It is unclear whether severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019, can enter the brain. Severe acute respiratory syndrome coronavirus 2 binds to cells via ...the S1 subunit of its spike protein. We show that intravenously injected radioiodinated S1 (I-S1) readily crossed the blood-brain barrier in male mice, was taken up by brain regions and entered the parenchymal brain space. I-S1 was also taken up by the lung, spleen, kidney and liver. Intranasally administered I-S1 also entered the brain, although at levels roughly ten times lower than after intravenous administration. APOE genotype and sex did not affect whole-brain I-S1 uptake but had variable effects on uptake by the olfactory bulb, liver, spleen and kidney. I-S1 uptake in the hippocampus and olfactory bulb was reduced by lipopolysaccharide-induced inflammation. Mechanistic studies indicated that I-S1 crosses the blood-brain barrier by adsorptive transcytosis and that murine angiotensin-converting enzyme 2 is involved in brain and lung uptake, but not in kidney, liver or spleen uptake.
Extracellular vesicles can cross the blood-brain barrier (BBB), but little is known about passage. Here, we used multiple-time regression analysis to examine the ability of 10 exosome populations ...derived from mouse, human, cancerous, and non-cancerous cell lines to cross the BBB. All crossed the BBB, but rates varied over 10-fold. Lipopolysaccharide (LPS), an activator of the innate immune system, enhanced uptake independently of BBB disruption for six exosomes and decreased uptake for one. Wheatgerm agglutinin (WGA) modulated transport of five exosome populations, suggesting passage by adsorptive transcytosis. Mannose 6-phosphate inhibited uptake of J774A.1, demonstrating that its BBB transporter is the mannose 6-phosphate receptor. Uptake rates, patterns, and effects of LPS or WGA were not predicted by exosome source (mouse vs. human) or cancer status of the cell lines. The cell surface proteins CD46, AVβ6, AVβ3, and ICAM-1 were variably expressed but not predictive of transport rate nor responses to LPS or WGA. A brain-to-blood efflux mechanism variably affected CNS retention and explains how CNS-derived exosomes enter blood. In summary, all exosomes tested here readily crossed the BBB, but at varying rates and by a variety of vesicular-mediated mechanisms involving specific transporters, adsorptive transcytosis, and a brain-to-blood efflux system.
BACKGROUNDDaylight savings time transitions affect approximately 1.6 billion people worldwide. Prior studies have documented associations between daylight savings time transitions and adverse health ...outcomes, but it remains unknown whether they also cause an increase in the incidence rate of depressive episodes. This seems likely because daylight savings time transitions affect circadian rhythms, which are implicated in the etiology of depressive disorder. Therefore, we investigated the effects of daylight savings time transitions on the incidence rate of unipolar depressive episodes.
METHODSUsing time series intervention analysis of nationwide data from the Danish Psychiatric Central Research Register from 1995 to 2012 we compared the observed trend in the incidence rate of hospital contacts for unipolar depressive episodes after the transitions to and from summer time to the predicted trend in the incidence rate.
RESULTSThe analyses were based on 185.419 hospital contacts for unipolar depression and showed that the transition from summer time to standard time were associated with an 11% increase (95% CI7%, 15%) in the incidence rate of unipolar depressive episodes that dissipated over approximately 10 weeks. The transition from standard time to summer time was not associated with a parallel change in the incidence rate of unipolar depressive episodes.
CONCLUSIONThis study shows that the transition from summer time to standard time was associated with an increase in the incidence rate of unipolar depressive episodes. Distress associated with the sudden advancement of sunset, marking the coming of a long period of short days, may explain this finding.
