Evaluation of the anti-inflammatory effects of synthesised tanshinone I and isotanshinone I analogues in zebrafish

During inflammation, dysregulated neutrophil behaviour can play a major role in a range of chronic inflammatory diseases, for many of which current treatments are generally ineffective. Recently, specific naturally occurring tanshinones have shown promising anti-inflammatory effects by targeting neutrophils in vivo, yet such tanshinones, and moreover, their isomeric isotanshinone counterparts, are still a largely underexplored class of compounds, both in terms of synthesis and biological effects. To explore the anti-inflammatory effects of isotanshinones, and the tanshinones more generally, a series of substituted tanshinone and isotanshinone analogues was synthesised, alongside other structurally similar molecules. Evaluation of these using a transgenic zebrafish model of neutrophilic inflammation revealed differential anti-inflammatory profiles in vivo, with a number of compounds exhibiting promising effects. Several compounds reduce initial neutrophil recruitment and/or promote resolution of neutrophilic inflammation, of which two also result in increased apoptosis of human neutrophils. In particular, the methoxy-substituted tanshinone 39 specifically accelerates resolution of inflammation without affecting the recruitment of neutrophils to inflammatory sites, making this a particularly attractive candidate for potential pro-resolution therapeutics, as well as a possible lead for future development of functionalised tanshinones as molecular tools and/or chemical probes. The structurally related β-lapachones promote neutrophil recruitment but do not affect resolution. We also observed notable differences in toxicity profiles between compound classes. Overall, we provide new insights into the in vivo anti-inflammatory activities of several novel tanshinones, isotanshinones, and structurally related compounds

Dolichol: A Component of the Cellular Antioxidant Machinery

Dolichol, an end product of the mevalonate pathway, has been proposed a biomarker of aging, but its biological role, not to mention its catabolism, has not been fully understood. UV-B radiation was used to induce oxidative stress in isolated rat hepatocytes by the collagenase method. Effects on dolichol, phospholipids-bound polyunsaturated fatty acids (PL PUFA) and known lipid soluble antioxidants [coenzyme Q (CoQ) and α-tocopherol] were studied. The increase in oxidative stress was detected by a probe sensitive to reactive oxygen species (ROS). Peroxidation of lipids was assessed by measuring the release of thiobarbituric acid reactive substances (TBARS). Dolichol, CoQ and α-tocopherol were assessed by high-pressure liquid chromatography (HPLC), PL PUFA by gas-liquid chromatography (GC). UV-B radiation caused an immediate increase in ROS as well as lipid peroxidation and a simultaneous decrease in the levels of dolichol and lipid soluble antioxidants. Decrease in dolichol paralleled changes in CoQ levels and was smaller than that in α-tocopherol. The addition of mevinolin, a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoAR), magnified the loss of dolichol and was associated with an increase in TBARS production. Changes in PL PUFA were minor. These findings highlight that oxidative stress has very early and similar effects on dolichol and lipid soluble antioxidants. Lower levels of dolichol are associated with enhanced peroxidation of lipids, which suggest that dolichol may have a protective role in the antioxidant machinery of cell membranes and perhaps be a key to understanding some adverse effects of statin therapy

Chronic kidney disease and coenzyme Q10 supplementation

Among the potential causes of chronic kidney disease (CKD), mitochondrial respiratory chain (MRC) dysfunction, oxidative stress and inflammation have been implicated as contributor factors to the pathogenesis of this disorder. It is thought that CoQ10 supplementation may offer some therapeutic potential in the treatment of patients with CKD, since CoQ10 has a key role in normal MRC function, as well as having antioxidant and anti-inflammatory action. This article will outline the current knowledge on the use of CoQ10 in the treatment of CK

Stress among medical students during clinical courses : a longitudinal study using contextual activity sampling system

Objectives: To investigate medical students’ experiences of stress and other emotions related to their professional roles, as defined by the CanMEDS framework, by using the Contextual Activity Sampling System (CASS). Methods: Ninety-eight medical students agreed to participate of whom 74 completed this longitudinal cohort study. Data was collected between 6th and 8th term via CASS methodology: A questionnaire was e-mailed to the participants every 3rd week (21questionnaires/measurements) during clinical rotations and scientific project work term. Emotions were measured by a 7-point Likert scale (e.g., maximum stress = 7). Answers were registered through mobile technology. We used a linear mixed-model regression approach to study the association between stress over time in relation to socio-demographic and learning activities related to CanMEDS roles. Results: Participants completed 1390 questionnaires. Mean stress level over all time points was 3.6. Stress was reported as highest during the scientific project term. Learning activities related to ‘Communicator,’ ‘Collaborator,’ ‘Scholar,’ ‘Manager’ and ‘Professional’ were associated with increased stress, e.g. ’Scholar’ increased stress with 0.5 points (t=3.91, p<0.001). A reduced level of stress was associated with ’Health Advocate’ of 0.39 points (t=-2.15, p=0.03). No association between perceived stress and demographic factors, such as gender or age was found. Conclusions: An association between different learning activities related to CanMEDS Roles and feelings of stress were noted. The CASS methodology was found to be useful when observing learning experiences and might support educational development by identifying course activities linked to stress