Artificial Intelligence, Wearables and Remote Monitoring for Heart Failure: Current and Future Applications.

Substantial milestones have been attained in the field of heart failure (HF) diagnostics and therapeutics in the past several years that have translated into decreased mortality but a paradoxical increase in HF-related hospitalizations. With increasing data digitalization and access, remote monitoring via wearables and implantables have the potential to transform ambulatory care workflow, with a particular focus on reducing HF hospitalizations. Additionally, artificial intelligence and machine learning (AI/ML) have been increasingly employed at multiple stages of healthcare due to their power in assimilating and integrating multidimensional multimodal data and the creation of accurate prediction models. With the ever-increasing troves of data, the implementation of AI/ML algorithms could help improve workflow and outcomes of HF patients, especially time series data collected via remote monitoring. In this review, we sought to describe the basics of AI/ML algorithms with a focus on time series forecasting and the current state of AI/ML within the context of wearable technology in HF, followed by a discussion of the present limitations, including data integration, privacy, and challenges specific to AI/ML application within healthcare.

Easy, Fast Self-Heating Polyurethane Nanocomposite with the Introduction of Thermally Annealed Carbon Nanotubes Using Near-Infrared Lased Irradiation.

In this study, high-crystallinity single walled carbon nanotubes (H-SWNTs) were prepared by high-temperature thermal annealing at 1800 °C and a self-heating shape memory polyurethane nanocomposite with excellent self-heating characteristics was developed within a few seconds by irradiation with near-infrared rays. With a simple method (heat treatment), impurities at the surface of H-SWNTs were removed and at the same time the amorphous structure converted into a crystalline structure, improving crystallinity. Therefore, high conductivity (electric, thermal) and interfacial affinity with PU were increased, resulting in improved mechanical, thermal and electric properties. The electrical conductivity of neat polyurethane was enhanced from ~10-11 S/cm to 4.72 × 10-8 S/cm, 1.07 × 10-6 and 4.66 × 10-6 S/cm, while the thermal conductivity was enhanced up to 60% from 0.21 W/mK, 0.265 W/mK and 0.338 W/mK for the composites of 1, 3 and 5 wt%, respectively. Further, to achieve an effective photothermal effect, H-SWNTs were selected as nanofillers to reduce energy loss while increasing light-absorption efficiency. Thereafter, near-infrared rays of 818 nm were directly irradiated onto the nanocomposite film to induce photothermal properties arising from the local surface plasmon resonance effect on the CNT surface. A self-heating shape memory composite material that rapidly heated to 270 °C within 1 min was developed, even when only 3 wt.% of H-SWNTs were added. The results of this study can be used to guide the development of heat-generating coating materials and de-icing materials for the wing and body structures of automobiles or airplanes, depending on the molding method.

Rapid and Local Self-Healing Ability of Polyurethane Nanocomposites Using Photothermal Polydopamine-Coated Graphene Oxide Triggered by Near-Infrared Laser.

In this study, we report the self-healing ability of polyurethane (PU) nanocomposites based on the photothermal effect of polydopamine-coated graphene oxide (PDA-rGO). Polydopamine (PDA) was coated on the graphene oxide (GO) surface, while simultaneously reducing GO by the oxidation of dopamine hydrochloride in an alkaline aqueous solution. The PDA-rGO was characterized by Fourier-transform infrared spectroscopy, X-ray diffraction, Raman spectroscopy, thermogravimetric analysis, and scanning electron microscopy-energy-dispersive X-ray analysis. PDA-rGO/PU nanocomposites with nanofiller contents of 0.1, 0.5 and 1 wt% were prepared by ex situ mixing method. The photothermal effect of the PDA-rGO in the PU matrix was investigated at 0.1 W/cm2 using an 808 nm near-infrared (NIR) laser. The photothermal properties of the PDA-rGO/PU nanocomposites were superior to those of the GO/PU nanocomposites, owing to an increase in the local surface plasmon resonance effect by coating with PDA. Subsequently, the self-healing efficiency was confirmed by recovering the tensile stress of the damaged nanocomposites using the thermal energy generated by the NIR laser.

Changes in Gait Parameters and Gait Variability in Young Adults during a Cognitive Task while Slope and Flat Walking.

