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1.
J Neurochem ; 168(6): 1113-1142, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38339785

ABSTRACT

The small-molecule drug, FTY720 (fingolimod), is a synthetic sphingosine 1-phosphate (S1P) analogue currently used to treat relapsing-remitting multiple sclerosis in both adults and children. FTY720 can cross the blood-brain barrier (BBB) and, over time, accumulate in lipid-rich areas of the central nervous system (CNS) by incorporating into phospholipid membranes. FTY720 has been shown to enhance cell membrane fluidity, which can modulate the functions of glial cells and neuronal populations involved in regulating behaviour. Moreover, direct modulation of S1P receptor-mediated lipid signalling by FTY720 can impact homeostatic CNS physiology, including neurotransmitter release probability, the biophysical properties of synaptic membranes, ion channel and transmembrane receptor kinetics, and synaptic plasticity mechanisms. The aim of this study was to investigate how chronic FTY720 treatment alters the lipid composition of CNS tissue in adolescent mice at a key stage of brain maturation. We focused on the hippocampus, a brain region known to be important for learning, memory, and the processing of sensory and emotional stimuli. Using mass spectrometry-based lipidomics, we discovered that FTY720 increases the fatty acid chain length of hydroxy-phosphatidylcholine (PCOH) lipids in the mouse hippocampus. It also decreases PCOH monounsaturated fatty acids (MUFAs) and increases PCOH polyunsaturated fatty acids (PUFAs). A total of 99 lipid species were up-regulated in the mouse hippocampus following 3 weeks of oral FTY720 exposure, whereas only 3 lipid species were down-regulated. FTY720 also modulated anxiety-like behaviours in young mice but did not affect spatial learning or memory formation. Our study presents a comprehensive overview of the lipid classes and lipid species that are altered in the hippocampus following chronic FTY720 exposure and provides novel insight into cellular and molecular mechanisms that may underlie the therapeutic or adverse effects of FTY720 in the central nervous system.


Subject(s)
Fingolimod Hydrochloride , Hippocampus , Lipidomics , Mice, Inbred C57BL , Animals , Fingolimod Hydrochloride/pharmacology , Hippocampus/drug effects , Hippocampus/metabolism , Mice , Male , Sphingosine/analogs & derivatives , Sphingosine/pharmacology , Sphingosine/metabolism , Lysophospholipids/metabolism , Lipid Metabolism/drug effects , Immunosuppressive Agents/pharmacology
2.
Phys Biol ; 21(2)2024 Feb 05.
Article in English | MEDLINE | ID: mdl-38266283

ABSTRACT

In recentin vitroexperiments on co-culture between breast tumour spheroids and activated immune cells, it was observed that the introduction of the stress hormone cortisol resulted in a decreased immune cell infiltration into the spheroids. Moreover, the presence of cortisol deregulated the normal levels of the pro- and anti-inflammatory cytokines IFN-γand IL-10. We present an individual-based model to explore the interaction dynamics between tumour and immune cells under psychological stress conditions. With our model, we explore the processes underlying the emergence of different levels of immune infiltration, with particular focus on the biological mechanisms regulated by IFN-γand IL-10. The set-up of numerical simulations is defined to mimic the scenarios considered in the experimental study. Similarly to the experimental quantitative analysis, we compute a score that quantifies the level of immune cell infiltration into the tumour. The results of numerical simulations indicate that the motility of immune cells, their capability to infiltrate through tumour cells, their growth rate and the interplay between these cell parameters can affect the level of immune cell infiltration in different ways. Ultimately, numerical simulations of this model support a deeper understanding of the impact of biological stress-induced mechanisms on immune infiltration.


