phenanthrenes and Shock--Septic

NLRP3 inflammasome activation is implicated in the pathogenesis of a wide range of inflammatory diseases, but medications targeting the NLRP3 inflammasome are not available for clinical use. Here, we demonstrate that cryptotanshinone (CTS), a major component derived from the traditional medicinal herb Salvia miltiorrhiza Bunge, is a specific inhibitor for the NLRP3 inflammasome. Cryptotanshinone inhibits NLRP3 inflammasome activation in macrophages, but has no effects on AIM2 or NLRC4 inflammasome activation. Mechanistically, cryptotanshinone blocks Ca

Topics: Animals; Cells, Cultured; Female; Inflammasomes; Interleukin-1beta; Lipopolysaccharides; Liver; Macrophages; Male; Mice, Inbred C57BL; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Non-alcoholic Fatty Liver Disease; Phenanthrenes; Reactive Oxygen Species; Shock, Septic; T-Lymphocytes, Regulatory; Th17 Cells; Tumor Necrosis Factor-alpha

Tanshinones, the active ingredients derived from the roots of Salvia miltiorrhiza, have been widely used as traditional medicinal herbs for treating human diseases. Although tanshinones showed anti-inflammatory effects in many studies, large knowledge gaps remain regarding their underlying mechanisms. Here, we identified 15 tanshinones that suppressed the activation of NLRP3 inflammasome and studied their structure-activity relationships. Three tanshinones (tanshinone IIA, isocryptotanshinone, and dihydrotanshinone I) reduced mitochondrial reactive-oxygen species production in lipopolysaccharide (LPS)/nigericin-stimulated macrophages and correlated with altered mitochondrial membrane potentials, mitochondria complexes activities, and adenosine triphosphate and protonated-nicotinamide adenine dinucleotide production. The tanshinones may confer mitochondrial protection by promoting autophagy and the AMP-activated protein kinase pathway. Importantly, our findings demonstrate that dihydrotanshinone I improved the survival of mice with LPS shock and ameliorated inflammatory responses in septic and gouty animals. Our results suggest a potential pharmacological mechanism whereby tanshinones can effectively treat inflammatory diseases, such as septic and gouty inflammation.

Topics: Abietanes; AMP-Activated Protein Kinases; Animals; Autophagy; Disease Models, Animal; Female; Furans; Gout; Humans; Inflammasomes; Inflammation; Male; Mice; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Phenanthrenes; Quinones; Rats; Reactive Oxygen Species; Shock, Septic; Uric Acid

BACKGROUND The aim of this study was to evaluate the protective effects of sodium tanshinone IIA sulfonate (STS) on hemodynamic parameters, cytokine release, and multiple organ damage in an animal model of lipopolysaccharide (LPS)-induced endotoxemia. MATERIAL AND METHODS Twenty-four rabbits were randomly divided into 3 groups: control (n=8), LPS (n=8), and STS pretreatment + LPS (n=8) groups. With arterial invasive monitoring, hemodynamic variables were observed at 30 min before and at 0, 10, 20, 30, 60, 120, 180, 240, and 300 min after LPS injection. Circulatory inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10), and relevant biochemical markers, including arterial partial pressure of oxygen (PaO2), plasma cardiac troponin I (cTnI), alanine aminotransferase (ALT), and creatinine (Cr), were measured at each time point. At the end of the experiment, all rabbits were sacrificed; histopathological examination of the heart, lung, liver, and kidney tissue was performed and organ injury was semi-quantitatively scored for each organ. RESULTS Mean arterial pressure (MAP) and heart rate (HR) significantly decreased within 30 min and again after 120 min following LPS injection. However, STS pretreatment gradually normalized MAP and HR after 120 min following LPS injection. In addition, STS ameliorated LPS-induced decrease of PaO2, LPS-induced increase of TNF-α, cTnI, and ALT, and enhanced LPS-induced increase of IL-10. Moreover, STS reduced heart, lung, and liver histopathologic injury. CONCLUSIONS STS can significantly stabilize LPS-induced hemodynamic deterioration, regulate inflammatory cytokine secretion, and protect heart, lung, and liver in rabbits.

