Reactive oxygen species induce Cys106-mediated anti-parallel HMGB1 dimerization that protects against DNA damage.

Oxidative stress can induce covalent disulfide bond formation between protein-protein thiol groups and generate hydroxyl free radicals that damage DNA. HMGB1 is a DNA chaperone and damage-associated molecular pattern molecule. As a redox-sensitive protein, HMGB1 contains three cysteine residues: Cys23, Cys45, and Cys106. In this study, we focused on the relationship between HMGB1 dimerization and DNA stabilization under oxidative stress conditions. HMGB1 dimerization was positively modulated by CuCl2 and H2O2. Mutation of the Cys106 residue blocked dimer formation. Treatment of HEK293T cells with CuCl2 and H2O2 enhanced the oxidative self-dimerization of HMGB1, whereas this dimerization was inhibited in mutant HMGB1C106A cells. Furthermore, we performed a bimolecular fluorescence complementation assay to visualize Cys106 oxidation-induced HMGB1 dimerization in live cells exposed to oxidative stress and were able to reproduce the dimerization effect of HMGB1 in fluorescence resonance energy transfer analysis. Interestingly, dimerized HMGB1 bound to DNA with higher affinity than monomeric HMGB1. Dimerized HMGB1 protected DNA from damage due to hydroxyl free radicals and prevented cell death. In conclusion, dimerized HMGB1 may play a regulatory role in DNA stabilization under oxidative stress.

Needle-free jet injection of hyaluronic acid improves skin remodeling in a mouse model.

PURPOSE: The purpose of this study was to improve methods of jet injection using a mouse model. We investigated the mechanism of action, efficacy, and safety of the pneumatic device using injection of hyaluronic acid (HA) solution into a mouse model. METHODS: We evaluated the efficacy and safety of an INNOJECTOR™ pneumatic device that pneumatically accelerates a jet of HA solution under high pressure into the dermis of mouse skin. We examined the treatment effects using skin hybrid model jet dispersion experiments, photographic images, microscopy, and histological analyses. RESULTS: Use of the INNOJECTOR™ successfully increased dermal thickness and collagen synthesis in our mouse model. Jet dispersion experiments were performed using agarose gels and a polyacrylamide gel model to understand the dependence of jet penetration on jet power. The mechanisms by which pneumatic injection using HA solution exerts its effects may involve increased dermal thickening, triggering of a wound healing process, and activation of vimentin and collagen synthesis. CONCLUSIONS: Collagen synthesis and increased dermal thickening were successfully achieved in our mouse model using the INNOJECTOR™. Pneumatic injection of HA under high pressure provides a safe and effective method for improving the appearance of mouse skin. Our findings indicate that use of the INNOJECTOR™ may induce efficient collagen remodeling with subsequent marked dermal layer thickening by targeting vimentin.

Effects of short-term radiation emitted by WCDMA mobile phones on teenagers and adults.

BACKGROUND: With the rapid increasing use of third generation (3 G) mobile phones, social concerns have arisen concerning the possible health effects of radio frequency-electromagnetic fields (RF-EMFs) emitted by wideband code division multiple access (WCDMA) mobile phones in humans. The number of people, who complain of various symptoms such as headache, dizziness, and fatigue, has also increased. Recently, the importance of researches on teenagers has been on the rise. However, very few provocation studies have examined the health effects of WCDMA mobile phone radiation on teenagers. METHODS: In this double-blind study, two volunteer groups of 26 adults and 26 teenagers were simultaneously investigated by measuring physiological changes in heart rate, respiration rate, and heart rate variability for autonomic nervous system (ANS), eight subjective symptoms, and perception of RF-EMFs during sham and real exposure sessions to verify its effects on adults and teenagers. Experiments were conducted using a dummy phone containing a WCDMA module (average power, 250 mW at 1950 MHz; specific absorption rate, 1.57 W/kg) within a headset placed on the head for 32 min. RESULTS: Short-term WCDMA RF-EMFs generated no significant changes in ANS, subjective symptoms or the percentages of those who believed they were being exposed in either group. CONCLUSIONS: Considering the analyzed physiological data, the subjective symptoms surveyed, and the percentages of those who believed they were being exposed, 32 min of RF radiation emitted by WCDMA mobile phones demonstrated no effects in either adult or teenager subjects.

Tyrosine-mediated two-dimensional peptide assembly and its role as a bio-inspired catalytic scaffold.

