In humans, exposure to electromagnetic millimeter waves (MMW) has a hypoalgesic effect. In animals, this effect has been shown to depend on innervation density of the area exposed. This study aims to ...assess hypoalgesic and parasympathetic effects of MMW applied on the palmar side of the wrist in healthy participants. In a within-subject design, 10 healthy participants had the palmar side of their wrist exposed to MMW (61.25 GHz, 17 mW/cm
2
) for 30 minutes, 1 h, & 1 h30, and 30 minutes of sham exposure. Experimental pain was induced after the exposure sessions with the Cold Pressor Test, and pain threshold and pain tolerance values were compared to that of the sham condition. Participants' heart rate and blood pressure were measured before and after exposures. Finally, innocuity of the exposure system was controlled with a pre-post exposure visual examination scale and skin temperature measured by a thermal camera. Exposure to 30 minutes, but not 1 h or 1 h30, of MMW led to significant increases in pain thresholds compared to the sham condition, but no increase of pain tolerance. All conditions led to decreased heart rate, while no change in blood pressure was observed. No change in skin state or temperature was observed for any of the conditions. MMW applied on the inner part of the wrist diminish pain sensations more effectively than placebo, and seem to increase parasympathetic activities, while remaining innocuous. Building a miniaturized MMW emission system to be worn on the wrist would provide access to ambulatory MMW therapy for pain management.
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Dequalinium (DQ) has been proposed as a mitochondrial targeting ligand for nanomedicines, including liposomes, given the implication of these organelles in many diseases. This ...original study focuses on the interactions of DQ with phosphatidylcholine bilayers during the formation of liposomes. Firstly, PEGylated liposomes suitable for drug delivery were studied and were found to be more stable when made in water than in phosphate-buffered saline, emphasizing the role of electrostatic interactions between positive charges on DQ and the polar head groups of the lipids. To gain more information, differential scanning calorimetry, small- and wide-angle X-ray scattering and diffraction, 31P and 2H NMR spectroscopy and freeze-fracture electron microscopy were performed on dimyristoylphosphatidylcholine (DMPC) model membranes in the presence of DQ. This molecule was shown to be located at the level of polar head groups and to induce electrostatic repulsions between adjacent lipid bilayers leading to membrane budding in water. These findings indicate that DQ is not completely inert towards lipid membranes and therefore is not an ideal candidate for encapsulation in liposomes. Overall, our work stresses the necessity for thorough physico-chemical characterization to better understand the mechanisms underlying the development of nanomedicines.
This retrospective cohort study deals with the causes of death among 57,000 military personnel who served in the French Navy surface vessels and were observed over the period 1975-2000. We ...successively compared the mortality rate and the specific causes of death between two groups differing in their potential exposure levels to radar. Occupational exposure was defined according to the on-board workplace (radar and control groups). The age-adjusted death ratios of the navy personnel were compared. For all causes of death, the results showed that 885 deaths in the radar group and 299 in the control group occurred (RR = 1.00 (95 % CI: 0.88-1.14)). RRs were 0.92 (95 % CI: 0.69-1.24) for neoplasms. For the duration of follow-up, the results did not show an increased health risk for military personnel exposed to higher levels of radio frequencies in the radar group, but the number of deaths was very small for some cancer sites.
Human plasma and fatty acid free human albumin were incubated with soman at pH 8.0 and 25 °C. Four methods were used to monitor the reaction of albumin with soman: progressive inhibition of the aryl ...acylamidase activity of albumin, the release of fluoride ion from soman, 31P NMR, and mass spectrometry. Inhibition (phosphonylation) was slow with a bimolecular rate constant of 15 ± 3 M−1 min−1. MALDI-TOF and tandem mass spectrometry of the soman−albumin adduct showed that albumin was phosphonylated on tyrosine 411. No secondary dealkylation of the adduct (aging) occurred. Covalent docking simulations and 31P NMR experiments showed that albumin has no enantiomeric preference for the four stereoisomers of soman. Spontaneous reactivation at pH 8.0 and 25 °C, measured as regaining of aryl acylamidase activity and decrease of covalent adduct (pinacolyl methylphosphonylated albumin) by NMR, occurred at a rate of 0.0044 h−1, indicating that the adduct is quite stable (t 1/2 = 6.5 days). At pH 7.4 and 22 °C, the covalent soman−albumin adduct, measured by MALDI-TOF mass spectrometry, was more stable (t 1/2 = 20 days). Though the concentration of albumin in plasma is very high (about 0.6 mM), its reactivity with soman (phosphonylation and phosphotriesterase activity) is too slow to play a major role in detoxification of the highly toxic organophosphorus compound soman. Increasing the bimolecular rate constant of albumin for organophosphates is a protein engineering challenge that could lead to a new class of bioscavengers to be used against poisoning by nerve agents. Soman-albumin adducts detected by mass spectrometry could be useful for the diagnosis of soman exposure.