Exosomes mediate intercellular communication, shuttling messages between cells and tissues. We explored whether exosome tissue sequestration is determined by the exosomes or the tissues using ten ...radiolabeled exosomes from human or murine, cancerous or noncancerous cell lines. We measured sequestration of these exosomes by the liver, kidney, spleen, and lung after intravenous injection into male CD-1 mice. Except for kidney sequestration of three exosomes, all exosomes were incorporated by all tissues, but sequestration levels varied greatly among exosomes and tissues. Species of origin (mouse vs. human) or source (cancerous vs. noncancerous cells) did not influence tissue sequestration. Sequestration of J774A.1 exosomes by liver involved the mannose-6 phosphate (M6P) receptor. Wheatgerm agglutinin (WGA) or lipopolysaccharide (LPS) treatments enhanced sequestration of exosomes by brain and lung but inhibited sequestration by liver and spleen. Response to LPS was not predictive of response to WGA. Path and heat map analyses included our published results for brain and found distinct clusters among the exosomes and the tissues. In conclusion, we found no evidence for a universal binding site controlling exosome-tissue interactions. Instead, sequestration of exosomes by tissues is differentially regulated by both exosomes and tissues and may be stimulated or inhibited by WGA and inflammation.
Abstract
Background
Gliomas are the most common primary brain tumors and are universally fatal. Mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) define a distinct glioma subtype ...associated with an immunosuppressive tumor microenvironment. Mechanisms underlying systemic immunosuppression in IDH mutant (mutIDH) gliomas are largely unknown. Here, we define genotype-specific local and systemic tumor immunomodulatory functions of tumor-derived glioma small extracellular vesicles (TEX).
Methods
TEX produced by human and murine wildtype and mutant IDH glioma cells (wtIDH and mutIDH, respectively) were isolated by size exclusion chromatography (SEC). TEX morphology, size, quantity, molecular profiles and biodistribution were characterized. TEX were injected into naive and tumor-bearing mice, and the local and systemic immune microenvironment composition was characterized.
Results
Using in vitro and in vivo glioma models, we show that mutIDH TEX are more numerous, possess distinct morphological features and are more immunosuppressive than wtIDH TEX. mutIDH TEX cargo mimics their parental cells, and induces systemic immune suppression in naive and tumor-bearing mice. TEX derived from mutIDH gliomas and injected into wtIDH tumor-bearing mice reduce tumor-infiltrating effector lymphocytes, dendritic cells and macrophages, and increase circulating monocytes. Astonishingly, mutIDH TEX injected into brain tumor-bearing syngeneic mice accelerate tumor growth and increase mortality compared with wtIDH TEX.
Conclusions
Targeting of mutIDH TEX represents a novel therapeutic approach in gliomas.
Traumatic brain injury (TBI) in its various forms has emerged as a major problem for modern society. Acute TBI can transform into a chronic condition and be a risk factor for neurodegenerative ...diseases such as Alzheimer's and Parkinson's diseases, probably through induction of oxidative stress and neuroinflammation. Here, we examined the ability of the antioxidant molecular hydrogen given in drinking water (molecular hydrogen water; mHW) to alter the acute changes induced by controlled cortical impact (CCI), a commonly used experimental model of TBI. We found that mHW reversed CCI-induced edema by about half, completely blocked pathological tau expression, accentuated an early increase seen in several cytokines but attenuated that increase by day 7, reversed changes seen in the protein levels of aquaporin-4, HIF-1, MMP-2, and MMP-9, but not for amyloid beta peptide 1-40 or 1-42. Treatment with mHW also reversed the increase seen 4 h after CCI in gene expression related to oxidation/carbohydrate metabolism, cytokine release, leukocyte or cell migration, cytokine transport, ATP and nucleotide binding. Finally, we found that mHW preserved or increased ATP levels and propose a new mechanism for mHW, that of ATP production through the Jagendorf reaction. These results show that molecular hydrogen given in drinking water reverses many of the sequelae of CCI and suggests that it could be an easily administered, highly effective treatment for TBI.
Key points
Pregnancy increases sympathetic nerve activity (SNA), although the mechanisms responsible for this remain unknown. We tested whether insulin or leptin, two sympathoexcitatory hormones ...increased during pregnancy, contribute to this.
Transport of insulin across the blood–brain barrier in some brain regions, and into the cerebrospinal fluid (CSF), was increased, although brain insulin degradation was also increased. As a result, brain and CSF insulin levels were not different between pregnant and non‐pregnant rats.
The sympathoexcitatory responses to insulin and leptin were abolished in pregnant rats.
Blockade of arcuate nucleus insulin receptors did not lower SNA in pregnant or non‐pregnant rats.