In two-dimensional interfacial assemblies, there is an interplay between molecular ordering and interface geometry, which determines the final morphology and order of entire systems. Here we present the interfacial phenomenon of spontaneous facet formation in a water droplet driven by designed peptide assembly. The identified peptides can flatten the rounded top of a hemispherical droplet into a plane by forming a macroscopic two-dimensional crystal structure. Such ordering is driven by the folding geometry of the peptide, interactions of tyrosine and crosslinked stabilization by cysteine. We discover the key sequence motifs and folding structures and study their sequence-specific assembly. The well-ordered, densely packed, redox-active tyrosine units in the YYACAYY (H-Tyr-Tyr-Ala-Cys-Ala-Tyr-Tyr-OH) film can trigger or enhance chemical/electrochemical reactions, and can potentially serve as a platform to fabricate a molecularly tunable, self-repairable, flat peptide or hybrid film.

Drug-loaded gold plasmonic nanoparticles for treatment of multidrug resistance in cancer.

To investigate the possibility of treating multidrug-resistant tumors with targeted chemo-photothermal treatment, we conducted in vitro and in vivo studies using a doxorubicin (DOX)-resistant DLD-1 cell line (DLD-1/DOX) and nude mice with human xenograft tumors, respectively. The chemo-photothermal treatment consisted of DOX-loaded-poly(lactic-co-glycolic acid)-Au half-shell nanoparticles with targeting moieties of anti-death receptor-4 monoclonal antibody conjugated to the Au surface. The cells or xenografted tumors treated with nanoparticles were exposed to near infrared light for 10 min, which caused an increase in temperature to 45 °C. Chemo-photothermal treatment resulted in a large reduction in the rate of tumor xenograft growth on DLD-1/DOX tumor-bearing mice with a much smaller dose of DOX than conventional DOX chemotherapy. These results demonstrate that targeted chemo-photothermal treatment can provide high therapeutic efficacy and low toxicity in the treatment of multidrug-resistant tumors.

Effects of 60 Hz magnetic fields on teenagers and adults.

BACKGROUND: As use of electrical devices has increased, social concerns about the possible effects of 60 Hz electromagnetic fields on human health have increased. Accordingly, the number of people who complain of various symptoms such as headache and insomnia has risen. Many previous studies of the effects of extremely low frequency (ELF) magnetic field exposure on children have focused on the occurrence of childhood leukaemia and central nervous system cancers. However, very few provocation studies have examined the health effects of ELF magnetic fields on teenagers. METHODS: In this double-blind study, we simultaneously investigated physiological changes (heart rate, respiration rate, and heart rate variability), subjective symptoms, and magnetic field perception to determine the reliable effects of 60 Hz 12.5 µT magnetic fields on teenagers. Two volunteer groups of 30 adults and 30 teenagers were tested with exposure to sham and real magnetic fields for 32 min. RESULTS: ELF magnetic field exposure did not have any effects on the physiological parameters or eight subjective symptoms in either group. Neither group correctly perceived the magnetic fields. CONCLUSIONS: Physiological data were analysed, subjective symptoms surveyed, and the percentages of those who believed they were being exposed were measured. No effects were observed in adults or teenagers resulting from 32 min of 60 Hz 12.5 µT magnetic field exposure.

Chaperone-like activity of high-mobility group box 1 protein and its role in reducing the formation of polyglutamine aggregates.

High-mobility group box 1 protein (HMGB1), which mainly exists in the nucleus, has recently been shown to function as a sentinel molecule for viral nucleic acid sensing and an autophagy regulator in the cytoplasm. In this study, we studied the chaperone-like activity of HMGB1 and found that HMGB1 inhibited the chemically induced aggregation of insulin and lysozyme, as well as the heat-induced aggregation of citrate synthase. HMGB1 also restored the heat-induced suppression of cytoplasmic luciferase activity as a reporter protein in hamster lung fibroblast O23 cells with expression of HMGB1. Next, we demonstrated that HMGB1 inhibited the formation of aggregates and toxicity caused by expanded polyglutamine (polyQ), one of the main causes of Huntington disease. HMGB1 directly interacted with polyQ on immunofluorescence and coimmunoprecipitation assay, whereas the overexpression of HMGB1 or exogenous administration of recombinant HMGB1 protein remarkably reduced polyQ aggregates in SHSY5Y cells and hmgb1(-/-) mouse embryonic fibroblasts upon filter trap and immunofluorescence assay. Finally, overexpressed HMGB1 proteins in mouse embryonic primary striatal neurons also bound to polyQ and decreased the formation of polyQ aggregates. To this end, we have demonstrated that HMGB1 exhibits chaperone-like activity and a possible therapeutic candidate in polyQ disease.