This study investigates the effects of a cognitive task while walking on a slope or a flat surface on gait parameters and gait variability in young adults. The participants consisted of thirty healthy young subjects. They were instructed to walk on a slope or on a flat surface while performing or not performing a cognitive task, which involved speaking a four-syllable word in reverse. A wearable inertia measurement unit (IMU) system was used to measure spatiotemporal parameters and gait variability. Flat gait (FG) while performing the cognitive task (FGC) and uphill gait (UG) while performing the cognitive task (UGC) significantly altered stride times, gait speeds, and cadence as compared with FG and UG, respectively. Downhill gait (DG) while performing the cognitive task (DGC) caused no significant difference as compared with DG. Gait variability comparisons showed no significant difference between UGC and UG or between FGC and FG, respectively. On the other hand, variabilities of stride times and gait speeds were significantly greater for DGC than DG. FGC and UGC induce natural changes in spatiotemporal gait parameters that enable the cognitive task to be performed safely. DGC should be regarded as high complexity tasks involving greater gait variability to reduce fall risk.

Pharmacokinetic and pharmacodynamic evaluation according to absorption differences in three formulations of ibuprofen.

OBJECTIVE: Prostaglandin E2 (PGE2) synthesis is modulated by COX2. Changes in PGE2 could be used to quantify the COX2 inhibition after ibuprofen administration. This study investigated the pharmacokinetic and pharmacodynamic relationships for COX2 inhibition according to three formulations of ibuprofen in healthy male subjects. MATERIALS AND METHODS: A randomized, open-label, single-dose, three-treatment, six-sequence crossover study was performed in 36 healthy South Korean male volunteers. Enrolled subjects received the following three 200 mg ibuprofen formulations: ibuprofen arginine, solubilized ibuprofen capsule, and standard ibuprofen. Pharmacokinetic and pharmacodynamic blood samples were collected for 16 hours following treatment. For pharmacodynamic evaluations, lipopolysaccharide (LPS)-induced PGE2 inhibition at each time point compared to predose was measured. Noncompartmental analysis was used for pharmacokinetic assessment, and time-weighted average inhibition (WAI) of PGE2 was applied to the pharmacodynamic evaluation. RESULTS: After a single oral dose of the ibuprofen formulations, the median times to maximum concentration were 0.42, 0.5, and 1.25 hours in ibuprofen arginine, solubilized ibuprofen capsule, and ibuprofen, respectively. The maximum observed plasma concentration was lower in ibuprofen, and the area under the plasma concentration-time curve was comparable among the three formulations. A significant difference was observed between fast-acting formulations and standard ibuprofen tablets for both maximum concentration and time taken to reach it. Individual formulations had an effect on PGE2 WAI during the 8 hours following treatment, resulting in significantly lower WAI in standard ibuprofen: ibuprofen arginine 18.4%, solubilized ibuprofen capsule 18.4%, and standard ibuprofen 11.6%. CONCLUSION: Rapid absorption and higher peak concentration were observed in ibuprofen arginine and the solubilized ibuprofen capsule. Additionally, fast-acting formulations had more predominant inhibitory activity on the COX2 enzyme.

The rs662 polymorphism of paraoxonase 1 affects the difference in the inhibition of butyrylcholinesterase activity by organophosphorus pesticides in human blood.

OBJECTIVES: Organophosphorus pesticides (OPs) are a human health hazard. OPs inhibit acetylcholinesterase (AChE) at nerve endings and accumulate acetylcholine (ACh) at these sites. High levels of ACh and long exposure promote cholinergic crisis. The hydrolysis of OPs by serum paraoxonase 1 (PON1) plays a role in cholinergic crisis in humans. Human serum PON1 can break down organophosphate before binding to ChE. We investigated the effect of PON1 polymorphisms on AChE activity after OP treatment. METHODS: 50 healthy volunteers were randomly recruited with informed consent. We investigated butyrylcholinesterase (BuChE) activity changes in plasma as a biomarker of AChE after OP treatment in human blood samples immediately following blood sampling. After the standardization of BuChE activity in human blood, we correlated changes in BuChE activity with changes in blood pH. We analyzed the PON1 polymorphisms (rs854560 and rs662) of 50 participants to retrospectively investigate the interindividual variability of changes in BuChE activity. RESULTS: Changes in BuChE activity are strongly correlated with pH changes after OP treatment (R2 = 0.913). We used changes in pH as a surrogate marker for BuChE inhibition after OP treatment. OP treatment significantly decreased BuChE activity by 56.4 ± 5.1% (p < 0.001). The degree of BuChE inhibition was significantly different in the PON1 rs662 genotype (56.10 ± 4.74% vs. 57.96 ± 5.67% vs. 52.34 ± 1.51%; GG vs. GA vs. AA, respectively). CONCLUSION: Changes in pH can be used as a surrogate marker for the detection of BuChE inhibition after OP exposure. The rs662 polymorphism of PON1 may explain the inter-individual variability in BuChE inhibition.