Subject(s)
Interleukin-10 , Neoplasms , Humans , Hydrocortisone , Neoplasms/pathology , Biophysical Phenomena , Stress, Psychological , Spheroids, Cellular
3.
Front Immunol ; 14: 1092799, 2023.
Article in English | MEDLINE | ID: mdl-37954581

ABSTRACT

The canonical NOD-like receptor family pyrin domain containing 3 (NLRP3) pathway involves a priming step to induce pro-IL-1ß followed by a secondary signal such as K+ efflux to activate inflammasome formation. This then leads to the maturation of IL-1ß and the formation of gasdermin D (GSDMD) pores that initiate pyroptosis and mediate IL-1ß release. In contrast, primary human monocytes also engage an alternative pathway in response to toll-like receptor (TLR) 4 activation, without the need for a secondary signal. Data from a monocyte-like cell line suggest that the alternative pathway functions via the TLR adaptor protein TIR-domain-containing adapter-inducing interferon-ß (TRIF), receptor-interacting protein kinase 1 (RIPK1), FAS-associated death domain (FADD) and caspase-8 upstream of NLRP3 activation, but in the absence of K+ efflux or pyroptosis. Usage of the alternative pathway by other members of the TLR family that induce IL-1ß but do not signal through TRIF, has yet to be explored in primary human monocytes. Furthermore, the mechanism by which IL-1ß is released from monocytes remains unclear. Therefore, this study investigated if the alternative NLRP3 inflammasome pathway is initiated following activation of TLRs other than TLR4, and if GSDMD was necessary for the release of IL-1ß. Monocytes were stimulated with ligands that activate TLR1/2, TLR2/6, TLR4 and TLR7 and/or TLR8 (using a dual ligand). Similar to TLR4, all of the TLRs investigated induced IL-1ß release in a NLRP3 and caspase-1 dependent manner, indicating that TRIF may not be an essential upstream component of the alternative pathway. Furthermore, inhibition of RIPK1 kinase activity had no effect on IL-1ß release. Although IL-1ß was released independently of K+ efflux and pyroptosis, it was significantly reduced by an inhibitor of GSDMD. Therefore, it is feasible that low level GSDMD pore formation may facilitate the release of IL-1ß from the cell, but not be present in sufficient quantities to initiate pyroptosis. Together these data suggest that the alternative pathway operates independently of RIPK1 kinase activity, downstream of diverse TLRs including TLR4 in primary human monocytes and supports the potential for IL-1ß release via GSDMD pores alongside other unconventional secretory pathways.


Subject(s)
Inflammasomes , Monocytes , Humans , Monocytes/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Toll-Like Receptor 4/metabolism , Toll-Like Receptors/metabolism , Adaptor Proteins, Vesicular Transport/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
4.
Chem Res Toxicol ; 36(2): 129-131, 2023 02 20.
Article in English | MEDLINE | ID: mdl-36661325

ABSTRACT

Higher stress and anxiety levels are often reported globally. While anecdotal evidence has attributed a myriad of health conditions to stress, the mechanisms are often overlooked. Understanding the role of stress hormones on DNA damage/oxidative stress has implications for disease.


Subject(s)
DNA Damage , Oxidative Stress
5.
Gene ; 851: 147022, 2023 Jan 30.
Article in English | MEDLINE | ID: mdl-36347335

ABSTRACT

The response to psychological stress can differ depending on the type and duration of the stressor. Acute stress can facilitate a "fight or flight response" and aid survival, whereas chronic long-term stress with the persistent release of stress hormones such as cortisol has been shown to be detrimental to health. We are now beginning to understand how this stress hormone response impacts important processes such as DNA repair and cell proliferation processes in breast cancer. However, it is not known what epigenetic changes stress hormones induce in breast cancer. Epigenetic mechanisms include modification of DNA and histones within chromatin that may be involved in governing the transcriptional processes in cancer cells in response to changes by endogenous stress hormones. The contribution of endogenous acute or long-term exposure of glucocorticoid stress hormones, and exogenous glucocorticoids to methylation patterns in breast cancer tissues with different aetiologies remains to be evaluated. In vitro and in vivo models were developed to investigate the epigenetic modifications and their contribution to breast cancer progression and aetiology. A panel of triple negative breast cancer cell lines were treated with the glucocorticoid, cortisol which resulted in epigenetic alteration characterised by loss of methylation on promoter regions of tumour suppressor genes including ESR1, and loss of methylation on LINE-1 repetitive element used as a surrogate marker for global methylation. This was verified in vivo in MDA-MB-231 xenografts; the model verified the loss of methylation on ESR1 promoter, and subsequent increase in ESR1 expression in primary tumours in mice subjected to restraint stress. Our study highlights that DNA methylation landscape in breast cancer can be altered in response to stress and glucocorticoid treatment.


