Fabrice Merien

The therapeutic potential of targeting ABC transporters to combat multi-drug resistance

ABSTRACT Introduction: Most disseminated cancers remain fatal despite the availability of a variety of conventional and novel treatments including surgery, chemotherapy, radiotherapy, immunotherapy, and biologically targeted therapy. A major factor responsible for the failure of chemotherapy in the treatment of cancer is the development of multidrug resistance (MDR). The overexpression of various ABC transporters in cancer cells can efficiently remove the anticancer drug from the cell, thus causing the drug to lose its effect. Areas covered: In this review, we summarised the ongoing research related to the mechanism, function, and regulation of ABC transporters. We integrated our current knowledge at different levels from molecular biology to clinical trials. We also discussed potential therapeutic strategies of targeting ABC transporters to reverse MDR in cancer cells. Expert opinion: Involvement of various ABC transporters to cancer MDR lays the foundation for developing tailored therapies that can overcome MDR. An ideal MDR reversal agent should have broad-spectrum ABC-transporter inhibitory activity, be potent, have good pharmacokinetics, have no trans-stimulation effects, and have low or no toxicity. Alternatively, nanotechnology-based drug delivery systems containing both the cytotoxic drug and reversing agent may represent a useful approach to reversing MDR with minimal off-target toxicity.

Differential expression of novel metabolic and immunological biomarkers in oysters challenged with a virulent strain of OsHV-1

&NA; Early lifestages of the Pacific oyster (Crassostrea gigas) are highly susceptible to infection by OsHV‐1 &mgr;Var, but little information exists regarding metabolic or pathophysiological responses of larval hosts. Using a metabolomics approach, we identified a range of metabolic and immunological responses in oyster larvae exposed to OsHV‐1 &mgr;Var; some of which have not previously been reported in molluscs. Multivariate analyses of entire metabolite profiles were able to separate infected from non‐infected larvae. Correlation analysis revealed the presence of major perturbations in the underlying biochemical networks and secondary pathway analysis of functionally‐related metabolites identified a number of prospective pathways differentially regulated in virus‐exposed larvae. These results provide new insights into the pathogenic mechanisms of OsHV‐1 infection in oyster larvae, which may be applied to develop disease mitigation strategies and/or as new phenotypic information for selective breeding programmes aiming to enhance viral resistance. Graphical abstract Figure. No caption available. HighlightsHerpesvirus‐induced metabolic responses were investigated in oyster larvae by GC‐MS.Host metabolism changes are suggestive of Irg‐1‐like activation.Energy and lipid metabolism was substantially disturbed during infection.Activation of immunoresponsive gene 1 and the Warburg effect is hypothesised.Metabolomics is a powerful approach to study disease in early oyster life stage.

Low-Active Male Adolescents: A Dose Response to High-Intensity Interval Training.

PURPOSEnHigh-intensity interval training (HIIT) is a potential alternative to traditionally recommended steady state exercise for providing health benefits in adolescents, yet its dose-response relationship in this cohort remains unclear, as does its translatability to real-world, nonclinical settings. The present study adopts a novel dose-response design to investigate the effects of undertaking 8 wk of HIIT on the cardiometabolic health of low-active male adolescents.nnnMETHODSnTwenty-six male adolescents (age 16 ± 1 yr), identified as low active by nonparticipation in structured sport and physical education classes, were randomly assigned to one of five treatment groups. Corresponding with their group numbers (1-5), participants completed a number of HIIT sets, which consisted of 4 repeated bouts of 20-s near-maximal exertion interspersed with 10-s passive recovery. Participants performed two HIIT sessions and one resistance training session each week for 8 wk. Baseline and follow-up health measures consisted of peak oxygen uptake (V˙O2peak) with an incremental ramp test to volitional exhaustion; body composition (including visceral fat mass, body fat, and lean tissue mass) with dual-energy x-ray absorptiometry; and lipid profile, glucose, insulin, and interleukin-6 from blood analysis. All health outcomes were analyzed as percentage changes, and data were modeled using a quadratic function to explore dose-response relationships.nnnRESULTSnSignificant improvements were observed for V˙O2peak (∼6%), body fat percentage (∼4%), visceral fat mass (∼10%), and waist circumference-to-height ratio (∼3%), but there was no clear effect of dose across groups.nnnCONCLUSIONSnLow-active adolescent males performing a single HIIT set twice weekly, in addition to one resistance training session, gained meaningful improvements in fitness and body composition. Performing additional HIIT sets provided no additional improvements to those of the lowest dose in this study.

Innovative application of classic and newer techniques for the characterization of haemocytes in the New Zealand black-footed abalone (Haliotis iris).

