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  • 1
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 16 ( 2021-08-09), p. 8546-
    Abstract: Gulf War Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune system and the brain communicate through several signaling pathways, including the hypothalamic–pituitary–adrenal (HPA) axis, it underlies many of the behavioral and physiological responses to stressors via blood-borne mediators, such as cytokines, chemokines, and hormones. Signaling by these molecules is mediated by the semipermeable blood–brain barrier (BBB) made up of a monocellular layer forming an integral part of the neuroimmune axis. BBB permeability can be altered and even diminished by both external factors (e.g., chemical agents) and internal conditions (e.g., acute or chronic stress, or cross-signaling from the hypothalamic–pituitary–gonadal (HPG) axis). Such a complex network of regulatory interactions that possess feed-forward and feedback connections can have multiple response dynamics that may include several stable homeostatic states beyond normal health. Here we compare immune and hormone measures in the blood of human clinical samples and mouse models of Gulf War Illness (GWI) subtyped by exposure to traumatic stress for subtyping this complex illness. We do this via constructing a detailed logic model of HPA–HPG–Immune regulatory behavior that also considers signaling pathways across the BBB to neuronal–glial interactions within the brain. We apply conditional interactions to model the effects of changes in BBB permeability. Several stable states are identified in the system beyond typical health. Following alignment of the human and mouse blood profiles in the context of the model, mouse brain sample measures were used to infer the neuroinflammatory state in human GWI and perform treatment simulations using a genetic algorithm to optimize the Monte Carlo simulations of the putative treatment strategies aimed at returning the ill system back to health. We identify several ideal multi-intervention strategies and potential drug candidates that may be used to treat chronic neuroinflammation in GWI.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 2
    In: Molecules, MDPI AG, Vol. 25, No. 1 ( 2019-12-19), p. 26-
    Abstract: The main aim of this study was to evaluate the volatile profile, sensory perception, and phytochemical content of bovine milk produced from cows fed on three distinct feeding systems, namely grass (GRS), grass/clover (CLV), and total mixed ration (TMR). Previous studies have identified that feed type can influence the sensory perception of milk directly via the transfer of volatile aromatic compounds, or indirectly by the transfer of non-volatile substrates that act as precursors for volatile compounds. In the present study, significant differences were observed in the phytochemical profile of the different feed and milk samples. The isoflavone formonoetin was significantly higher in CLV feed samples, but higher in raw GRS milk, while other smaller isoflavones, such as daidzein, genistein, and apigenin were highly correlated to raw CLV milk. This suggests that changes in isoflavone content and concentration in milk relate to diet, but also to metabolism in the rumen. This study also found unique potential volatile biomarkers in milk (dimethyl sulfone) related to feeding systems, or significant differences in the concentration of others (toluene, p-cresol, ethyl and methyl esters) based on feeding systems. TMR milk scored significantly higher for hay-like flavor and white color, while GRS and CLV milk scored significantly higher for a creamy color. Milk samples were easily distinguishable by their volatile profile based on feeding system, storage time, and pasteurization.
    Type of Medium: Online Resource
    ISSN: 1420-3049
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2008644-1
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  • 3
    In: Brain Sciences, MDPI AG, Vol. 13, No. 4 ( 2023-04-06), p. 623-
    Abstract: Traumatic brain injury (TBI) is a major cause of death and disability and is experienced by nearly 3 million people annually as a result of falls, vehicular accidents, or from being struck by or against an object. While TBIs can range in severity, the majority of injuries are considered to be mild. However, TBI of any severity has the potential to have long-lasting neurological effects, including headaches, cognitive/memory impairments, mood dysfunction, and fatigue as a result of neural damage and neuroinflammation. Here, we modified a projectile concussive impact (PCI) model of TBI to deliver a closed-head impact with variable severity dependent on the material of the ball-bearing projectile. Adult male Sprague Dawley rats were evaluated for neurobehavioral, neuroinflammatory, and neural damage endpoints both acutely and longer-term (up to 72 h) post-TBI following impact with either an aluminum or stainless-steel projectile. Animals that received TBI using the stainless-steel projectile exhibited outcomes strongly correlated to moderate-severe TBI, such as prolonged unconsciousness, impaired neurobehavior, increased risk for hematoma and death, as well as significant neuronal degeneration and neuroinflammation throughout the cortex, hippocampus, thalamus, and cerebellum. In contrast, rats that received TBI with the aluminum projectile exhibited characteristics more congruous with mild TBI, such as a trend for longer periods of unconsciousness in the absence of neurobehavioral deficits, a lack of neurodegeneration, and mild neuroinflammation. Moreover, alignment of cytokine mRNA expression from the cortex of these rats with a computational model of neuron–glia interaction found that the moderate-severe TBI produced by the stainless-steel projectile strongly associated with the neuroinflammatory state, while the mild TBI existed in a state between normal and inflammatory neuron–glia interactions. Thus, these modified PCI protocols are capable of producing TBIs that model the clinical and experimental manifestations associated with both moderate-severe and mild TBI producing relevant models for the evaluation of the potential underlying roles of neuroinflammation and other chronic pathophysiology in the long-term outcomes associated with TBI.