Effects of radiation emitted by WCDMA mobile phones on electromagnetic hypersensitive subjects.

BACKGROUND: With the use of the third generation (3 G) mobile phones on the rise, social concerns have arisen concerning the possible health effects of radio frequency-electromagnetic fields (RF-EMFs) emitted by wideband code division multiple access (WCDMA) mobile phones in humans. The number of people with self-reported electromagnetic hypersensitivity (EHS), who complain of various subjective symptoms such as headache, dizziness and fatigue, has also increased. However, the origins of EHS remain unclear. METHODS: In this double-blind study, two volunteer groups of 17 EHS and 20 non-EHS subjects were simultaneously investigated for physiological changes (heart rate, heart rate variability, and respiration rate), eight subjective symptoms, and perception of RF-EMFs during real and sham exposure sessions. Experiments were conducted using a dummy phone containing a WCDMA module (average power, 24 dBm at 1950 MHz; specific absorption rate, 1.57 W/kg) within a headset placed on the head for 32 min. RESULTS: WCDMA RF-EMFs generated no physiological changes or subjective symptoms in either group. There was no evidence that EHS subjects perceived RF-EMFs better than non-EHS subjects. CONCLUSIONS: Considering the analyzed physiological data, the subjective symptoms surveyed, and the percentages of those who believed they were being exposed, 32 min of RF radiation emitted by WCDMA mobile phones demonstrated no effects in either EHS or non-EHS subjects.

Origins of electromagnetic hypersensitivity to 60 Hz magnetic fields: A provocation study.

With increasing electrical device usage, social concerns about the possible effects of 60 Hz electromagnetic fields on human health have increased. The number of people with self-attributed electromagnetic hypersensitivity (EHS) who complain of various subjective symptoms such as headache and insomnia has also increased. However, it is unclear whether EHS results from physiological or other origins. In this double-blinded study, we simultaneously investigated physiological changes (heart rate, respiration rate, and heart rate variability), subjective symptoms, and perception of the magnetic field to assess origins of the subjective symptoms. Two volunteer groups of 15 self-reported EHS and 16 non-EHS individuals were tested with exposure to sham and real (60 Hz, 12.5 µT) magnetic fields for 30 min. Magnetic field exposure did not have any effects on physiological parameters or eight subjective symptoms in either group. There was also no evidence that the EHS group perceived the magnetic field better than the non-EHS group. In conclusion, the subjective symptoms did not result from the 60 Hz, 12.5 µT magnetic field exposures but from other non-physiological factors.

EHS subjects do not perceive RF EMF emitted from smart phones better than non-EHS subjects.

As the use of smart phones increases, social concerns have arisen concerning the possible effects of radio frequency-electromagnetic fields (RF-EMFs) emitted from wideband code division multiple access (WCDMA) mobile phones on human health. The number of people with self-reported electromagnetic hypersensitivity (EHS) who complain of various subjective symptoms, such as headache, insomnia, etc., has also recently increased. However, it is unclear whether EHS subjects can detect RF-EMFs exposure or not. In this double-blind study, two volunteer groups of 17 EHS and 20 non-EHS subjects were investigated in regards to their perception of RF-EMFs with real and sham exposure sessions. Experiments were conducted using a WCDMA module inside a dummy phone with an average power of 24 dBm at 1950 MHz and a specific absorption rate of 1.57 W/kg using a dummy headphone for 32 min. In conclusion, there was no indication that EHS subjects perceive RF-EMFs better than non-EHS subjects.

Effects of posture and acute sleep deprivation on heart rate variability.

PURPOSE: In our previous study to investigate autonomic nervous system (ANS) activity due to radio frequency (RF) radiation using heart rate variability (HRV), drowsiness was observed in approximately half of all subjects. Therefore, the usage of HRV with unwanted drowsiness could falsely indicate the effects of RF radiation by mobile phones on the ANS. The objective of this study was to determine which posture is appropriate for accurate HRV analysis for provocation study. MATERIALS AND METHODS: A total of 52 healthy subjects (25 males and 27 females) participated in this experiment. We measured the number of times a subject showed drowsiness or sleep deprivation due to awakening, and analyzed HRV six times over 30 minutes in sitting and recumbent postures, using power spectrum. RESULTS: We employed the ratio of low frequency power to high frequency power (LFP/HFP) to analyze the changes in the ANS. The number of sleep deprivation occurrences in the sitting posture was significantly less than that in the recumbent posture (p<0.01), resulting in smaller increase of LFP/HFP. Although LFP/HFP of the two postures varied with time without any provocation, it was more stable in sitting than in recumbent postures. CONCLUSION: A sitting posture is preferable to a recumbent posture for analyzing HRV, because of decreased drowsiness and sleep deprivation, thereby decreasing variation of LFP/HFP during experiment. Considering the drowsiness, it is also recommended that any experiment should be completed within 15 minutes, if possible.