Topics: Animals; Biomarkers; Cytokines; Endotoxemia; Hemodynamics; Inflammation Mediators; Interleukin-10; Lipopolysaccharides; Male; Multiple Organ Failure; Organ Specificity; Oxygen; Partial Pressure; Phenanthrenes; Rabbits; Shock, Septic; Tumor Necrosis Factor-alpha

The lack of efficacy of anti-inflammatory drugs, anti-coagulants, anti-oxidants, etc. in critically ill patients has shifted interest towards developing alternative treatments. Since inhibitors of the nuclear enzyme poly-(ADP-ribose) polymerase (PARP) were found to be beneficial in many pathophysiological conditions associated with oxidative stress and PARP-1 knock-out mice proved to be resistant to bacterial lipopolysaccharide (LPS)-induced septic shock, PARP inhibitors are candidates for such a role. In this study, the mechanism of the protective effect of a potent PARP-1 inhibitor, PJ34 was studied in LPS-induced (20mg/kg, i.p.) septic shock in mice. We demonstrated a significant inflammatory response by magnetic resonance imaging in the dorsal subcutaneous region, in the abdominal regions around the kidneys and in the inter-intestinal cavities. We have found necrotic and apoptotic histological changes as well as obstructed blood vessels in the liver and small intestine. Additionally, we have detected elevated tumor necrosis factor-alpha levels in the serum and nuclear factor kappa B activation in liver of LPS-treated mice. Pre-treating the animals with PJ34 (10mg/kg, i.p.), before the LPS challenge, besides rescuing the animals from LPS-induced death, attenuated all these changes presumably by activating the phosphatidylinositol 3-kinase-Akt/protein kinase B cytoprotective pathway.

Topics: Animals; Base Sequence; Binding Sites; Consensus Sequence; Endotoxins; Enzyme Inhibitors; Escherichia coli; Inflammation; Lipopolysaccharides; Mice; Mice, Inbred BALB C; NF-kappa B; Phenanthrenes; Poly(ADP-ribose) Polymerase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Sepsis; Shock, Septic

The influence of quercetin, chlorpromazine, aristolochic acid, and indomethacin on group I phospholipase A2 (PLA2) from porcine pancreas and on group II PLA2 from Vipera russelli was compared. Quercetin and chlorpromazine were found to inhibit PLA2 activity in lower concentrations (< 100 microM), while aristolochic acid and indomethacin were inhibitory only in higher concentrations (> 100 microM). The order of potency against Vipera PLA2 was: quercetin > chlorpromazine > aristolochic acid > indomethacin, while the order of potency against pancreatic PLA2 was: chlorpromazine > aristolochic acid > indomethacin >> quercetin. Thus, quercetin was a potent inhibitor towards group II PLA2 (IC50 = 2 microM), but a very weak inhibitor against group I PLA2, with maximum 30% inhibition. Aristolochic acid and indomethacin were three to four times more potent towards group II PLA2 than towards group I PLA2, while chlorpromazine was equally potent towards the two PLA2 types. Quercetin and chlorpromazine were also tested against two PLA2 fractions purified from the plasma of septic shock patients; chlorpromazine was then equally potent towards the two PLA2 fractions, whereas quercetin was a potent inhibitor of only one of the two PLA2 fractions (IC50 = 4 microM). Together, these results indicate that (1) different PLA2 inhibitors have different potency depending on which type of PLA2 they are used against, (2) quercetin selectively inhibits group II PLA2 and may therefore be used to discriminate between different PLA2 forms in biological materials, and (3) both PLA2 of group I and group II are present in septic shock plasma.

Topics: Animals; Aristolochic Acids; Chlorpromazine; Humans; Indomethacin; Pancreas; Phenanthrenes; Phospholipases A; Phospholipases A2; Quercetin; Shock, Septic; Substrate Specificity; Swine; Viper Venoms