Stress, inflammation, and cellular vulnerability during early stages of affective disorders: biomarker strategies and opportunities for prevention and intervention

The mood disorder prodrome is conceptualized as a symptomatic, but not yet clinically diagnosable stage of an affective disorder. Although a growing area, more focused research is needed in the pediatric population to better characterize psychopathological symptoms and biological markers that can reliably identify this very early stage in the evolution of mood disorder pathology. Such information will facilitate early prevention and intervention, which has the potential to affect a person’s disease course.This review focuses on the prodromal characteristics, risk factors, and neurobiological mechanisms of mood disorders. In particular, we consider the influence of early-life stress, inflammation, and allostatic load in mediating neural mechanisms of neuroprogression. These inherently modifiable factors have known neuroadaptive and neurodegenerative implications, and consequently may provide useful biomarker targets. Identification of these factors early in the course of the disease will accordingly allow for the introduction of early interventions which augment an individual’s capacity for psychological resilience through maintenance of synaptic integrity and cellular resilience. A targeted and complementary approach to boosting both psychological and physiological resilience simultaneously during the prodromal stage of mood disorder pathology has the greatest promise for optimizing the neurodevelopmental potential of those individuals at risk of disabling mood disorders.

Current and emerging therapeutic strategies for preventing inflammation and aggrecanase-mediated cartilage destruction in arthritis

Arthritis is a multifactorial disease for which current therapeutic intervention with high efficacy remains challenging. Arthritis predominately affects articular joints, and cartilage deterioration and inflammation are key characteristics. Current therapeutics targeting inflammatory responses often cause severe side effects in patients because of the systemic inhibition of cytokines or other global immunosuppressive activities. Furthermore, a lack of primary response or failure to sustain a response to treatment through acquired drug resistance is an ongoing concern. Nevertheless, treatments such as disease-modifying anti-rheumatic drugs, biological agents, and corticosteroids have revealed promising outcomes by decreasing pain and inflammation in patients and in some cases reducing radiographic progression of the disease. Emerging and anecdotal therapeutics with anti-inflammatory activity, alongside specific inhibitors of the A Disintegrin-like And Metalloproteinase domain with Thrombospondin-1 repeats (ADAMTS) cartilage-degrading aggrecanases, provide promising additions to current arthritis treatment strategies. Thus, it is paramount that treatment strategies be optimized to increase efficacy, reduce debilitating side effects, and improve the quality of life of patients with arthritis. Here, we review the current strategies that attempt to slow or halt the progression of osteoarthritis and rheumatoid arthritis, providing an up-to-date summary of pharmaceutical treatment strategies and side effects. Importantly, we highlight their potential to indirectly regulate ADAMTS aggrecanase activity through their targeting of inflammatory mediators, thus providing insight into a mechanism by which they might inhibit cartilage destruction to slow or halt radiographic progression of the disease. We also contrast these with anecdotal or experimental administration of statins that could equally regulate ADAMTS aggrecanase activity and are available to arthritis sufferers worldwide. Finally, we review the current literature regarding the development of synthetic inhibitors directed toward the aggrecanases ADAMTS4 and ADAMTS5, a strategy that might directly inhibit cartilage destruction and restore joint function in both rheumatoid arthritis and osteoarthritis.

Inhibition of reactive oxygen species production ameliorates inflammation induced by influenza A viruses via upregulation of SOCS1 and SOCS3.

Highly pathogenic avian influenza virus infection is associated with severe mortality in both humans and poultry. The mechanisms of disease pathogenesis and immunity are poorly understood although recent evidence suggests that cytokine/chemokine dysregulation contributes to disease severity following H5N1 infection. Influenza A virus infection causes a rapid influx of inflammatory cells, resulting in increased reactive oxygen species production, cytokine expression, and acute lung injury. Proinflammatory stimuli are known to induce intracellular reactive oxygen species by activating NADPH oxidase activity. We therefore hypothesized that inhibition of this activity would restore host cytokine homeostasis following avian influenza virus infection. A panel of airway epithelial and immune cells from mammalian and avian species were infected with A/Puerto Rico/8/1934 H1N1 virus, low-pathogenicity avian influenza H5N3 virus (A/duck/Victoria/0305-2/2012), highly pathogenic avian influenza H5N1 virus (A/chicken/Vietnam/0008/2004), or low-pathogenicity avian influenza H7N9 virus (A/Anhui/1/2013). Quantitative real-time reverse transcriptase PCR showed that H5N1 and H7N9 viruses significantly stimulated cytokine (interleukin-6, beta interferon, CXCL10, and CCL5) production. Among the influenza-induced cytokines, CCL5 was identified as a potential marker for overactive immunity. Apocynin, a Nox2 inhibitor, inhibited influenza-induced cytokines and reactive oxygen species production, although viral replication was not significantly altered in vitro. Interestingly, apocynin treatment significantly increased influenza virus-induced mRNA and protein expression of SOCS1 and SOCS3, enhancing negative regulation of cytokine signaling. These findings suggest that apocynin or its derivatives (targeting host responses) could be used in combination with antiviral strategies (targeting viruses) as therapeutic agents to ameliorate disease severity in susceptible species.

Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research.

Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g., interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here, we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways. Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g., activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, and activation of the toll-like receptor and neuroprogressive pathways. Thirdly, anti-inflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e., path and drug discovery processes, omics-based techniques, and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, immunoproteomics and metagenomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular networks, pathways, and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways.

Nanoformulated mutant SurR9-C84A: a possible key for alzheimer's and its associated inflammation

PURPOSE: Alzheimer's disease (AD) is one of the untreatable neurodegenerative diseases characterised by the pathologic amyloid plaque deposition and inflammation. The aim of this study is to evaluate the neuroprotective effects of nanoformulated SurR9-C84A, a survivin mutant belonging to the inhibitors of the apoptosis (IAP) protein family. The effect of SurR9-C84A was studied against the β-amyloid toxicity and various inflammatory insults in the differentiated SK-N-SH neurons. METHOD: SurR9-C84A loaded poly(lactic-co-glycolic acid) nanoparticles were prepared following the modified double emulsion technique. The neuroprotective effect of SurR9-C84A was evaluated against the amyloid-β (Aβ) peptide fragment, N-methyl-D-aspartate (NMDA) toxicity and the inflammatory assaults. To mimic the in vivo situation, a co-culture of neurons and microglia was also studied to validate these results. RESULTS: SurR9-C84A treatments showed improved neuronal health following Aβ, and NMDA toxicity in addition to inflammatory insults induced in mono and co-cultures. The neuroprotective effect was evident with the reduced neuronal death, accelerated expression of neuronal integrity markers (neurofilaments, beta-tubulin III etc.,) and the neuroprotective ERK/MAPK signalling. CONCLUSION: The current results demonstrated that the SurR9-C84A nanoformulation was very effective in rescuing the neurons and holds a potential future application against AD.

Hydroxyoctadecadienoic acids: Oxidised derivatives of linoleic acid and their role in inflammation associated with metabolic syndrome and cancer

Linoleic acid (LA) is a major constituent of low-density lipoproteins. An essential fatty acid, LA is a polyunsaturated fatty acid, which is oxidised by endogenous enzymes and reactive oxygen species in the circulation. Increased levels of low-density lipoproteins coupled with oxidative stress and lack of antioxidants drive the oxidative processes. This results in synthesis of a range of oxidised derivatives, which play a vital role in regulation of inflammatory processes. The derivatives of LA include, hydroxyoctadecadienoic acids, oxo-​octadecadienoic acids, epoxy octadecadecenoic acid and epoxy-keto-octadecenoic acids. In this review, we examine the role of LA derivatives and their actions on regulation of inflammation relevant to metabolic processes associated with atherogenesis and cancer. The processes affected by LA derivatives include, alteration of airway smooth muscles and vascular wall, affecting sensitivity to pain, and regulating endogenous steroid hormones associated with metabolic syndrome. LA derivatives alter cell adhesion molecules, this initial step, is pivotal in regulating inflammatory processes involving transcription factor peroxisome proliferator-activated receptor pathways, thus, leading to alteration of metabolic processes. The derivatives are known to elicit pleiotropic effects that are either beneficial or detrimental in nature hence making it difficult to determine the exact role of these derivatives in the progress of an assumed target disorder. The key may lie in understanding the role of these derivatives at various stages of development of a disorder. Novel pharmacological approaches in altering the synthesis or introduction of synthesised LA derivatives could possibly help drive processes that could regulate inflammation in a beneficial manner. Chemical Compounds: Linoleic acid (PubChem CID: 5280450), 9- hydroxyoctadecadienoic acid (PubChem CID: 5312830), 13- hydroxyoctadecadienoic acid (PubChem CID: 6443013), 9-oxo-​octadecadienoic acid (PubChem CID: 3083831), 13-oxo-​octadecadienoic acid (PubChem CID: 4163990), 9,10-epoxy-12-octadecenoate (PubChem CID: 5283018), 12,13-epoxy-9-keto-10- trans -octadecenoic acid (PubChem CID: 53394018), Pioglitazone (PubChem CID: 4829).

