Oral cannabidiol (CBD) consumption is widespread in North America and Europe, as it has analgesic, neuroprotective and antitumor effects. Although oral CBD consumption in humans affords beneficial ...effects in epileptic and inflammatory states, its pharmacokinetics and subsequent uptake into tissue are largely unknown. This study investigated plasma pharmacokinetics and accumulation of CBD in gastrocnemius muscle, liver and adipose tissue in adult rats following oral gavage. CBD was fed relative to body mass at 0 (control), 30, 115, or 230 mg/Kg/day for 28 days; with 6 males and 6 females per dosing group. Pharmacokinetics were assessed on day 1 and day 28 in the group receiving CBD at 115 mg/Kg/day. The rise in tissue CBD was closely related to specific pharmacokinetic parameters, and adipose tissue levels were ~10 to ~100 fold greater than liver or muscle. Tissue CBD levels were moderately correlated between adipose and muscle, and adipose and liver, but were highly correlated for liver and muscle. CBD feeding resulted in several gender-specific effects, including changes in pharmacokinetics, relationships between pharmacokinetic parameters and tissue CBD and differences in tissue CBD levels. CBD accumulation in mammalian tissues has the potential to influence receptor binding and metabolism; therefore, the present findings may have relevance for developing oral dosing regimens.
Exertional heat stroke (EHS) is a life-threatening medical condition involving thermoregulatory failure and is the most severe condition along a continuum of heat-related illnesses. Current EHS ...policy guidance principally advocates a thermoregulatory management approach, despite growing recognition that gastrointestinal (GI) microbial translocation contributes to disease pathophysiology. Contemporary research has focused to understand the relevance of GI barrier integrity and strategies to maintain it during periods of exertional-heat stress. GI barrier integrity can be assessed non-invasively using a variety of in vivo techniques, including active inert mixed-weight molecular probe recovery tests and passive biomarkers indicative of GI structural integrity loss or microbial translocation. Strenuous exercise is strongly characterised to disrupt GI barrier integrity, and aspects of this response correlate with the corresponding magnitude of thermal strain. The aetiology of GI barrier integrity loss following exertional-heat stress is poorly understood, though may directly relate to localised hyperthermia, splanchnic hypoperfusion-mediated ischemic injury, and neuroendocrine-immune alterations. Nutritional countermeasures to maintain GI barrier integrity following exertional-heat stress provide a promising approach to mitigate EHS. The focus of this review is to evaluate: (1) the GI paradigm of exertional heat stroke; (2) techniques to assess GI barrier integrity; (3) typical GI barrier integrity responses to exertional-heat stress; (4) the aetiology of GI barrier integrity loss following exertional-heat stress; and (5) nutritional countermeasures to maintain GI barrier integrity in response to exertional-heat stress.
Autophagy is a cellular degradation process that can capture and eliminate intracellular microbes by delivering them to lysosomes for destruction. However, pathogens have evolved mechanisms to ...subvert this process. The intracellular bacterium
Brucella abortus ensures its survival by forming the
Brucella-containing vacuole (BCV), which traffics from the endocytic compartment to the endoplasmic reticulum (ER), where the bacterium proliferates. We show that
Brucella replication in the ER is followed by BCV conversion into a compartment with autophagic features (aBCV). While
Brucella trafficking to the ER was unaffected in autophagy-deficient cells, aBCV formation required the autophagy-initiation proteins ULK1, Beclin 1, and ATG14L and PI3-kinase activity. However, aBCV formation was independent of the autophagy-elongation proteins ATG5, ATG16L1, ATG4B, ATG7, and LC3B. Furthermore, aBCVs were required to complete the intracellular
Brucella lifecycle and for cell-to-cell spreading, demonstrating that
Brucella selectively co-opts autophagy-initiation complexes to subvert host clearance and promote infection.
►
Brucella translocates to endosomal vacuoles following replication in the ER ►
Brucella selectively co-opts proteins involved in autophagosome nucleation ► Subversion of autophagy by
Brucella promotes completion of its infection cycle
Ligation of Dectin-1 by fungal glucans elicits a Th17 response that is necessary for clearing many fungal pathogens. Laminarin is a (1→3, 1→6)-β-glucan that is widely reported to be a Dectin-1 ...antagonist, however, there are reports that laminarin is also a Dectin-1 agonist. To address this controversy, we assessed the physical properties, structure, purity, Dectin-1 binding, and biological activity of five different laminarin preparations from three different commercial sources. The proton nuclear magnetic resonance analysis indicated that all of the preparations contained laminarin although their molecular mass varied considerably (4400-34,400 Da). Two of the laminarins contained substantial quantities of very low m.w. compounds, some of which were not laminarin. These low m.w. moieties could be significantly reduced by extensive dialysis. All of the laminarin preparations were bound by recombinant human Dectin-1 and mouse Dectin-1, but the affinity varied considerably, and binding affinity did not correlate with Dectin-1 agonism, antagonism, or potency. In both human and mouse cells, two laminarins were Dectin-1 antagonists and two were Dectin-1 agonists. The remaining laminarin was a Dectin-1 antagonist, but when the low m.w. moieties were removed, it became an agonist. We were able to identify a laminarin that is a Dectin-1 agonist and a laminarin that is Dectin-1 antagonist, both of which are relatively pure preparations. These laminarins may be useful in elucidating the structure and activity relationships of glucan/Dectin-1 interactions. Our data demonstrate that laminarin can be either a Dectin-1 antagonist or agonist, depending on the physicochemical properties, purity, and structure of the laminarin preparation employed.