Subject(s)
Estrogen Receptor alpha , Triple Negative Breast Neoplasms , Humans , Mice , Animals , Fulvestrant , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Glucocorticoids/pharmacology , Hydrocortisone/pharmacology , DNA Methylation
6.
J Vis Exp ; (186)2022 08 02.
Article in English | MEDLINE | ID: mdl-35993751

ABSTRACT

Brain metastasis is a cause of severe morbidity and mortality in cancer patients. Critical aspects of metastatic diseases, such as the complex neural microenvironment and stromal cell interaction, cannot be entirely replicated with in vitro assays; thus, animal models are critical for investigating and understanding the effects of therapeutic intervention. However, most brain tumor xenografting methods do not produce brain metastases consistently in terms of the time frame and tumor burden. Brain metastasis models generated by intracardiac injection of cancer cells can result in unintended extracranial tumor burden and lead to non-brain metastatic morbidity and mortality. Although intracranial injection of cancer cells can limit extracranial tumor formation, it has several caveats, such as the injected cells frequently form a singular tumor mass at the injection site, high leptomeningeal involvement, and damage to brain vasculature during needle penetration. This protocol describes a mouse model of brain metastasis generated by internal carotid artery injection. This method produces intracranial tumors consistently without the involvement of other organs, enabling the evaluation of therapeutic agents for brain metastasis.


Subject(s)
Brain Neoplasms , Carotid Artery, Internal , Animals , Brain Neoplasms/pathology , Disease Models, Animal , Injections , Mice , Neoplasm Metastasis/pathology , Tumor Burden , Tumor Microenvironment
7.
Front Physiol ; 12: 738594, 2021.
Article in English | MEDLINE | ID: mdl-34621187

ABSTRACT

Selective SGLT2 inhibition reduces the risk of worsening heart failure and cardiovascular death in patients with existing heart failure, irrespective of diabetic status. We aimed to investigate the effects of dual SGLT1/2 inhibition, using sotagliflozin, on cardiac outcomes in normal diet (ND) and high fat diet (HFD) mice with cardiac pressure overload. Five-week-old male C57BL/6J mice were randomized to receive a HFD (60% of calories from fat) or remain on ND for 12 weeks. One week later, transverse aortic constriction (TAC) was employed to induce cardiac pressure-overload (50% increase in right:left carotid pressure versus sham surgery), resulting in left ventricular hypertrophic remodeling and cardiac fibrosis, albeit preserved ejection fraction. At 4 weeks post-TAC, mice were treated for 7 weeks by oral gavage once daily with sotagliflozin (10 mg/kg body weight) or vehicle (0.1% tween 80). In ND mice, treatment with sotagliflozin attenuated cardiac hypertrophy and histological markers of cardiac fibrosis induced by TAC. These benefits were associated with profound diuresis and glucosuria, without shifts toward whole-body fatty acid utilization, increased circulating ketones, nor increased cardiac ketolysis. In HFD mice, sotagliflozin reduced the mildly elevated glucose and insulin levels but did not attenuate cardiac injury induced by TAC. HFD mice had vacuolation of proximal tubular cells, associated with less profound sotagliflozin-induced diuresis and glucosuria, which suggests dampened drug action. We demonstrate the utility of dual SGLT1/2 inhibition in treating cardiac injury induced by pressure overload in normoglycemic mice. Its efficacy in high fat-fed mice with mild hyperglycemia and compromised renal morphology requires further study.

8.
Cancer Res ; 81(20): 5131-5140, 2021 10 15.
Article in English | MEDLINE | ID: mdl-34266894

ABSTRACT

The hypothesis that the physiologic response to psychologic stress influences the initiation of cancer is highly controversial. The link between initiating stressors, the psychologic stress response, and disease is plausible, considering that the stress response is associated with defined physiologic outcomes and molecular mechanisms. In light of this, we review the clinical relevance of psychologic stress on the risk of cancer, and we propose potential molecular pathways that may link the stress response to early stages of malignant cell transformation.


