Methylmercury-induced inhibition of paraoxonase-1 (PON1)-implications for cardiovascular risk

Methylmercury (MeHg) has been associated with increased risk for cardiovascular disease in some but not all epidemiology studies. These inconsistent results may stem from the fact that exposure typically occurs in the context of fish consumption, which is also associated with cardioprotective factors such as omega-3 fatty acids. Mechanistic information may help to understand whether MeHg represents a risk to cardiovascular health. MeHg is a pro-oxidant that inactivates protein sulfhydryls. These biochemical effects may diminish critical antioxidant defense mechanism(s) involved in protecting against atherosclerosis. One such defense mechanism is paraoxonase-1 (PON1), an enzyme present on high-density lipoproteins and that prevents the oxidation of blood lipids and their deposition in vascular endothelium. PON1 is potentially useful as a clinical biomarker of cardiovascular risk, as well as a critical enzyme in the detoxification of certain organophosphate oxons. MeHg and other metals are known to inhibit PON1 activity in vitro. MeHg is associated with lowered serum PON1 activity in a fish-eating population. The implications of lowering PON1 are evaluated by predicting the shift in PON1 population distribution induced by various doses of MeHg. An MeHg dose of 0.3 μg/kg/d is estimated to decrease the population average PON1 level by 6.1% and to increase population risk of acute cardiovascular events by 9.7%. This evaluation provides a plausible mechanism for MeHg-induced cardiovascular risk and suggests means to quantify the risk. This case study exemplifies the use of upstream disease biomarkers to evaluate the additive effect of chemical toxicity with background disease processes in assessing human risk.

Recent insights into microbial catalases: isolation, production and purification

Catalase, an oxidoreductase enzyme, works as a detoxification system inside living cells against reactive oxygen species formed as a by-product of different metabolic reactions. The enzyme is found in a wide range of aerobic and anaerobic organisms. Catalase has also been employed in various analytical and diagnostic methods in the form of biosensors and biomarkers in addition to its other applications in textile, paper, food and pharmaceutical industries. New applications for catalases are constantly emerging thanks to their high turnover rate, distinct evolutionary origin, relatively simple and well-defined reaction mechanisms. The following review provides comprehensive information on isolation, production and purification of catalases with different techniques from various microbial sources along with their types, structure, mechanism of action and applications.

The Glutathione System: a new drug target in neuroimmune disorders

Glutathione (GSH) has a crucial role in cellular signaling and antioxidant defenses either by reacting directly with reactive oxygen or nitrogen species or by acting as an essential cofactor for GSH S-transferases and glutathione peroxidases. GSH acting in concert with its dependent enzymes, known as the glutathione system, is responsible for the detoxification of reactive oxygen and nitrogen species (ROS/RNS) and electrophiles produced by xenobiotics. Adequate levels of GSH are essential for the optimal functioning of the immune system in general and T cell activation and differentiation in particular. GSH is a ubiquitous regulator of the cell cycle per se. GSH also has crucial functions in the brain as an antioxidant, neuromodulator, neurotransmitter, and enabler of neuron survival. Depletion of GSH leads to exacerbation of damage by oxidative and nitrosative stress; hypernitrosylation; increased levels of proinflammatory mediators and inflammatory potential; dysfunctions of intracellular signaling networks, e.g., p53, nuclear factor-κB, and Janus kinases; decreased cell proliferation and DNA synthesis; inactivation of complex I of the electron transport chain; activation of cytochrome c and the apoptotic machinery; blockade of the methionine cycle; and compromised epigenetic regulation of gene expression. As such, GSH depletion has marked consequences for the homeostatic control of the immune system, oxidative and nitrosative stress (O&NS) pathways, regulation of energy production, and mitochondrial survival as well. GSH depletion and concomitant increase in O&NS and mitochondrial dysfunctions play a role in the pathophysiology of diverse neuroimmune disorders, including depression, myalgic encephalomyelitis/chronic fatigue syndrome and Parkinson’s disease, suggesting that depleted GSH is an integral part of these diseases. Therapeutical interventions that aim to increase GSH concentrations in vivo include N-acetyl cysteine; Nrf-2 activation via hyperbaric oxygen therapy; dimethyl fumarate; phytochemicals, including curcumin, resveratrol, and cinnamon; and folate supplementation.