Physiological properties of Scomber japonicus meat hydrolysate prepared by subcritical water hydrolysis.

The health-beneficial biological activities, including antioxidant and tyrosinase inhibitory activities, of Scomber japonicus muscle protein hydrolysates prepared by subcritical water hydrolysis were investigated. After 5 min of subcritical hydrolysis at 140 degrees C, 59.76% of S. japonicus muscle protein was hydrolyzed, the highest degree of hydrolysis in all the groups were tested. According to the response surface methodology results, as the reaction temperature and reaction time became lower and shorter, the yield became higher. The highest 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity (90.63%) occurred in hydrolysates treated at 140 degrees C for 5 min, and the highest tyrosinase inhibitory activity (65.54%) was identified in hydrolysates treated at 200 degreesC for 15 min. Changes in the molecular weight distribution of S. japonicus muscle proteins after subcritical water hydrolysis were observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Subcritical water hydrolysis is a suitable technique for obtaining S.japonicus muscle protein hydrolysates with useful biological activities, within a short time (5-15 min).

Pitavastatin Regulates Ang II Induced Proliferation and Migration via IGFBP-5 in VSMC.

Angiotensin II (Ang II), a key mediator of hypertensive, causes structural changes in the arteries (vascular remodeling), which involve alterations in cell growth, vascular smooth muscle cell (VSMC) hypertrophy. Ang II promotes fibrotic factor like IGFBP5, which mediates the profibrotic effects of Ang II in the heart and kidneys, lung and so on. The purpose of this study was to identify the signaling pathway of IGFBP5 on cell proliferation and migration of Ang II-stimulated VSMC. We have been interested in Ang II-induced IGFBP5 and were curious to determine whether a Pitavastatin would ameliorate the effects. Herein, we investigated the question of whether Ang II induced the levels of IGFBP5 protein followed by proliferation and migration in VSMC. Pretreatment with the specific Angiotensin receptor type 1 (AT1) inhibitor (Losartan), Angiotensin receptor type 2 (AT2) inhibitor (PD123319), MAPK inhibitor (U0126), ERK1/2 inhibitor (PD98059), P38 inhibitor (SB600125) and PI3K inhibitor (LY294002) resulted in significantly inhibited IGFBP5 production, proliferation, and migration in Ang II-stimulated VSMC. In addition, IGFBP5 knockdown resulted in modulation of Ang II induced proliferation and migration via IGFBP5 induction. In addition, Pitavastatin modulated Ang II induced proliferation and migration in VSMC. Taken together, our results indicated that Ang II induces IGFBP5 through AT1, ERK1/2, P38, and PI3K signaling pathways, which were inhibited by Pitavastatin. These findings may suggest that Pitavastatin has an effect on vascular disease including hypertension.

Ascorbic acid reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and improves survival rate in septic mice by activation of Nrf2/HO-1 signals.

High mobility group box 1 (HMGB1) is now recognized as a late mediator of sepsis. We tested hypothesis that ascorbic acid (AscA) induces heme oxygenase (HO)-1 which inhibits HMGB1 release in lipopolysaccharide (LPS)-stimulated cells and increases survival of septic mice. AscA increased HO-1 protein expression in a concentration- and time-dependent manner via Nrf2 activation in RAW 264.7 cells. HO-1 induction by AscA was significantly reduced by Nrf2 siRNA-transfected cells. Mutation of cysteine to serine of keap-1 proteins (C151S, C273S, and C288S) lost the ability of HO-1 induction by AscA, due to failure of translocation of Nrf-2 to nucleus. The PI3 kinase inhibitor, LY294002, inhibited HO-1 induction by AscA. Oxyhemoglobin (HbO2), LY294002, and ZnPPIX (HO-1 enzyme inhibitor) reversed effect of AscA on HMGB1 release. Most importantly, administration of AscA (200mg/kg, i.p.) significantly increased survival in LPS-induced endotoxemic mice. In cecal ligation and puncture (CLP)-induced septic mice, AscA reduced hepatic injury and serum HMGB1 and plasminogen activator inhibitor (PAI)-1 in a ZnPPIX-sensitive manner. In addition, AscA failed to increase survival in Nrf2 knockout mice by LPS. Thus, we concluded that high dose of AscA may be useful in the treatment of sepsis, at least, by activation of Nrf2/HO-1 signals.