Subject(s)
Cell Transformation, Neoplastic , Neoplasms/etiology , Neoplasms/psychology , Stress, Psychological , Carcinogenesis , DNA Damage , DNA Repair , Disease Progression , Epigenesis, Genetic , Female , Germ-Line Mutation , Hormones/metabolism , Humans , Inflammation , Middle Aged , Psychophysiology , Risk , Risk Factors
9.
Physiol Rep ; 9(14): e14968, 2021 07.
Article in English | MEDLINE | ID: mdl-34291605

ABSTRACT

This study aimed to assess how female breast cancer survivors (BCS) respond physiologically, hematologically, and perceptually to exercise under heat stress compared to females with no history of breast cancer (CON). Twenty-one females (9 BCS and 12 CON [age; 54 ± 7 years, stature; 167 ± 6 cm, body mass; 68.1 ± 7.62 kg, and body fat; 30.9 ± 3.8%]) completed a warm (25℃, 50% relative humidity, RH) and hot (35℃, 50%RH) trial in a repeated-measures crossover design. Trials consisted of 30 min of rest, 30 min of walking at 4 metabolic equivalents, and a 6-minute walk test (6MWT). Physiological measurements (core temperature (Tre ), skin temperature (Tskin ), heart rate (HR), and sweat analysis) and perceptual rating scales (ratings of perceived exertion, thermal sensation [whole body and localized], and thermal comfort) were taken at 5- and 10-min intervals throughout, respectively. Venous blood samples were taken before and after to assess; IL-6, IL-10, CRP, IFN-γ, and TGF-ß1 . All physiological markers were higher during the 35 versus 25℃ trial; Tre (~0.25℃, p = 0.002), Tskin (~3.8℃, p < 0.001), HR (~12 beats·min-1 , p = 0.023), and whole-body sweat rate (~0.4 L·hr-1 , p < 0.001), with no difference observed between groups in either condition (p > 0.05). Both groups covered a greater 6MWT distance in 25 versus 35℃ (by ~200 m; p = 0.003). Nevertheless, the control group covered more distance than BCS, regardless of environmental temperature (by ~400 m, p = 0.03). Thermoregulation was not disadvantaged in BCS compared to controls during moderate-intensity exercise under heat stress. However, self-paced exercise performance was reduced for BCS regardless of environmental temperature.


Subject(s)
Body Temperature Regulation/physiology , Breast Neoplasms/physiopathology , Cancer Survivors , Exercise/physiology , Heat-Shock Response/physiology , Hot Temperature/adverse effects , Breast Neoplasms/diagnosis , Cross-Over Studies , Female , Heart Rate/physiology , Humans , Middle Aged
10.
Commun Biol ; 4(1): 781, 2021 06 24.
Article in English | MEDLINE | ID: mdl-34168276

ABSTRACT

Investigational in vitro models that reflect the complexity of the interaction between the immune system and tumours are limited and difficult to establish. Herein, we present a platform to study the tumour-immune interaction using a co-culture between cancer spheroids and activated immune cells. An algorithm was developed for analysis of confocal images of the co-culture to evaluate the following quantitatively; immune cell infiltration, spheroid roundness and spheroid growth. As a proof of concept, the effect of the glucocorticoid stress hormone, cortisol was tested on 66CL4 co-culture model. Results were comparable to 66CL4 syngeneic in vivo mouse model undergoing psychological stress. Furthermore, administration of glucocorticoid receptor antagonists demonstrated the use of this model to determine the effect of treatments on the immune-tumour interplay. In conclusion, we provide a method of quantifying the interaction between the immune system and cancer, which can become a screening tool in immunotherapy design.


Subject(s)
Coculture Techniques , Triple Negative Breast Neoplasms/immunology , Algorithms , Animals , Cell Line, Tumor , Female , Hydrocortisone/blood , Mice , Mice, Inbred BALB C , Receptors, Glucocorticoid/antagonists & inhibitors , Spheroids, Cellular , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/therapy
11.
Br J Pharmacol ; 178(19): 3977-3996, 2021 10.
Article in English | MEDLINE | ID: mdl-34029379

ABSTRACT

People that develop extracranial cancers often display co-morbid neurological disorders, such as anxiety, depression and cognitive impairment, even before commencement of chemotherapy. This suggests bidirectional crosstalk between non-CNS tumours and the brain, which can regulate peripheral tumour growth. However, the reciprocal neurological effects of tumour progression on brain homeostasis are not well understood. Here, we review brain regions involved in regulating peripheral tumour development and how they, in turn, are adversely affected by advancing tumour burden. Tumour-induced activation of the immune system, blood-brain barrier breakdown and chronic neuroinflammation can lead to circadian rhythm dysfunction, sleep disturbances, aberrant glucocorticoid production, decreased hippocampal neurogenesis and dysregulation of neural network activity, resulting in depression and memory impairments. Given that cancer-related cognitive impairment diminishes patient quality of life, reduces adherence to chemotherapy and worsens cancer prognosis, it is essential that more research is focused at understanding how peripheral tumours affect brain homeostasis.


