septic; Treatment Outcome; Tumor Necrosis Factor-alpha

Monocyte-derived myeloid cells play vital roles in inflammation-related autoimmune/inflammatory diseases and cancers. Here, we report that exosomes can deliver anti-inflammatory agents, such as curcumin, to activated myeloid cells in vivo. This technology provides a means for anti-inflammatory drugs, such as curcumin, to target the inflammatory cells as well as to overcome unwanted off-target effects that limit their utility. Using exosomes as a delivery vehicle, we provide evidence that curcumin delivered by exosomes is more stable and more highly concentrated in the blood. We show that the target specificity is determined by exosomes, and the improvement of curcumin activity is achieved by directing curcumin to inflammatory cells associated with therapeutic, but not toxic, effects. Furthermore, we validate the therapeutic relevance of this technique in a lipopolysaccharide (LPS)-induced septic shock mouse model. We further show that exosomes, but not lipid alone, are required for the enhanced anti-inflammatory activity of curcumin. The specificity of using exosomes as a drug carrier creates opportunities for treatments of many inflammation-related diseases without significant side effects due to innocent bystander or off-target effects.

Topics: Animals; Anti-Inflammatory Agents; Blotting, Western; Cell Line, Tumor; Cells, Cultured; Curcumin; Drug Carriers; Exosomes; Female; Flow Cytometry; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Nanoparticles; Shock, Septic