Haemocytes play an important role in innate immune responses within invertebrate organisms. However, identification and quantification of different types of haemocytes can be extremely challenging, and has led to numerous inconsistencies and misinterpretations within the literature. As a step to rectify this issue, we present a comprehensive and detailed approach to characterize haemocytes using a combination of classical (cytochemical and phagocytosis assays with optical microscopy) and novel (flow cytometry with Sysmex XN-1000 and Muse(®) Cell analyser) techniques. The Sysmex XN-1000 is an innovative fluorescent flow cytometric analyser that can effectively detect, identify and count haemocytes, while the Muse(®) Cell analyser provides accurate and rapid haemocyte cell counts and viability. To illustrate this approach, we present the first report on morphological and functional features of New Zealand black-footed abalone (Haliotis iris) haemocyte cells. Two types of haemocytes were identified in this study, including type I (monocyte-like) and type II (lymphocyte-like) cells. Granular cells, which have been reported in other molluscan species, were not detected in H.xa0iris. Cell types were categorized based on shape, size, internal structures and function. The lymphocyte-like haemocytes were the most abundant hemocytes in the haemolymph samples, and they had large nuclei and basic cytoplasms. Monocyte-like cells generally were larger cells compared to lymphocyte-like cells, and had low nucleus-cytoplasm ratios. Monocyte-like cells showed higher phagocytic activity when encountering Zymosan A particles compared to lymphocyte-like cells. The present study provides a comprehensive and accurate new approach to identify and quantify haemocyte cells for future comparative studies on the immune system of abalone and other molluscan species.

T-cells and their cytokine production: The anti-inflammatory and immunosuppressive effects of strenuous exercise

ABSTRACT Strenuous exercise bouts and heavy training are associated with a heightened anti‐inflammatory state and a transient suppression of several immune components. In turn, many athletes are susceptible to illness, particularly upper respiratory symptoms (e.g. cough, sore throat, running nose). T‐lymphocytes (T‐cells) are important for orchestrating the immune response and can be categorised into subsets according to their phenotypical characteristics resulting from polarisation (i.e. type‐1, type‐2 and regulatory T‐cells). Each T‐cell subset has a unique functional role, including their capacity to produce pro‐ and anti‐inflammatory cytokines in response to an immune challenge. Prolonged and exhaustive exercise typically reduces peripheral blood type‐1 T‐cell number and their capacity to produce the pro‐inflammatory cytokine, interferon‐&ggr;. Moreover, heavy training loads are associated with elevated numbers of resting peripheral blood type‐2 and regulatory T‐cells, which characteristically produce the anti‐inflammatory cytokines, interleukin‐4 and interleukin‐10, respectively. This appears to increase the risk of upper respiratory symptoms, potentially due to the cross‐regulatory effect of interleukin‐4 on interferon‐&ggr; production and immunosuppressive action of IL‐10. Catecholamines significantly influence the number of peripheral blood T‐cells in response to exercise. Whereas, glucocorticoids and prostaglandin E2 promote the production of anti‐inflammatory cytokines by T‐cells. In summary, strenuous exercise bouts and heavy training shifts T‐cell immunity towards an anti‐inflammatory state. This impairs the ability of the immune system to mount an inflammatory response to an immune challenge, which may weaken defences against intracellular pathogens (e.g. viruses), and increase the risk of infection and viral reactivation.

Metabolomics Study of Immune Responses of New Zealand Greenshell™ Mussels ( Perna canaliculus ) Infected with Pathogenic Vibrio sp.

Vibrio coralliilyticus is a bacterial pathogen which can affect a range of marine organisms, such as corals, fish and shellfish, with sometimes devastating consequences. However, little is known about the mechanisms involved in the host-pathogen interaction, especially within molluscan models. We applied gas chromatography-mass spectrometry (GC-MS)-based metabolomics to characterize the physiological responses in haemolymph of New Zealand Greenshell™ mussels (Perna canaliculus) injected with Vibrio sp. DO1 (V. coralliilyticus/neptunius-like isolate). Univariate data analyses of metabolite profiles in Vibrio-exposed mussels revealed significant changes in 22 metabolites at 6xa0h post-infection, compared to non-exposed mussels. Among them, 10 metabolites were up-regulated, while 12 metabolites were down-regulated in infected mussels. Multivariate analyses showed a clear distinction between infected and non-infected mussels. In addition, secondary pathway analyses indicated perturbations of the host innate immune system following infection, including oxidative stress, inflammation and disruption of the TCA cycle, change in amino acid metabolism and protein synthesis. These findings provide new insights into the pathogenic mechanisms of Vibrio infection of mussels and demonstrate our ability to detect detailed and rapid host responses from haemolymph samples using a metabolomics approach.