Subject(s)
Neoplasms , Quality of Life , Brain , Cognition , Humans , Mood Disorders , Neoplasms/complications , Neoplasms/drug therapy
12.
Mech Ageing Dev ; 191: 111337, 2020 10.
Article in English | MEDLINE | ID: mdl-32866520

ABSTRACT

Social isolation (SI) is a major health risk in older people leading to cognitive decline. This study examined how SI and age influence performance in the novel object recognition (NOR) and elevated plus maze (EPM) tasks in C57BL/6 mice aged 3 or 24 months. Mice were group-housed (groups of 2-3) or isolated for 2 weeks prior to experimentation. Following NOR and EPM testing hippocampal norepinephrine (NE), 5, hydroxytryptamine (5-HT), 5, hydroxyindole acetic acid (5-HIAA), corticosterone (CORT) and interleukin-6 (IL-6) were determined and serum collected for basal CORT analysis. A separate set of mice were exposed to the forced swim test (FST), sacrificed immediately and serum CORT determined. SI impaired performance in the NOR and the FST, reduced hippocampal 5-HT, increased hippocampal IL-6 and increased serum CORT post-FST in young mice. Aged mice either failed to respond significantly to SI (NOR, FST, hippocampal 5-HT, serum CORT post FST) or SI had synergistic effects with age (hippocampal NE, 5-HIAA:5-HT). In conclusion, the lack of response to SI in the aged mice may affect health by preventing them adapting to new stressors, while the synergistic effects of SI with age would increase allostatic load and enhance the deleterious effects of the ageing process.


Subject(s)
Behavior, Animal , Hippocampus/metabolism , Social Isolation , Aging , Animals , Brain Chemistry , Hippocampus/physiopathology , Male , Mice
13.
J Therm Biol ; 90: 102577, 2020 May.
Article in English | MEDLINE | ID: mdl-32479383

ABSTRACT

INTRODUCTION: the aim of this study was to assess the validity of a novel wearable sweat rate monitor against an array of sweat analysis techniques which determine sudomotor function when exercising moderately under heat stress. Construct validity was determined utilising a 5-day short-term heat acclimation (STHA) intervention. METHODS: Nineteen healthy individuals (age: 41 ± 23 years, body mass: 74.0 ± 12.2 kg, height: 174.9 ± 6.9 cm) [male; n = 15, female; n = 4] completed nine trials over a three-week period, in a controlled chamber set to 35 °C, 50% relative humidity for all sessions. The pre and post-trials were separated by five consecutive controlled hyperthermia HA sessions. Sweat analysis was compared from pre and post-trial, whereby whole body sweat rate (WBSR) was assessed via pre and post nude body mass. Local sweat rate (LSR) was determined via technical absorbent patches (TA) (weighed pre and post) and a novel wearable KuduSmart® (SMART) monitor which was placed on the left arm during the 30-min of exercise. Tegaderm patches, used to measure sweat sodium chloride conductivity (SC), and TA patches were placed on the back, chest and forearm for the 30-min cycling. RESULTS: Sudomotor function significantly adapted via STHA (p < 0.05); demonstrated by a WBSR increase of 24%, LSR increase via the TA method (back: 26%, chest: 45% and arm: 48%) and LSR increase by the SMART monitor (35%). Finally, SC decreased (back: -21%, chest: -25% and arm: -24%, p < 0.05). CONCLUSION: All sweat techniques were sensitive to sudomotor function adaptation following STHA, reinforcing their validity. The real time data given by the wearable KuduSmart® monitor provides coaches and athletes instant comparable sudomotor function feedback to traditional routinely used sweat analysis techniques.