    Type of Medium: Online Resource
    ISSN: 2076-3425
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2651993-8
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  • 4
    In: Current Oncology, MDPI AG, Vol. 25, No. 6 ( 2018-12-01), p. 516-526
    Abstract: Background Adrenergic receptor stimulation is involved in the development of hypertension (htn) and has been implicated in cancer progression and dissemination of metastases in various tumours, including colon cancer. Adrenergic antagonists such as beta-blockers (bbs) demonstrate inhibition of invasion and migration in colon cancer cell lines and have been associated with decreased mortality in colorectal cancer (crc). We examined the association of baseline htn and bb use with overall (os) and progression-free survival (pfs) in patients with pretreated, chemotherapy refractory, metastatic crc (mcrc). We also examined baseline htn as a predictor of cetuximab efficacy. Methods Using data from the Canadian Cancer Trials Group co.17 study [cetuximab vs. best supportive care (bsc)], we coded baseline htn and use of anti-htn medications, including bbs, for 572 patients. The chi-square test was used to assess the associations between those variables and baseline characteristics. Cox regression models were used for univariate and multivariate analyses of os and pfs by htn diagnosis and bb use. Results Baseline htn, bb use, and anti-htn medication use were not found to be prognostic for improved os. Baseline htn and bb use were not significant predictors of cetuximab benefit. Conclusions In chemorefractory mcrc, neither baseline htn nor bb use is a significant prognostic factor. Baseline htn and bb use are not predictive of cetuximab benefit. Further investigation to determine whether baseline htn or bb use have a similarly insignificant impact on prognosis in patients receiving earlier lines of treatment remains warranted.
    Type of Medium: Online Resource
    ISSN: 1718-7729
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2270777-3
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  • 5
    In: Sustainability, MDPI AG, Vol. 12, No. 15 ( 2020-07-27), p. 6018-
    Abstract: Currently, nitrogen fertilizers are utilized to meet 48% of the total global food demand. The demand for nitrogen fertilizers is expected to grow as global populations continue to rise. The use of nitrogen fertilizers is associated with many negative environmental impacts and is a key source of greenhouse and harmful gas emissions. In recent years, urease and nitrification inhibitors have emerged as mitigation tools that are presently utilized in agriculture to prevent nitrogen losses and reduce greenhouse and harmful gas emissions that are associated with the use of nitrogen-based fertilizers. Both classes of inhibitor work by different mechanisms and have different physiochemical properties. Consequently, each class must be evaluated on its own merits. Although there are many benefits associated with the use of these inhibitors, little is known about their potential to enter the food chain, an event that may pose challenges to food safety. This phenomenon was highlighted when the nitrification inhibitor dicyandiamide was found as a residual contaminant in milk products in 2013. This comprehensive review aims to discuss the uses of inhibitor technologies in agriculture and their possible impacts on dairy product safety and quality, highlighting areas of concern with regards to the introduction of these inhibitor technologies into the dairy supply chain. Furthermore, this review discusses the benefits and challenges of inhibitor usage with a focus on EU regulations, as well as associated health concerns, chemical behavior, and analytical detection methods for these compounds within milk and environmental matrices.
    Type of Medium: Online Resource
    ISSN: 2071-1050
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2518383-7
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