A Survey on Ubiquitous Healthcare Service Demand among Diabetic Patients.

BACKGROUND: Advanced information technology can be used when developing diagnostic and treatment strategies to provide better care for diabetic patients. However, the levels of need and demand for the use of technological advances have not been investigated in diabetic patients. We proposed and developed an individualized, ubiquitous (U)-healthcare service using advanced information technology for more effective glucose control. Prior to our service initiation, we surveyed patient needs and other pertinent information. METHODS: During August 2009, we conducted a 34-item questionnaire survey among patients with diabetes who were older than 40 years in two certain hospitals in Korea. RESULTS: The mean age of the 228 participants was 61.2±9 years, and males made up 49.1% of the sample. Seventy-one percent replied that they wanted individualized healthcare service, and they also wanted their health information to be delivered through mobile devices such as a cellular phone or a personal digital assistant (40.4%). Most patients had never heard of U-healthcare services (81.1%); however, after explaining the concept, 71.1% of participants responded that they would use the service if it was provided. Despite their willingness, participants were concerned about technical difficulty in using the service (26.3%) as well as the cost of the service (29.8%). CONCLUSION: The current study suggests that more than 70% of diabetic patients are interested in using U-healthcare services. To encourage widespread use, the application program or device of U-healthcare services should be simple, easy to use and affordable while also including a policy for the protection of private information.

Renoprotective antioxidant effect of alagebrium in experimental diabetes.

BACKGROUND: Despite the beneficial effects of alagebrium (ALA), a putative advanced glycation end-product (AGE) breaker, on diabetic nephropathy, its renoprotective mechanisms are incompletely understood. Since oxidative stress exacerbates diabetic renal injury through interaction with AGE, the present study examined the antioxidative property of ALA in db/db mice, mesangial cells cultured under high glucose or H(2)O(2) and a test tube. METHODS: ALA (2 mg/kg/day) was administered intraperitoneally for 12 weeks to 8-week-old db/m and db/db (D(ALA)E) mice or for 4 weeks to 16-week-old db/db mice (D(ALA)L). Oxidative stress markers (nitrotyrosine accumulation, expression and translocation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, cellular DCF-DA fluorescence) together with urinary albumin excretion and histological changes including mesangial expansion were measured. The concentration of H(2)O(2) in the presence and absence of ALA was measured by iodometric analysis in a test tube. RESULTS: ALA significantly reduced not only urinary albumin excretion and renal pathological changes but also accumulation of pentosidine and nitrotyrosine and expression of NADPH oxidase subunits in db/db mice regardless of treatment protocol. In mesangial cells, ALA effectively prevented not only high glucose- but also H(2)O(2)-induced membrane translocation of NADPH oxidase subunit (p47 phox, p67 phox and rac1) and protein kinase C isoform (α, ßI and ßII) and Nox4 messenger RNA expression concomitant with cellular reactive oxygen species. Furthermore, ALA directly decreased H(2)O(2) in a test tube. CONCLUSION: ALA has both direct and indirect antioxidant effects that may play important roles in ALA's renoprotective effect in diabetic kidneys.

Comparison of survival predictions for rats with hemorrhagic shocks using an artificial neural network and support vector machine.

Hemorrhagic shock is the cause of one third of deaths resulting from injury in the world. Early diagnosis of hemorrhagic shock makes it possible for physicians to treat patients successfully. The objective of this study was to select an optimal survival prediction model using physiological parameters from rats during our hemorrhagic experiment. These physiological parameters were used for the training and testing of survival prediction models using an artificial neural network (ANN) and support vector machine (SVM). To avoid over-fitting, we chose the optimal survival prediction model according to performance measured by a 5-fold cross validation method. We selected an ANN with three hidden neurons and one hidden layer and an SVM with Gaussian kernel function as a trained survival prediction model. For the ANN model, the sensitivity, specificity, and accuracy of survival prediction were 97.8 ± 3.3 %, 96.3 ± 2.7 %, and 96.8 ± 1.7 %, respectively. For the SVM model, the sensitivity, specificity, and accuracy were 97.5 ± 2.9 %, 99.3 ± 1.1 %, and 98.5 ± 1.2 %, respectively. SVM was preferable to ANN for the survival prediction.

