Depurated fish as an alternative reference for field-based biomarker monitoring

The whole of the Swan-Canning Estuary, in the south-west of Australia, is impacted by human activity, and the selection of a local reference site to assess the impact of environmental contamination on the health of biota is not possible. To determine whether fish depurated under laboratory conditions could be used as an alternative to a reference site; adult black bream (Acanthopagrus butcheri) were collected from the estuary and maintained in clean water (S24) for 3 months. A suite of biomarkers of fish health were assessed, and the results were compared with field-captured black bream from three sites within the estuary (Ascot, Claisebrook, and Riverton). Comparisons of a subset of biomarkers were also made between hatchery-bred juvenile fish and the depurated fish. Biomarker levels were up to 3.8 times higher in field captured fish compared with depurated fish, while DNA integrity was lower. EROD activity was comparable in the hatchery-bred black bream to the depurated fish while s-SDH levels were two times higher in the hatchery fish. From the results obtained, field-captured black bream depurated for 3 months are suitable to determine reference/baseline levels for biomarker of health studies in estuarine environments

Proteostasis in cardiac health and disease

The incidence and prevalence of cardiac diseases, which are the main cause of death worldwide, are likely to increase because of population ageing. Prevailing theories about the mechanisms of ageing feature the gradual derailment of cellular protein homeostasis (proteostasis) and loss of protein quality control as central factors. In the heart, loss of protein patency, owing to flaws in genetically-determined design or because of environmentally-induced 'wear and tear', can overwhelm protein quality control, thereby triggering derailment of proteostasis and contributing to cardiac ageing. Failure of protein quality control involves impairment of chaperones, ubiquitin-proteosomal systems, autophagy, and loss of sarcomeric and cytoskeletal proteins, all of which relate to induction of cardiomyocyte senescence. Targeting protein quality control to maintain cardiac proteostasis offers a novel therapeutic strategy to promote cardiac health and combat cardiac disease. Currently marketed drugs are available to explore this concept in the clinical setting

Mitochondrial involvement in drug-induced liver injury.

International audienceMitochondrial dysfunction is a major mechanism of liver injury. A parent drug or its reactive metabolite can trigger outer mitochondrial membrane permeabilization or rupture due to mitochondrial permeability transition. The latter can severely deplete ATP and cause liver cell necrosis, or it can instead lead to apoptosis by releasing cytochrome c, which activates caspases in the cytosol. Necrosis and apoptosis can trigger cytolytic hepatitis resulting in lethal fulminant hepatitis in some patients. Other drugs severely inhibit mitochondrial function and trigger extensive microvesicular steatosis, hypoglycaemia, coma, and death. Milder and more prolonged forms of drug-induced mitochondrial dysfunction can also cause macrovacuolar steatosis. Although this is a benign liver lesion in the short-term, it can progress to steatohepatitis and then to cirrhosis. Patient susceptibility to drug-induced mitochondrial dysfunction and liver injury can sometimes be explained by genetic or acquired variations in drug metabolism and/or elimination that increase the concentration of the toxic species (parent drug or metabolite). Susceptibility may also be increased by the presence of another condition, which also impairs mitochondrial function, such as an inborn mitochondrial cytopathy, beta-oxidation defect, certain viral infections, pregnancy, or the obesity-associated metabolic syndrome. Liver injury due to mitochondrial dysfunction can have important consequences for pharmaceutical companies. It has led to the interruption of clinical trials, the recall of several drugs after marketing, or the introduction of severe black box warnings by drug agencies. Pharmaceutical companies should systematically investigate mitochondrial effects during lead selection or preclinical safety studies