Abstract DWCNTs have numerous industrial and biomedical applications and several studies reported that they could act as immunomodulator systems. The immune system is the first line of defence of the ...human body when exposed to particulate matter. In order to investigate DWCNTs’ role on innate immunity, we used THP-1 monocytic cells for the purpose of this study. We showed that DWCNTs were not cytotoxic until 6 h, 24 h, 48 h and 72 h of incubation with THP-1 monocytic cells (concentrations tested from 10 to 50 μg/mL). From 6 h to 72 h of incubation of THP-1 cells with DWCNTs, we measured a significant increase of the baseline cell index using xCELLigence® technology showing cell adhesion. After 24 h of exposure, DWCNTs agglomerates were localized in THP-1 monocyte cytoplasm and cell adhesion was observed simultaneously with a significant increase in the expression of CD11b and CD14 cell surface proteins. Pro-inflammatory cytokine secretion (IL-1β, IL-6, IL-8, TNF-α and IL-10) was also measured in supernatants after 6 h or 24 h of exposure to DWCNTs. This pro-inflammatory response was increased in THP-1 monocytic cells pre-treated with LPS. Altogether, our data indicate that DWCNTs induce an increased pro-inflammatory response of THP-1 monocytes and seem to modulate cell surface protein expression confirming that DWCNTs could act as stimulators of innate immunity.
The synthesis and the antiviral activities of C-3 acyclic nucleoside analogues of imidazo1,2-apyridine and pyrimidine are reported. From these compounds, 20, 21, 22, 23, 28, and 34 showed a specific ...activity against cytomegalovirus and/or varicella-zoster virus.
Vaccinia virus (VACV) was used as a surrogate of Variola virus (genus
Orthopoxvirus), the causative agent of smallpox, to study orthopoxvirus infection
via the respiratory airway. Lung surfactant, a ...physiological barrier to infection encountered by the virus, is predominantly composed of phospholipids whose role during orthopoxvirus infection has not been investigated. An attenuated Lister strain, derived from the traditional smallpox vaccine and the Western Reserve (WR) strain, lethal for mice infected by the respiratory route, were examined for their ability to bind various surfactant phospholipids. Dipalmitoyl phosphatidylglycerol (DPPG) was found to interact with both VACV strains. DPPG incorporated in small unilamellar vesicle (SUV-DPPG) inhibited VACV cell infection, unlike other phospholipids tested. Both pre-incubation of virus with SUV-DPPG and pretreatment of the cell with SUV-DPPG inhibited cell infection. This specific DPPG effect was shown to be concentration and time dependent and to prevent the first step of the viral cycle, i.e. virus cell attachment. Cryo-electron microscopy highlighted the interaction between the virus and SUV-DPPG. In the presence of the phospholipid, virus particles displayed a hedgehog-like appearance due to the attachment of lipid vesicles. Mice infected intranasally with VACV-WR pre-incubated with SUV-DPPG survived a lethal infection. These data suggest that DPPG in lung surfactant could reduce the amount of orthopoxvirus particles able to infect pneumocytes at the beginning of a respiratory poxvirus infection. The knowledge acquired during this study of virus–DPPG interactions may be used to develop novel chemotherapeutic strategies for smallpox.