Collectively, these data suggest that pregnancy renders the brain resistant to the sympathoexcitatory effects of insulin and leptin, and that these hormones do not mediate pregnancy‐induced sympathoexcitation. Increased muscle SNA stimulates glucose uptake. Therefore, during pregnancy, peripheral insulin resistance coupled with blunted insulin‐ and leptin‐induced sympathoexcitation ensures adequate delivery of glucose to the fetus.
Pregnancy increases basal sympathetic nerve activity (SNA), although the mechanism responsible for this remains unknown. Insulin and leptin are two sympathoexcitatory hormones that increase during pregnancy, yet, pregnancy impairs central insulin‐ and leptin‐induced signalling. Therefore, to test whether insulin or leptin contribute to basal sympathoexcitation or, instead, whether pregnancy induces resistance to the sympathoexcitatory effects of insulin and leptin, we investigated α‐chloralose anaesthetized late pregnant rats, which exhibited increases in lumbar SNA (LSNA), splanchnic SNA and heart rate (HR) compared to non‐pregnant animals. In pregnant rats, transport of insulin into cerebrospinal fluid and across the blood–brain barrier in some brain regions increased, although brain insulin degradation was also increased; brain and cerebrospinal fluid insulin levels were not different between pregnant and non‐pregnant rats. Although i.c.v. insulin increased LSNA and HR and baroreflex control of LSNA and HR in non‐pregnant rats, these effects were abolished in pregnant rats. In parallel, pregnancy completely prevented the actions of leptin with respect to increasing lumbar, splanchnic and renal SNA, as well as baroreflex control of SNA. Blockade of insulin receptors (with S961) in the arcuate nucleus, the site of action of insulin, did not decrease LSNA in pregnant rats, despite blocking the effects of exogenous insulin. Thus, pregnancy is associated with central resistance to insulin and leptin, and these hormones are not responsible for the increased basal SNA of pregnancy. Because increases in LSNA to skeletal muscle stimulates glucose uptake, blunted insulin‐ and leptin‐induced sympathoexcitation reinforces systemic insulin resistance, thereby increasing the delivery of glucose to the fetus.
Key points
Pregnancy increases sympathetic nerve activity (SNA), although the mechanisms responsible for this remain unknown. We tested whether insulin or leptin, two sympathoexcitatory hormones increased during pregnancy, contribute to this.
Transport of insulin across the blood–brain barrier in some brain regions, and into the cerebrospinal fluid (CSF), was increased, although brain insulin degradation was also increased. As a result, brain and CSF insulin levels were not different between pregnant and non‐pregnant rats.
The sympathoexcitatory responses to insulin and leptin were abolished in pregnant rats.
Blockade of arcuate nucleus insulin receptors did not lower SNA in pregnant or non‐pregnant rats.
Collectively, these data suggest that pregnancy renders the brain resistant to the sympathoexcitatory effects of insulin and leptin, and that these hormones do not mediate pregnancy‐induced sympathoexcitation. Increased muscle SNA stimulates glucose uptake. Therefore, during pregnancy, peripheral insulin resistance coupled with blunted insulin‐ and leptin‐induced sympathoexcitation ensures adequate delivery of glucose to the fetus.
•HMGB1 crosses the blood–brain barrier in the blood-to-brain direction.•The likely mechanism of transport is adsorptive transcytosis.•The transport system is non-saturable and enhanced by wheatgerm ...agglutinin.•The rate of transport is greatly enhanced in mice pre-treated with lipopolysaccharide.•HMGB1 crosses the blood–brain barrier in the brain-to-blood direction.
