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Background: Multiple sclerosis (MS) is a severe and common autoimmune disorder of the central nervous system. Despite the availability of several novel treatment options, the disease is still poorly controlled, since the pathophysiological mechanisms are not fully understood., Methods: We tested the role of the acid sphingomyelinase/ceramide system in a model of MS, i.e. experimental autoimmune encephalomyelitis (EAE). Mice were immunized with myelin-oligodendrocyte glycoprotein and the development of the disease was analyzed by histology, immunological tests and clinical assessment in wildtype and acid sphingomyelinase (Asm)-deficient mice., Results: Genetic deficiency of acid sphingomyelinase (Asm) protected against clinical symptoms in EAE and markedly attenuated the characteristic detrimental neuroinflammatory response. T lymphocyte adhesion, integrity of tight junctions, blood-brain barrier disruption and subsequent intracerebral infiltration of inflammatory cells were blocked in Asm-deficient mice after immunization. This resulted in an almost complete block of the development of disease symptoms in these mice, while wildtype mice showed severe neurological symptoms typical for EAE., Conclusion: Activation of the Asm/ceramide system is a central step for the development of EAE. Our findings may serve to identify novel therapeutic strategies for MS patients., (© 2017 The Author(s). Published by S. Karger AG, Basel.)

Unlabelled: Pulmonary edema associated with increased vascular permeability is a severe complication of Staphylococcus aureus-induced sepsis and an important cause of human pathology and death. We investigated the role of the mammalian acid sphingomyelinase (Asm)/ceramide system in the development of lung edema caused by S. aureus. Our findings demonstrate that genetic deficiency or pharmacologic inhibition of Asm reduced lung edema in mice infected with S. aureus. The Asm/ceramide system triggered the formation of superoxide, resulting in degradation of tight junction proteins followed by lung edema. Treatment of infected mice with amitriptyline, a potent inhibitor of Asm, protected mice from lung edema caused by S. aureus, but did not reduce systemic bacterial numbers. In turn, treatment with antibiotics reduced bacterial numbers but did not protect mice from lung edema. In contrast, only the combination of antibiotics and amitriptyline inhibited both pulmonary edema and bacteremia protecting mice from lethal sepsis and lung dysfunction suggesting the combination of both drugs as novel treatment option for sepsis., Key Messages: Antibiotics are often insufficient to cure S. aureus-induced sepsis. S. aureus induces lung edema via the Asm/ceramide system. Genetic deficiency of Asm inhibits lung dysfunction upon infection with S. aureus. Pharmacologic inhibition of Asm reduces lung edema induced by S. aureus. Antibiotics plus amitriptyline protect mice from lung edema and lethal S. aureus sepsis.

Gram-positive bacterial pathogens that secrete cytotoxic pore-forming toxins, such as Staphylococcus aureus and Streptococcus pneumoniae, cause a substantial burden of disease. Inspired by the principles that govern natural toxin-host interactions, we have engineered artificial liposomes that are tailored to effectively compete with host cells for toxin binding. Liposome-bound toxins are unable to lyse mammalian cells in vitro. We use these artificial liposomes as decoy targets to sequester bacterial toxins that are produced during active infection in vivo. Administration of artificial liposomes within 10 h after infection rescues mice from septicemia caused by S. aureus and S. pneumoniae, whereas untreated mice die within 24-33 h. Furthermore, liposomes protect mice against invasive pneumococcal pneumonia. Composed exclusively of naturally occurring lipids, tailored liposomes are not bactericidal and could be used therapeutically either alone or in conjunction with antibiotics to combat bacterial infections and to minimize toxin-induced tissue damage that occurs during bacterial clearance.

The antihyperglycaemic and antioxidant activities of a Ghanaian medicinal plant namely Adenia lobata Engl (Passifloraceae), used to treat diabetes mellitus in traditional medicine, was investigated. The dried stem powder of A. lobata was successively extracted by Soxhlet with petroleum ether and 70% ethanol to obtain the crude petroleum ether (PEAL: yield =1.1 w/w %) and ethanol (EEAL: yield = 5.4 w/w %) extracts. The extracts were assessed for their antihyperglycaemic and antioxidant activities. The antihyperglycaemic activity of PEAL and EEAL were determined in streptozotocin-induced diabetic rats (70 mg/kg body weight). Five groups of diabetic rats were given 150, 300 and 600 mg/kg body weight of PEAL and EEAL orally once daily for 20 days. Glibenclamide (5 mg/kg body weight) was used as positive control while distilled water (5 ml) acted as the normal diabetic control. The blood glucose levels were monitored initially for 6 hours and subsequently over 24 days. Both extracts exhibited statistically significant (p< 0.001) antihyperglycaemic activity throughout the study period, with EEAL showing the greatest activity. The antioxidant properties of the petroleum ether and ethanol extracts of A. lobata (PEAL and EEAL) were evaluated using five assays; total phenolic content, total antioxidant capacity, reducing power, DPPH scavenging effect and lipid peroxidation activity. In all these assays, the antioxidant properties increased with increasing concentration of the extracts.