Subject(s)
Acclimatization/physiology , Exercise/physiology , Monitoring, Physiologic/instrumentation , Sweating , Wearable Electronic Devices , Adolescent , Adult , Female , Hot Temperature , Humans , Male , Middle Aged , Young Adult
14.
mBio ; 11(2)2020 03 24.
Article in English | MEDLINE | ID: mdl-32209691

ABSTRACT

People with diabetes are two times more likely to die from influenza than people with no underlying medical condition. The mechanisms underlying this susceptibility are poorly understood. In healthy individuals, small and short-lived postprandial peaks in blood glucose levels occur. In diabetes mellitus, these fluctuations become greater and more frequent. This glycemic variability is associated with oxidative stress and hyperinflammation. However, the contribution of glycemic variability to the pathogenesis of influenza A virus (IAV) has not been explored. Here, we used an in vitro model of the pulmonary epithelial-endothelial barrier and novel murine models to investigate the role of glycemic variability in influenza severity. In vitro, a history of glycemic variability significantly increased influenza-driven cell death and destruction of the epithelial-endothelial barrier. In vivo, influenza virus-infected mice with a history of glycemic variability lost significantly more body weight than mice with constant blood glucose levels. This increased disease severity was associated with markers of oxidative stress and hyperinflammation both in vitro and in vivo Together, these results provide the first indication that glycemic variability may help drive the increased risk of severe influenza in people with diabetes mellitus.IMPORTANCE Every winter, people with diabetes are at increased risk of severe influenza. At present, the mechanisms that cause this increased susceptibility are unclear. Here, we show that the fluctuations in blood glucose levels common in people with diabetes are associated with severe influenza. These data suggest that glycemic stability could become a greater clinical priority for patients with diabetes during outbreaks of influenza.


Subject(s)
Blood Glucose/analysis , Diabetes Mellitus, Type 2/complications , Influenza, Human/physiopathology , Severity of Illness Index , Animals , Biomarkers/blood , Cell Death , Cells, Cultured , Coculture Techniques , Diabetes Mellitus, Type 2/blood , Endothelial Cells/immunology , Endothelial Cells/virology , Glycemic Load , Humans , Inflammation , Influenza A virus/pathogenicity , Male , Mice , Mice, Inbred C57BL , Orthomyxoviridae Infections/physiopathology , Oxidative Stress
15.
Cancer Lett ; 459: 59-71, 2019 09 10.
Article in English | MEDLINE | ID: mdl-31132432

ABSTRACT

Stress hormones have been shown to be important mediators in driving malignant growth and reducing treatment efficacy in breast cancer. Glucocorticoids can induce DNA damage through an inducible nitric oxide synthase (iNOS) mediated pathway to increase levels of nitric oxide (NO). Using an immune competent mouse breast cancer model and 66CL4 breast cancer cells we identified a novel role of NOS inhibition to reduce stress-induced breast cancer metastasis. On a mechanistic level we show that the glucocorticoid cortisol induces expression of keys genes associated with angiogenesis, as well as pro-tumourigenic immunomodulation. Transcriptomics analysis confirmed that in the lungs of tumour-bearing mice, stress significantly enriched pathways associated with tumourigenesis, some of which could be regulated with NOS inhibition. These results demonstrate the detrimental involvement of NOS in stress hormone signalling, and the potential future benefits of NOS inhibition in highly stressed patients.


Subject(s)
Breast Neoplasms/pathology , Enzyme Inhibitors/pharmacology , Hydrocortisone/pharmacology , Mammary Neoplasms, Experimental/pathology , Nitric Oxide Synthase/antagonists & inhibitors , Stress, Psychological/metabolism , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Cell Line, Tumor , DNA Damage , Drug Interactions , Female , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , MCF-7 Cells , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/enzymology , Mammary Neoplasms, Experimental/genetics , Mice , Mice, Inbred BALB C , Mifepristone/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/biosynthesis , Nitric Oxide/metabolism , Nitric Oxide Synthase/metabolism , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism , Stress, Psychological/pathology
16.
Anal Chem ; 91(7): 4436-4443, 2019 04 02.
Article in English | MEDLINE | ID: mdl-30869876