Metal ion ligands in hyperaccumulating plants

Metal-hyperaccumulating plants have the ability to take up extraordinary quantities of certain metal ions without succumbing to toxic effects. Most hyperaccumulators select for particular metals but the mechanisms of selection are not understood at the molecular level. While there are many metal-binding biomolecules, this review focuses only on ligands that have been reported to play a role in sequestering, transporting or storing the accumulated metal. These include citrate, histidine and the phytosiderophores. The metal detoxification role of metallothioneins and phytochelatins in plants is also discussed.

Histological, growth and 7-ethoxyresorufin 0-deethylase (EROD) activity responses of greenback flounder Rhombosolea tapirina to contaminated marine sediment and diet

Pathological abnormalities and mixed function oxygenase (MFO) enzyme changes are frequently used as indicators of anthropogenic contaminant exposure and effect. However, there is a paucity of research investigating the effects of contaminated sediment on native Australian benthic teleosts. As part of an ecotoxicological assessment of contaminated marine sediments in northern Tasmania, CYP1A induction, histological and growth response of the greenback flounder, Rhombosolea tapirina, exposed to contaminated marine sediments were examined. Hatchery reared flounder were exposed to reference sediment, contaminated sediment or contaminated sediment and diet for 6 weeks. CYP1A induction, using the ethoxyresorufin-O-deethylase (EROD) assay, and the histological and growth response in the flounder were examined on cessation of the exposure trial. Significant differences were found between treatments in histological, growth and EROD response. Exposure to contaminated sediment and diet elicited a multi-organ histological response: principally partial and total epidermal erosion and multifocal necrosis of the liver. The prevalence of total epidermal erosion was greatest with exposure to disturbed contaminated sediment (66.65±16.65%). The prevalence of multifocal necrosis of the liver was greatest with exposure to contaminanted sediment and diet (66.65±16.65%). Growth reduction, measured as percentage growth inhibition, was evident in flounder exposed to contaminated sediment and diet (18.2±11.99%). Additionally, exposure to contaminated sediment and diet elicited elevated induction of the EROD liver detoxification enzyme (139.65±24.22 pmol/min/mg protein) compared to exposure to contaminated sediment and non-contaminated diet (6.25±0.81 pmol/min/mg) indicating the presence and potential bioavailability of xenobiotics via food. Further, more inhibited growth and histological alteration associated with exposure to contaminated sediment and diet suggest contaminants in Deceitful Cove sediment are cytotoxic.

Metabolic consequences of knocking out UGT85B1, the gene encoding the glucosyltransferase required for synthesis of dhurrin in Sorghum bicolor (L. Moench)

Many important food crops produce cyanogenic glucosides as natural defense compounds to protect against herbivory or pathogen attack. It has also been suggested that these nitrogen-based secondary metabolites act as storage reserves of nitrogen. In sorghum, three key genes, CYP79A1, CYP71E1 and UGT85B1, encode two Cytochrome P450s and a glycosyltransferase, respectively, the enzymes essential for synthesis of the cyanogenic glucoside dhurrin. Here, we report the use of targeted induced local lesions in genomes (TILLING) to identify a line with a mutation resulting in a premature stop codon in the N-terminal region of UGT85B1. Plants homozygous for this mutation do not produce dhurrin and are designated tcd2 (totally cyanide deficient 2) mutants. They have reduced vigor, being dwarfed, with poor root development and low fertility. Analysis using liquid chromatography-mass spectrometry (LC-MS) shows that tcd2 mutants accumulate numerous dhurrin pathway-derived metabolites, some of which are similar to those observed in transgenic Arabidopsis expressing the CYP79A1 and CYP71E1 genes. Our results demonstrate that UGT85B1 is essential for formation of dhurrin in sorghum with no co-expressed endogenous UDP-glucosyltransferases able to replace it. The tcd2 mutant suffers from self-intoxication because sorghum does not have a feedback mechanism to inhibit the initial steps of dhurrin biosynthesis when the glucosyltransferase activity required to complete the synthesis of dhurrin is lacking. The LC-MS analyses also revealed the presence of metabolites in the tcd2 mutant which have been suggested to be derived from dhurrin via endogenous pathways for nitrogen recovery, thus indicating which enzymes may be involved in such pathways.