Acute effects of heated resistance exercise in female and male power athletes

PurposeTo determine the effects of heated resistance exercise on thermal strain, neuromuscular function and hormonal responses in power athletes.MethodsSixteen (nxa0=xa08 female; 8 male) highly trained power athletes completed a combined strength and power resistance exercise session in hot (HOT ~30xa0°C) and temperate (CON ~20xa0°C) conditions. Human growth hormone (hGH), cortisol and testosterone concentrations in plasma, peak power (counter-movement jump, CMJ) and peak force (isometric mid-thigh pull) were measured before and after each training session; thermoregulatory responses were monitored during training.ResultsSkin temperature, thermal sensation and thermal discomfort were higher in HOT compared with CON. Sweat rate was higher in HOT for males only. Compared with CON, HOT had trivial effects on core temperature and heart rate. During HOT, there was a possible increase in upper-body power (medicine ball throw) in females [3.4% (90% CL −1.5, 8.6)] and males [(3.3% (−0.1, 6.9)], while lower-body power (vertical jump) was enhanced in males only [3.2% (−0.4, 6.9)]. Following HOT, CMJ peak power [4.4% (2.5; 6.3)] and strength [8.2% (3.1, 13.6)] were enhanced in female athletes, compared with CON, while effects in males were unclear. Plasma hGH concentration increased in females [83% (18; 183)] and males [107% (−21; 444)] in HOT compared with CON, whereas differential changes occurred for cortisol and testosterone.ConclusionHeated resistance exercise enhanced power and increased plasma hGH concentration in female and males power athletes. Further research is required to assess the ergogenic potential of resistance exercise in the heat.

Metabolic and immunological responses of male and female new Zealand Greenshell™ mussels (Perna canaliculus) infected with Vibrio sp.

Massive mortalities due to pathogens are routinely reported in bivalve cultivation that have significant economic consequences for the global aquaculture industry. However, host-pathogen interactions and infection mechanisms that mediate these interactions are poorly understood. In addition, gender-specific immunological responses have been reported for some species, but the reasons for such differences have not been elucidated. In this study, we used a GC/MS-based metabolomics platform and flow cytometry approach to characterize metabolic and immunological responses in haemolymph of male and female mussels (Perna canaliculus) experimentally infected with Vibrio sp. Sex-based differences in immunological responses were identified, with male mussels displaying higher mortality, oxidative stress and apoptosis after pathogen exposure. However, central metabolic processes appeared to be similar between sexes at 24u202fh post injection with Vibrio sp. DO1. Significant alterations in relative levels of 37 metabolites were detected between infected and uninfected mussels. These metabolites are involved in major perturbations on the hosts innate immune system. In addition, there were alterations of seven metabolites in profiles of mussels sampled on the second day and mussels that survived six days after exposure. These metabolites include itaconic acid, isoleucine, phenylalanine, creatinine, malonic acid, glutaric acid and hydroxyproline. Among these, itaconic acid has the potential to be an important biomarker for Vibrio sp. DO1 infection. These findings provide new insights on the mechanistic relationship between a bivalve host and a pathogenic bacterium and highlight the need to consider host sex as a biological variable in future immunological studies.

A Journey with Elie Metchnikoff: From Innate Cell Mechanisms in Infectious Diseases to Quantum Biology.

Many reviews of Elie Metchnikoff’s work have been published, all unanimously acknowledging the significant contributions of his cellular theory to the fields of immunology and infectious diseases. In 1883, he published a key paper describing phagocytic cells in frogs. His descriptions were not just about phagocytes involved in host defense, he also described how these specialized cells eliminated degenerating or dying cells of the host. This perspective focuses on key concepts developed by Metchnikoff by presenting relevant excerpts of his 1883 paper and matching these concepts with challenges of modern immunology. A new approach to macrophage polarization is included to introduce some creative thinking about the exciting emerging area of quantum biology.

Comparing the effects of two distinct eccentric modalities to traditional resistance training in resistance trained, higher functioning older adults

Background: The effects of eccentric resistance exercise are of interest in the older adult cohort, but to our knowledge, there is no research on the relative effects of different eccentric modalities on a range of outcomes in higher functioning, resistance trained older adults. Methods: 33 resistance‐trained older adults (aged 67 ± 4.5 years) were randomized into one of three supervised training groups: traditional (TRE), eccentric only (ERE) or eccentrically biased resistance exercise (EBRE) on a 45°, plate‐loaded leg press machine. Participants trained twice per week with maximal strength, functional capacity, body composition and blood biomarkers measured before and after the eight‐week intervention. Results: Both eccentric and concentric strength, and important functional tasks for independent living significantly improved independent of group. Body composition and blood biomarkers were found to significantly improve in the EBRE group only however, no statistical differences were found between groups. Conclusion: Compared to traditional resistance training, the two eccentric modalities investigated here were equally effective for improvements in maximum muscular strength, functional capacity, body composition and metabolic biomarkers. When training the resistance trained older adult, very heavy isoinertial external loads (at least 70% of one repetition maximum) are effective irrespective of contraction mode. With heavy strength training, resistance trained older adults can continue to expect improvements in health and function. HighlightsHigh functioning, trained older adult preserve the capability to increase strength and improve their ability to perform everyday tasks.Eccentrically biased resistance exercise may be effective in increasing bone mineral content while decreasing fat mass, fasting plasma glucose and LDL levels.Very heavy loads should take precedence over modality type when prescribing resistance training to healthy, high functioning, resistance trained cohort.