High-mobility group box 1 (HMGB1) is a ubiquitous protein that regulates transcription in the nucleus, and is an endogenous damage-associated molecular pattern molecule that activates the innate immune system. HMGB1 activates the TLR4 and RAGE recepto, inducing downstream signals reminiscent of cytokines that have been found to cross the blood–brain barrier (BBB). Blood HMGB1 increases in stroke, sepsis, senescence, alcohol binge drinking and other conditions. Here, we examined the ability of HMGB1 radioactively labeled with iodine (I-HMGB1) to cross the BBB. We found that I-HMGB1 readily entered into mouse brain from the circulation with a unidirectional influx rate of 0.654 μl/g-min. All brain regions tested took up I-HMGB1; uptake was greatest by the olfactory bulb and least in the striatum. Transport was not reliably inhibited by unlabeled HMGB1 nor by inhibitors of TLR4, TLR2, RAGE, or CXCR4. Uptake was enhanced by co-injection of wheatgerm agglutinin, suggestive of involvement of absorptive transcytosis as a mechanism of transport. Induction of inflammation/neuroinflammation with lipopolysaccharide is known to increase blood HMGB1; we report here that brain transport is also increased by LPS-induced inflammation. Finally, we found that I-HMGB1 was also transported in the brain-to-blood direction, with both unlabeled HMGB1 or lipopolysaccharide increasing the transport rate. These results show that HMGB1 can bidirectionally cross the BBB and that those transport rates are enhanced by inflammation. Such transport provides a mechanism by which HMGB1 levels would impact neuroimmune signaling in both the brain and periphery.
IntroductionThe growing population of older drivers presents challenges for road safety attributed to age-related declines and increased crash fatality rates. However, enabling older people to ...maintain their health and independence through continued safe driving is important. This study focuses on the urgent need for cost-effective interventions that reduce crash risk while supporting older drivers to remain driving safely for longer. Our study aims to evaluate the effectiveness of three behavioural interventions for older driver safety. These include an online road-rules refresher workshop, tailored feedback on driving performance and two tailored driving lessons.Methods and analysisA single-blind three-parallel group superiority randomised controlled trial will be conducted with 198 urban licensed drivers aged 65 years and older, allowing for 4% attrition. This sample size provides 80% power to detect a difference with an alpha of 0.05. Participants will be selected based on a standardised on-road test that identifies them as moderately unsafe drivers. Interventions, spanning a 3-month period, aim to improve driving safety. Their effectiveness will be assessed through a standardised on-road assessment of driving safety at 3 months (T1) and 12 months postintervention (T2). Additionally, monthly self-reported driving diaries will provide data on crashes and incidents.This trial has the potential to identify cost-effective approaches for improving safety for older drivers and contribute to evidence-based health policy, clinical practice and guidelines.Ethics and disseminationEthical approval was obtained by the University of New South Wales Human Research Ethics Committee (HC190439, 22 August 2019). The results of the study will be disseminated in peer-reviewed journals and research conferences.Trial registration numberACTRN12622001515785.
Leptin is an adipocyte-secreted hormone that is delivered via a specific transport system across the blood-brain barrier (BBB) to the brain where it acts on the hypothalamus receptors to control ...appetite and thermogenesis. Peripheral resistance to leptin due to its impaired brain delivery prevents therapeutic use of leptin in overweight and moderately obese patients. To address this problem, we modified the N-terminal amine of leptin with Pluronic P85 (LepNP85) and administered this conjugate intranasally using the nose-to-brain (INB) route to bypass the BBB. We compared this conjugate with the native leptin, the N-terminal leptin conjugate with poly(ethylene glycol) (LepNPEG5K), and two conjugates of leptin with Pluronic P85 attached randomly to the lysine amino groups of the hormone. Compared to the random conjugates of leptin with P85, LepNP85 has shown higher affinity upon binding with the leptin receptor, and similarly to native hormone activated hypothalamus receptors after direct injection into brain. After INB delivery, LepNP85 conjugate was transported to the brain and accumulated in the hypothalamus and hippocampus to a greater extent than the native leptin and LepNPEG5K and activated leptin receptors in hypothalamus at lower dose than native leptin. Our work suggests that LepNP85 can access the brain directly after INB delivery and confirms our hypothesis that the improvement in brain accumulation of this conjugate is due to its enhanced brain absorption. In conclusion, the LepNP85 with optimized conjugation chemistry is a promising candidate for treatment of obesity.
Pluronic P85 is selectively attached to the N-terminal amine of leptin to reduce the steric hindrance to leptin receptor binding and enhance the direct nose-to-brain transport of leptin. Display omitted
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