Patient satisfaction with treatment for alcohol use disorders: comparing patients with and without severe mental health symptoms

BACKGROUND: Previous studies suggest patients with co-occurring alcohol use disorders (AUDs) and severe mental health symptoms (SMHS) are less satisfied with standard AUD treatment when compared to patients with an AUD alone. This study compared patient satisfaction with standard AUD treatment among patients with and without SMHS and explored how standard treatment might be improved to better address the needs of these patients.

METHODS: Eighty-nine patients receiving treatment for an AUD either at an inpatient hospital, outpatient clinic, inpatient detoxification, or residential/therapeutic community services were surveyed. Patient satisfaction with treatment was assessed using the Treatment Perception Questionnaire (range: 0-40). Patients were stratified according to their score on the Depression Anxiety Stress Scale. Forty patients scored in the extremely severe range of depression (score >14) and/or anxiety (score >10) (indicating SMHS) and 49 patients did not. An inductive content analysis was also conducted on qualitative data relating to areas of service improvement.

RESULTS: Patients with SMHS were found to be equally satisfied with treatment (mean =25.10, standard deviation =8.12) as patients with an AUD alone (mean =25.43, standard deviation =6.91). Analysis revealed that being an inpatient in hospital was associated with reduced treatment satisfaction. Patients with SMHS were found to be significantly less satisfied with staffs' understanding of the type of help they wanted in treatment, when compared to patients with AUDs alone. Five areas for service improvement were identified, including staff qualities, informed care, treatment access and continuity, issues relating to inpatient stay, and addressing patients' mental health needs.

CONCLUSION: While findings suggest that AUD treatment services adequately meet the needs of patients with SMHS in treatment, patients with SMHS do feel that staff lack understanding of their treatment needs. Findings have important implications as to how current health care practice might be improved according to the patient's perspective of care.

'I'm a sick person, not a bad person': patient experiences of treatments for alcohol use disorders

BACKGROUND: Emerging research indicates that standard treatments for alcohol use disorders may not fully meet the needs of patients with co-occurring severe mental health symptoms. Investigating health quality indicators may provide insight into how current treatment might be improved.

OBJECTIVE: To better understand the experiences of patients receiving treatment for alcohol use disorders and compare the experiences of patients with and without co-occurring severe mental health symptoms.

DESIGN: Cross-sectional qualitative research design using semi-structured interviews methods and framework analysis approach.

SETTING: Inpatient hospital, outpatient service, inpatient detoxification clinic and a residential/ therapeutic community.

PARTICIPANT'S: Thirty-four patients receiving treatment for an alcohol use disorder.

MAIN VARIABLES STUDIED: Themes relating to patients' experiences of continuity of care, treatment need and satisfaction with treatment were studied. The qualitative data were divided into two groups: patients with (n = 15) and without (n = 19) severe mental health symptoms.

RESULTS: Five themes relating to patient satisfaction with treatment were identified, including: perceived effectiveness of treatment, supportive relationships, specialized but holistic care, patient autonomy and continuity of care. A diverse range of patient treatment needs, staff and service continuity and stigma were also identified as major themes. Five basic themes were identified as more critical to the experiences of patients with severe mental health symptoms.

DISCUSSION AND CONCLUSIONS: Findings suggest that patients look for supportive relationships with others, to be involved in treatment decisions, effective specialized and holistic approaches to care and a non-judgemental treatment environment.