ABSTRACT

Minimally invasive, reliable and low-cost in vivo biosensors that enable real-time detection and monitoring of clinically relevant molecules and biomarkers can significantly improve patient health care. Microneedle array (MNA)-based electrochemical sensors offer exciting prospects in this respect, as they can sample directly from the skin. However, their acceptability is dependent on developing a highly scalable and cost-effective fabrication strategy. In this work, we evaluated the potential for poly(lactic acid)/carboxyl-multiwalled carbon nanotube (PLA/ f-MWCNT) composites to be developed into MNAs and their effectiveness for dermal biosensing. Our results show that MNAs are easily made from solvent-cast nanocomposite films by micromolding. A maximum carbon nanotube (CNT) loading of 6 wt % was attained with the current fabrication method. The MNAs were mechanically robust, being able to withstand axial forces up to 4 times higher than necessary for skin insertion. Electrochemical characterization of these MNAs by differential pulse voltammetry (DPV) produced a linear current response toward ascorbic acid, with a limit of detection of 180 µM. In situ electrochemical performance was assessed by DPV measurements in ex vivo porcine skin. This showed active changes characterized by two oxidative peaks at 0.23 and 0.69 V, as a result of the diffusion of phosphate-buffered saline. The diagnostic potential of this waveform was further evaluated through a burn wound model. This showed an attenuated oxidative response at 0.69 V. Importantly, the impact of the burn could be measured at progressive distances from the burn site. Overall, alongside the scalable fabrication strategy, the DPV results promise efficient electrochemical biosensors based on CNT nanocomposite MNAs.


Subject(s)
Biosensing Techniques/methods , Dermis/chemistry , Nanotubes, Carbon/chemistry , Polyesters/chemistry , Animals , Biosensing Techniques/instrumentation , Burns/diagnosis , Dermis/pathology , Electrochemical Techniques/instrumentation , Electrochemical Techniques/methods , Nanocomposites/chemistry , Needles , Oxidation-Reduction , Swine
17.
J Therm Biol ; 79: 209-217, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30612681

ABSTRACT

INTRODUCTION: The aim of the study was to evaluate the reliability of five different sweat analysis techniques which measure; whole body sweat rate [WBSR], local sweat rate [LSR] (via technical absorbent [TA] method and KuduSmart® monitor), sweat conductivity [SC] and sweat gland activation [SGA] in a female population when exercising moderately under heat stress. METHODS: Fourteen females (age; 26 ±â€¯7 years, body mass; 66.5 ±â€¯7.6 kg, height; 167.1 ±â€¯6.4 cm) completed a preliminary threshold walking test (to determine exercise intensity) and two main trials, separated by 2 days. Main trials consisted of 30-min seated rest in the environmental chamber (35 °C, 50% relative humidity) in an upper body sauna-suit, before its removal, and walking at a moderate intensity (4 metabolic equivalents) for 30-min (speeds ranged from 4.8 to 6.5 km h-1). WBSR was measured via nude mass pre and post exercise. The TA and Tegaderm patches (for sweat sodium chloride) were placed on the back, forearm and chest for the entire 60-min, replicated for all participants for both trials. SGA was assessed following the 60-min trial and the KuduSmart® monitor was placed on the left arm for the 30-min of exercise. RESULTS: WBSR, LSR methods and SC demonstrated no difference between trials (p > 0.05), good agreement (within limits), strong correlations (r ≥ 0.88) and low typical error of measurements [TEM] (< 0.04 L min-1, 0.13 mg min-1 cm-2 and 8 mmol L-1, respectively). SGA method showed moderate intra-class correlation (r = 0.80), with high TEM (5 glands) and large limits of agreement. CONCLUSION: Sudomotor function is reliable, as demonstrated by good reliability, small TEM and strong correlations. The use of these sweat techniques is appropriate and practical in females who are exercising at moderate intensity under heat stress, and so, may aid future interventions. SGA shows larger variation and should be used with caution.