The aim of this study was to characterize the early alterations of the liver mitochondrial function in ZDF (fa/fa) rats that develop diabetes compared to that of their lean counterparts ZDF (fa/+). ...Liver mitochondrial function was examined in 11‐ and 14‐week‐old ZDF (fa/fa) and ZDF lean (fa/+) rats. Oxygen consumption, H2O2 release, calcium retention capacity (CRC), membrane potential, membrane fluidity, and fatty acid composition were analyzed. State 3 oxygen consumption with palmitoyl‐carnitine increases between 11 and 14 weeks of age in lean but not in diabetic animals. This response was not seen with other substrates, suggesting that the use of fatty acids is impaired in diabetic rats. H2O2 release was lower in 14‐week‐old ZDF (fa/fa) rats as compared to ZDF lean (fa/+). These changes were not associated with differences in enzymatic activities of the respiratory complexes, suggesting regulatory mechanisms independent of their expression levels. Membrane fluidity and composition analyses show only slight effects linked to diabetes progression. The most salient feature was a reduction in CRC in the presence of CsA, an effect reflecting PTP dysregulation. Our data suggest few changes of mitochondrial function in ZDF fa/fa rats. At the age of 11 weeks, liver mitochondria have mainly a reduced effect of CsA on CRC.
ZDF liver mitochondrial function: Our data suggest few changes of mitochondrial function in ZDF fa/fa rats. At the age of 11 weeks, liver mitochondria have mainly a reduced effect of CsA on CRC.
Three imidazo1,2-
apyridine derivatives
3a–
c have been synthesized from p38 kinase inhibitor structures and evaluated as anti-apoptosis agents. These drugs were designed to interact with nucleic ...acids and membrane interactions by varying the chain length in position 6, from hydroxyethylamino (
3a), to hydroxybutylamino (
3b) and hydroxyhexylamino (
3c). First experiments showed that
3a and
3b were insoluble in water while
3c could be solubilized in water despite its partition coefficient (log
P
=
3.2). This latter feature was explained by the formation of a fifth intramolecular cycle thus allowing supramolecular structure formation (NMR and MD calculations).
The interactions with membranes have been studied using
1H,
2H,
31P Nuclear Magnetic Resonance (NMR), Electron Spin Resonance (ESR) and High Resolution-Magic Angle Spinning (HR-MAS). Despite the insolubility of
3a and
3b in water, these derivatives could be partially solubilized by synthetic phospholipidic model membranes (small unilamellar vesicles, SUV).
1H NMR paramagnetic broadening experiments performed on the same models showed that
3a was located in the external layer, probably close to the surface while
3b only formed external superficial adducts. Supplementary
31P,
2H NMR and ESR experiments on phospholipid dispersions confirmed the location of
3a close to the polar headgroup of the external layer of the membrane, this resulting in a 2
K lowering of the transition temperature. Moreover, no significant interaction was detected on the deep part of the layer (
2H NMR and 16NS ESR experiments). This binding was also found in the presence of cell cultures, as revealed by HR-MAS NMR experiments.
Conversely, no significant interaction with membranes was found with
3b or
3c.
From both the unexpected solubility of
3c and
3a interactions with membranes, further chemical modifications were finally proposed.
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Four 2,3-diarylimidazo1,2-
apyridines (
I,
1a–c) were synthesized as inhibitors of UV-induced apoptosis and showed quite different properties. First, only the pyridinyl derivative
I showed protection ...in molt cells. From the supposed intracellular target, phospholipid membrane models were studied by
1H,
2H and
31P NMR spectroscopy. All these molecules can incorporate the membrane bilayer of small unilamellar vesicles of lecithin (SUV). However,
I is clearly closed to the external polar head of the lipids, and is relatively mobile in the layer. Conversely, the other molecules are strongly immobilized in the deep part of the external layer.
31P solid-state NMR spectra recorded on phospholipid dispersions (multilayers vesicles (MLV)) completely excluded any detergent effect or any modification of temperature transition. The only structural or dynamic effect observed was a homogeneous, but limited, reduction in the chemical shift anisotropy in the presence of
I, in agreement with its superficial location.
2H NMR experiment performed on the same model using perdeuterated phospholipids showed no significant fluidity reduction at the level of terminal CD
3 groups in the presence of
1a–
c, according to their deep location. Finaly, their interactions with synthetic oligonucleotide, d(CGATCG)
2 was studied showing non specific interactions of
1a on the external GC pair, while no interaction was observed with the other derivatives.
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