Fish oil and multivitamin supplementation reduces oxidative stress but not inflammation in healthy older adults: a randomised controlled trial

The effects of daily fish oil supplementation, with and without multivitamins, on biochemical markers of health were examined. Healthy adults (N = 160) were randomised to receive 3 g of salmon oil with a multivitamin, 6 g of salmon oil with a multivitamin, 6 g of salmon oil in isolation or placebo in a double-blind fashion on a daily basis for 16 weeks. Relative to placebo, both 6 g salmon oil groups displayed significantly lower F2-isoprostane levels at endpoint. Increases in red blood cell polyunsaturated fatty acids correlated with reductions in F2-isoprostanes. Treatment had no effect on inflammatory cytokines, C-reactive protein, fibrinogen, cholesterol or triacylglycerol.

Ibuprofen ingestion does not affect markers of post-exercise muscle inflammation

PURPOSE: We investigated if oral ingestion of ibuprofen influenced leucocyte recruitment and infiltration following an acute bout of traditional resistance exercise Methods: Sixteen male subjects were divided into two groups that received the maximum over-the-counter dose of ibuprofen (1200mg d(-1)) or a similarly administered placebo following lower body resistance exercise. Muscle biopsies were taken from m.vastus lateralis and blood serum samples were obtained before and immediately after exercise, and at 3 and 24 h after exercise. Muscle cross-sections were stained with antibodies against neutrophils (CD66b and MPO) and macrophages (CD68). Muscle damage was assessed via creatine kinase and myoglobin in blood serum samples, and muscle soreness was rated on a ten-point pain scale.

RESULTS: The resistance exercise protocol stimulated a significant increase in the number of CD66b(+) and MPO(+) cells when measured 3 h post exercise. Serum creatine kinase, myoglobin and subjective muscle soreness all increased post-exercise. Muscle leucocyte infiltration, creatine kinase, myoglobin and subjective muscle soreness were unaffected by ibuprofen treatment when compared to placebo. There was also no association between increases in inflammatory leucocytes and any other marker of cellular muscle damage.

CONCLUSION: Ibuprofen administration had no effect on the accumulation of neutrophils, markers of muscle damage or muscle soreness during the first 24 h of post-exercise muscle recovery.

Stress, dopamine, inflammation and energy regulation: Examining the nature of antidepressant-resistance and response

This thesis investigated the nature of treatment-resistant depression and novel antidepressants utilizing a preclinical model of antidepressant-resistance. Chronic disruption of the stress response impaired response to antidepressants and altered dopamine signaling in this model. Inflammatory profile and energy regulation were identified as potential biomarkers for response to ketamine and lithium.

Biocatalysis of Soybean 15-Lipoxygenase for the production of lipid mediators of Inflammation

This thesis describes the application of a plant enzyme, soybean 15-lipoxygenase-1, in the production of lipid-based mediators of inflammation from omega-3 fatty acids. Several methods for the biosynthesis and characterisation of such compounds have been developed, which have also provided further insight into the catalytic mechanism of the enzyme.

Muscle damage and inflammation during recovery from exercise

Unaccustomed exercise consisting of eccentric (i.e., lengthening) muscle contractions often results in muscle damage characterized by ultrastructural alterations in muscle tissue, clinical signs and symptoms (e.g., reduced muscle strength and range of motion, increased muscle soreness and swelling, efflux of myocellular proteins). The time course of recovery following exercise-induced muscle damage depends on the extent of initial muscle damage, which in turn is influenced by the intensity and duration of exercise, joint angle/muscle length and muscle groups used during exercise. The effects of these factors on muscle strength, soreness and swelling are well characterized. By contrast, much less is known about how they affect intramuscular inflammation and molecular aspects of muscle adaptation/remodeling. Although inflammation has historically been viewed as detrimental for recovery from exercise, it is now generally accepted that inflammatory responses-if tightly regulated-are integral to muscle repair and regeneration. Animal studies have revealed that other cell types including mast cells, eosinophils, CD8 and T regulatory lymphocytes, fibro-adipogenic progenitors and pericytes also help to facilitate muscle tissue regeneration. However, more research is required to determine whether these cells respond to exercise-induced muscle damage. A large body of research has investigated the efficacy of physicotherapeutic, pharmacological and nutritional interventions for reducing the signs and symptoms of exercise-induced muscle damage, with mixed results. More research is needed to examine if/how these treatments influence inflammation and muscle remodeling during recovery from exercise.