Purpose
Exertional-heat stress adversely disrupts gastrointestinal (GI) barrier integrity, whereby subsequent microbial translocation (MT) can result in potentially serious health consequences. To ...date, the influence of aerobic fitness on GI barrier integrity and MT following exertional-heat stress is poorly characterised.
Method
Ten untrained (UT;
V
O
2max
= 45 ± 3 ml·kg
−1
·min
−1
) and ten highly trained (HT;
V
O
2max
= 64 ± 4 ml·kg
−1
·min
−1
) males completed an ecologically valid (military) 80-min fixed-intensity exertional-heat stress test (EHST). Venous blood was drawn immediately pre- and post-EHST. GI barrier integrity was assessed using the serum dual-sugar absorption test (DSAT) and plasma Intestinal Fatty-Acid Binding Protein (I-FABP). MT was assessed using plasma
Bacteroides
/total 16S DNA.
Results
UT experienced greater thermoregulatory, cardiovascular and perceptual strain (
p
< 0.05) than HT during the EHST. Serum DSAT responses were similar between the two groups (
p
= 0.59), although Δ I-FABP was greater (
p
= 0.04) in the UT (1.14 ± 1.36 ng·ml
−1
) versus HT (0.20 ± 0.29 ng·ml
−1
) group.
Bacteroides
/Total 16S DNA ratio was unchanged (Δ; -0.04 ± 0.18) following the EHST in the HT group, but increased (Δ; 0.19 ± 0.25) in the UT group (
p
= 0.05). Weekly aerobic training hours had a weak, negative correlation with Δ I-FABP and
Bacteroides
/total 16S DNA responses.
Conclusion
When exercising at the same absolute workload, UT individuals are more susceptible to small intestinal epithelial injury and MT than HT individuals. These responses appear partially attributable to greater thermoregulatory, cardiovascular, and perceptual strain.
The intracellular pathogenic bacterium Brucella generates a replicative vacuole (rBCV) derived from the endoplasmic reticulum via subversion of the host cell secretory pathway. rBCV biogenesis ...requires the expression of the Type IV secretion system (T4SS) VirB, which is thought to translocate effector proteins that modulate membrane trafficking along the endocytic and secretory pathways. To date, only a few T4SS substrates have been identified, whose molecular functions remain unknown. Here, we used an in silico screen to identify putative T4SS effector candidate proteins using criteria such as limited homology in other bacterial genera, the presence of features similar to known VirB T4SS effectors, GC content and presence of eukaryotic-like motifs. Using β-lactamase and CyaA adenylate cyclase reporter assays, we identified eleven proteins translocated into host cells by Brucella, five in a VirB T4SS-dependent manner, namely BAB1_0678 (BspA), BAB1_0712 (BspB), BAB1_0847 (BspC), BAB1_1671 (BspE) and BAB1_1948 (BspF). A subset of the translocated proteins targeted secretory pathway compartments when ectopically expressed in HeLa cells, and the VirB effectors BspA, BspB and BspF inhibited protein secretion. Brucella infection also impaired host protein secretion in a process requiring BspA, BspB and BspF. Single or combined deletions of bspA, bspB and bspF affected Brucella ability to replicate in macrophages and persist in the liver of infected mice. Taken together, these findings demonstrate that Brucella modulates secretory trafficking via multiple T4SS effector proteins that likely act coordinately to promote Brucella pathogenesis.
The importance of diet and nutrition to military readiness and performance has been recognized for centuries as dietary nutrients sustain health, protect against illness, and promote resilience, ...performance and recovery. Contemporary military nutrition research is increasingly inter-disciplinary with emphasis often placed on the broad topics of (1) determining operational nutrition requirements in all environments, (2) characterizing nutritional practices of military personnel relative to the required (role/environment) standards, and (3) developing strategies for improving nutrient delivery and individual choices. This review discusses contemporary issues shared internationally by military nutrition research programmes, and highlights emerging topics likely to influence future military nutrition research and policy. Contemporary issues include improving the diet quality of military personnel, optimizing operational rations, and increasing understanding of biological factors influencing nutrient requirements. Emerging areas include the burgeoning field of precision nutrition and its technological enablers.
l-Glutamine (GLN) is a conditionally essential amino acid which supports gastrointestinal (GI) and immune function prior to catabolic stress (e.g., strenuous exercise). Despite potential ...dose-dependent benefits, GI tolerance of acute high dose oral GLN supplementation is poorly characterised. Fourteen healthy males (25 ± 5 years; 1.79 ± 0.07 cm; 77.7 ± 9.8 kg; 14.8 ± 4.6% body fat) ingested 0.3 (LOW), 0.6 (MED) or 0.9 (HIGH) g·kg·FFM
GLN beverages, in a randomised, double-blind, counter-balanced, cross-over trial. Individual and accumulated GI symptoms were recorded using a visual analogue scale at regular intervals up to 24-h post ingestion. GLN beverages were characterised by tonicity measurement and microscopic observations. 24-h accumulated upper- and lower- and total-GI symptoms were all greater in the HIGH, compared to LOW and MED trials (
< 0.05). Specific GI symptoms (discomfort, nausea, belching, upper GI pain) were all more pronounced on the HIGH versus LOW GLN trial (
< 0.05). Nevertheless, most symptoms were still rated as mild. In comparison, the remaining GI symptoms were either comparable (flatulence, urge to regurgitate, bloating, lower GI pain) or absent (heart burn, vomiting, urge to defecate, abnormal stools, stitch, dizziness) between trials (
> 0.05). All beverages were isotonic and contained a dose-dependent number of GLN crystals. Acute oral GLN ingestion in dosages up to 0.9 g·kg·FFM
are generally well-tolerated. However, the severity of mild GI symptoms appeared dose-dependent during the first two hours post prandial and may be due to high-concentrations of GLN crystals.
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