Physiological variables and subjective symptoms by 60 Hz magnetic field in EHS and non-EHS persons.

Electromagnetic hypersensitivity (EHS) is a set of claims of adverse medical symptoms self attributed by exposure to electromagnetic field. In this study, we simultaneously investigated both physiological changes (heart rate, respiration rate, and heart rate variability) and subjective symptoms to determine the origin of EHS. Two volunteer groups (15 self-reported EHS and 16 non-EHS participants) were tested under both sham and real exposure to 12.5 µT magnetic fields at 60 Hz that lasted a half an hour. The magnetic field exposure did not have any effect on physiological variables or subjective symptoms in either group. We conclude that the subjective symptoms did not result from exposure to 12.5 µT magnetic field at 60 Hz.

Effects of RF fields emitted from smart phones on cardio-respiratory parameters: a preliminary provocation study.

This paper describes an experimental setup for evaluating the physiological effects of radiofrequency (RF) emitted from a Wideband Code Division Multiple Access (WCDMA) module with a 24 dBm at 1950 MHz for specific absorption rate (SAR(1g)) of 1.57 W/kg. This provocation study was executed in a double-blind study of two volunteer groups of 10 self-reported electromagnetic hypersensitivity (EHS) and 10 non-EHS subjects under both sham and real exposures in a randomly assigned and counter-balanced order. In the preliminary results, WCDMA RF exposure of 30 min did not have any effects on physiological changes in either group.

Reactive oxygen species mediate high glucose-induced plasminogen activator inhibitor-1 up-regulation in mesangial cells and in diabetic kidney.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) plays an important role in remodeling of extracellular matrix (ECM) in the glomeruli. PAI-1 is up-regulated by high glucose and is overexpressed in diabetic kidney. Since reactive oxygen species (ROS) mediate ECM accumulation in diabetic glomeruli and was recently found to mediate transforming growth factor-beta1 (TGF-beta1)-induced PAI-1 up-regulation in glomerular mesangial cells, we examined the role of ROS in high glucose-induced PAI-1 expression in cultured glomerular mesangial cells and in streptozotocin-induced diabetic rat glomeruli. METHODS: Growth arrested and synchronized primary rat mesangial cells were treated with different concentrations of glucose in the presence or absence of N-acetylcysteine (NAC) or trolox, or after cellular reduced form of glutathione (GSH) depleted with DL-buthionine-(S,R)-sulfoximine (BSO). Taurine was administered to diabetic rats from 2 days to 4 weeks after streptozotocin injection. Urinary protein excretion, glomerular volume, and fractional mesangial area were measured as markers of renal injury and lipid peroxide (LPO) as an oxidative stress marker. PAI-1 mRNA expression was measured by Northern blot analysis in mesangial cells and reverse transcription-polymerase chain reaction (RT-PCR) in glomeruli, PAI-1 protein by Western blot analysis and enzyme-linked immunosorbent assay (ELISA), and plasmin activity by fluorometry. RESULTS: High glucose significantly increased PAI-1 mRNA and protein expression and decreased plasmin activity in mesangial cells. Equimolar concentrations of l-glucose or mannitol did not affect PAI-1 expression. BSO pretreatment significantly increased basal PAI-1 expression and amplified the response to high glucose. NAC effectively inhibited high glucose-induced, but not basal, PAI-1 expression. Reduced plasmin activity in mesangial cells by high glucose was rescued by antioxidants. Anti-TGF-beta antibody inhibited both high glucose- and H(2)O(2)-induced PAI-1 up-regulation. Taurine significantly reduced plasma LPO, glomerular PAI-1 expression, glomerular volume, fractional mesangial area, and proteinuria in streptozotocin-induced diabetic rats. CONCLUSION: These results demonstrate that ROS mediate high glucose-induced up-regulation of PAI-1 expression in cultured mesangial cells and in diabetic glomeruli. Since both high glucose and TGF-beta1 induce cellular ROS and ROS mediate both high glucose- and TGF-beta1-induced PAI-1, ROS appear to amplify TGF-beta1 signaling in high glucose-induced PAI-1 up-regulation. Antioxidants can prevent accumulation of ECM protein in diabetic glomeruli partly by abrogating up-regulation of PAI-1 and suppression of plasmin activity.