The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation.

Serum ferritin concentrations increase during hepatic inflammation and correlate with the severity of chronic liver disease. Here, we report a molecular mechanism whereby the heavy subunit of ferritin (FTH) contributes to hepatic inflammation. We found that FTH induced activation of the NLRP3 inflammasome and secretion of the proinflammatory cytokine interleukin-1ß (IL-1ß) in primary rat hepatic stellate cells (HSCs) through intercellular adhesion molecule-1 (ICAM-1). FTH-ICAM-1 stimulated the expression of Il1b, NLRP3 inflammasome activation, and the processing and secretion of IL-1ß in a manner that depended on plasma membrane remodeling, clathrin-mediated endocytosis, and lysosomal destabilization. FTH-ICAM-1 signaling at early endosomes stimulated Il1b expression, implying that this endosomal signaling primed inflammasome activation in HSCs. In contrast, lysosomal destabilization was required for FTH-induced IL-1ß secretion, suggesting that lysosomal damage activated inflammasomes. FTH induced IL-1ß production in liver slices from wild-type mice but not in those from Icam1-/- or Nlrp3-/- mice. Thus, FTH signals through its receptor ICAM-1 on HSCs to activate the NLRP3 inflammasome. We speculate that this pathway contributes to hepatic inflammation, a key process that stimulates hepatic fibrogenesis associated with chronic liver disease.

The Geographic Distribution, Venom Components, Pathology and Treatments of Stonefish (Synanceia spp.) Venom.

Stonefish are regarded as one of the most venomous fish in the world. Research on stonefish venom has chiefly focused on the in vitro and in vivo neurological, cardiovascular, cytotoxic and nociceptive effects of the venom. The last literature review on stonefish venom was published over a decade ago, and much has changed in the field since. In this review, we have generated a global map of the current distribution of all stonefish (Synanceia) species, presented a table of clinical case reports and provided up-to-date information about the development of polyspecific stonefish antivenom. We have also presented an overview of recent advancements in the biomolecular composition of stonefish venom, including the analysis of transcriptomic and proteomic data from Synanceia horrida venom gland. Moreover, this review highlights the need for further research on the composition and properties of stonefish venom, which may reveal novel molecules for drug discovery, development or other novel physiological uses.

Non-invasive assessment of the cardiac effects of Chironex fleckeri and Carukia barnesi venoms in mice, using pulse wave doppler.

Both Chironex fleckeri venom (CFV) and Carukia barnesi venoms (CBV) are known to cause significant cardiac morbidity and mortality. Many animal studies have demonstrated cardiac dysfunction with these venoms. This study specifically examines the systolic and diastolic cardiac functions using non-invasive pulse wave doppler. Mitral and aortic doppler sonograms of anaesthetised mice were obtained utilising a 10 MHz doppler probe. These continuous sonograms were analysed to ascertain changes in cardiac function before and after the parenteral administration of the test venoms. We found that CFV administration causes rapid cardiac dysfunction without a change in heart rate. Analysis of the resulting sonograms shows both systolic and diastolic dysfunction which together is suggestive of a progressively poorly compliant, contracted left ventricle. Additionally, the rapidity of cardiac dysfunction suggests a direct effect of CFV on myocardial cells. In contrast CBV showed a moderate immediate inotropic and chronotropic effect that was sustained until precipitous cardiac decompensation. This is consistent with the hypotheses of a toxin induced stress cardiomyopathy from sustained catecholaminergic activity.

Heat deactivation of the stonefish Synanceia horrida venom - implications for first-aid management.

OBJECTIVES: To investigate the effects of temperature and hot water immersion time on neutralising venom lethality of the Australian estuarine stonefish (Synanceia horrida). DESIGN: Depths of the spines were measured while venom was extracted from S. horrida individuals. The venom was then exposed to temperatures of 4°C, 37.0°C, 40.1°C, 42.3°C, 45.0°C, 47.7°C, 55.2°C, and 60.0°C for either five or 20 minutes incubation periods. Venom samples were added to cultured human cardiomyocytes and cell viability curves were produced using the ACEA's xCELLigence real-time cell monitoring system. MAIN OUTCOME MEASURES: Determination of venom lethality on cardiomyocytes at a range of temperatures. RESULTS: The average depth of the spine required to go into a victims' flesh before the venom gland compressed and expelled venom was 18 mm. Cardiomyocytes exposed to heat-treated venom for five minutes required higher temperatures to neutralise 99% of the venom, namely 44.6°C in comparison to 42.1°C with an incubation time of 20 minutes. CONCLUSION: This study supports the use of hot water immersion therapy in the treatment of S. horrida stings. It is suggested that due to the depth of the puncture wound longer incubation times should be sought to allow heat to penetrate the deeper portions of the dermis and effectively begin venom deactivation.

Relationship between food and venom production in the estuarine stonefish Synanceia horrida.

BACKGROUND: The potential costs of venom production may be significant to many marine venomous taxa. In general, the parameters that influence the rate of venom production are poorly understood, but seem to be related to feeding frequency. METHODS: This study examines the effects of starvation on venom profile and venom yield on the estuarine stonefish (Synanceia horrida). In total, the venom of eight stonefishes was tested under two feeding regimes. Over a four week period, one of the two groups underwent an episode of suspended feeding, while the other was fed on a daily basis. The effect of time on venom replacement was determined by a paired T-test. ANOVA was performed to analyze differences in venom weight between fed and unfed treatments. RESULTS: Nutritional suspension was found to have a significant effect on the quantity of venom produced. SDS-PAGE gel and FPLC revealed that the components of the venom collected from both groups were similar, indicating that four weeks is an adequate time to regenerate key venom components but not replenish initial venom quantities. CONCLUSIONS: Venom production was found to be affected by starvation.

Cardiotoxic effects of venom fractions from the Australian box jellyfish Chironex fleckeri on human myocardiocytes.

An investigation into the cardiotoxic effects in human cardiomyocytes of different fractions (as produced from an FPLC) of the venom from Chironex fleckeri showed that whole venom caused cardiac cell death in minutes, measured as cell detachment using xCELLigence technology. However, only one fraction of the venom was responsible for this effect. When all extracted venoms were recombined a similar result was seen for the toxic fraction, however these effects were slower than unfractionated venom alone even though the concentrations were similar. The difference in the results between fractioned and unfractionated venom may have been caused by compounds remaining in the FPLC column, which may interact with the toxic fraction to cause rapid cell detachment or death.