Subject(s)
Exercise , Fitness Trackers/standards , Monitoring, Physiologic/standards , Sweat/chemistry , Sweating , Adult , Female , Humans , Monitoring, Physiologic/instrumentation , Reproducibility of Results , Sweat Glands/physiology
18.
Cancer Drug Resist ; 2(3): 773-786, 2019.
Article in English | MEDLINE | ID: mdl-35582576

ABSTRACT

Patients diagnosed with cancer often undergo considerable psychological distress, and the induction of the psychological stress response has been linked with a poor response to chemotherapy. The psychological stress response is mediated by fluctuations of the hormones glucocorticoids (GCs) and catecholamines. Binding to their respective receptors, GCs and the catecholamines adrenaline/noradrenaline are responsible for signalling a wide range of processes involved in cell survival, cell cycle and immune function. Synthetic GCs are also often prescribed as co-medication alongside chemotherapy, and increasing evidence suggests that GCs may induce chemoresistance in multiple cancer types. In this review, we bring together evidence linking psychological stress hormone signalling with resistance to chemo- and immune therapies, as well as mechanistic evidence regarding the effects of exogenous stress hormones on the efficacy of chemotherapies.

19.
Am J Physiol Regul Integr Comp Physiol ; 314(6): R858-R869, 2018 06 01.
Article in English | MEDLINE | ID: mdl-29443547

ABSTRACT

There is an increased incidence of heart failure in individuals with diabetes mellitus (DM). The coexistence of kidney disease in DM exacerbates the cardiovascular prognosis. Researchers have attempted to combine the critical features of heart failure, using transverse aortic constriction, with DM in mice, but variable findings have been reported. Furthermore, kidney outcomes have not been assessed in this setting; thus its utility as a model of heart failure in DM and kidney disease is unknown. We generated a mouse model of obesity, hyperglycemia, and mild kidney pathology by feeding male C57BL/6J mice a high-fat diet (HFD). Cardiac pressure overload was surgically induced using transverse aortic constriction (TAC). Normal diet (ND) and sham controls were included. Heart failure risk factors were evident at 8-wk post-TAC, including increased left ventricular mass (+49% in ND and +35% in HFD), cardiomyocyte hypertrophy (+40% in ND and +28% in HFD), and interstitial and perivascular fibrosis (Masson's trichrome and picrosirius red positivity). High-fat feeding did not exacerbate the TAC-induced cardiac outcomes. At 11 wk post-TAC in a separate mouse cohort, echocardiography revealed reduced left ventricular size and increased left ventricular wall thickness, the latter being evident in ND mice only. Systolic function was preserved in the TAC mice and was similar between ND and HFD. Thus combined high-fat feeding and TAC in mice did not model the increased incidence of heart failure in DM patients. This model, however, may mimic the better cardiovascular prognosis seen in overweight and obese heart failure patients.


Subject(s)
Aorta/physiopathology , Diabetes Mellitus, Experimental/metabolism , Diet, High-Fat/adverse effects , Heart Failure/etiology , Kidney Diseases/metabolism , Animals , Body Composition , Constriction, Pathologic , Diabetes Mellitus, Experimental/physiopathology , Echocardiography , Energy Metabolism/physiology , Heart/diagnostic imaging , Heart Failure/physiopathology , Heart Ventricles/diagnostic imaging , Hypertrophy, Left Ventricular/pathology , Kidney Diseases/physiopathology , Male , Mice , Mice, Inbred C57BL , Myocytes, Cardiac/physiology , Myocytes, Cardiac/ultrastructure , Risk Factors
20.
Cancer Clin Oncol ; 6(1): 12-24, 2017 May.
Article in English | MEDLINE | ID: mdl-28603578

ABSTRACT

The ability of stress to induce immune suppression is widely recognized, but the mechanisms underlying the effects of stress on the adaptive immune system during tumor progression are not completely understood. To study the effect of stress on the immune system in vivo, we used a preclinical immunocompetent mouse model bearing 4T1 mammary adenocarcinoma cells. Mice were randomized into 4 groups, including social isolation (SI), acute restraint stress (aRRS), chronic restraint stress (cRRS), or no stress (NS). We found that SI significantly decreased the number of tumor-bearing mice still alive at the end of protocol (28 days), compared to NS mice. Although we did not detect significant changes in primary tumor volume, we observed a significant increase in the endothelial marker CD31 in primary tumors of SI mice and in lung metastases in SI and RRS mice. Survival decline in SI mice was associated with significant decreases in splenic CD8 cells and in activated T cells. From a mechanistic standpoint, RRS increased expression of FOXP3, CXCL-10, and granzyme B in mouse tumors, and the effects were reversed by propranolol. Our data demonstrate that various forms of stress differentially impact adaptive immunity and tumor angiogenesis, and negatively impact survival.

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