Valsartan independent of AT1 receptor inhibits tissue factor, TLR-2 and -4 expression by regulation of Egr-1 through activation of AMPK in diabetic conditions.

Patients suffering from diabetes mellitus (DM) are at a severe risk of atherothrombosis. Early growth response (Egr)-1 is well characterized as a central mediator in vascular pathophysiology. We tested whether valsartan independent of Ang II type 1 receptor (AT1R) can reduce tissue factor (TF) and toll-like receptor (TLR)-2 and -4 by regulating Egr-1 in THP-1 cells and aorta in streptozotocin-induced diabetic mice. High glucose (HG, 15 mM) increased expressions of Egr-1, TF, TLR-2 and -4 which were significantly reduced by valsartan. HG increased Egr-1 expression by activation of PKC and ERK1/2 in THP-1 cells. Valsartan increased AMPK phosphorylation in a concentration and time-dependent manner via activation of LKB1. Valsartan inhibited Egr-1 without activation of PKC or ERK1/2. The reduced expression of Egr-1 by valsartan was reversed by either silencing Egr-1, or compound C, or DN-AMPK-transfected cells. Valsartan inhibited binding of NF-κB and Egr-1 to TF promoter in HG condition. Furthermore, valsartan reduced inflammatory cytokine (TNF-α, IL-6 and IL-1ß) production and NF-κB activity in HG-activated THP-1 cells. Interestingly, these effects of valsartan were not affected by either silencing AT1R in THP-1 cells or CHO cells, which were devoid of AT1R. Importantly, administration of valsartan (20 mg/kg, i.p) for 8 weeks significantly reduced plasma TF activity, expression of Egr-1, TLR-2, -4 and TF in thoracic aorta and improved glucose tolerance of streptozotocin-induced diabetic mice. Taken together, we concluded that valsartan may reduce atherothrombosis in diabetic conditions through AMPK/Egr-1 regulation.

Inhibitory effects of seaweed extracts on the growth of the vaginal bacterium Gardnerella vaginalis.

Of 44 species of seaweed screened for potential anti-Gardnerella vaginalis activity, 27 (61.4%) showed antimicrobial activity by the agar disk-diffusion method. Among them, the strongest activities against the pathogen were exhibited by Chlorophyta, with Ulva pertusa producing an 11.3-mm zone of inhibition at 5 mg disk⁻¹. The MIC values of U. pertusa extracts against both G. vaginalis KCTC 5096 and KCTC 5097, the main cause of vaginosis, were 312 µg ml⁻¹, while the MIC values against both Candida albicans KCTC 7270 and KCTC 7965, the main cause of candidiasis, were 2.5 mg ml⁻¹. Against Lactobacillus gasseri KCTC 3173 and Lactobacillus jensenii KCTC 5194, members of the normal vaginal microflora, no inhibitory effect was seen even at 10 mg ml⁻¹. To identify the primary active compounds, a U. pertusa powder was successively fractionated according to polarity, and the main active agents against G. vaginalis KCTC 5096 were determined to be nitrogenous compounds (156 µg ml⁻¹ of the MIC value). According to these results, it was suggested that extracts of the seaweed U. pertusa are valuable for the development of natural therapeutic agents for treating women with bacterial vaginosis.

Antibacterial effect of grapefruit seed extract (GSE) on Makgeolli-brewing microorganisms and its application in the preservation of fresh Makgeolli.

UNLABELLED: To develop a new preservation method, the antimicrobial activity of grapefruit seed extract (GSE) against Makgeolli-brewing microorganisms and food-borne pathogens was assessed, and a general analysis and sensory evaluation of fresh Makgeolli with added GSE was made. The minimum inhibitory concentration (MIC) values of GSE against 10 strains of Makgeolli-brewing microorganism were 0.0122 to 1.5625 µL/mL. The MIC values against 6 strains of food-borne pathogens were 0.0061 to 0.7813 µL/mL. On addition of 0.1% (v/v) and 0.2% GSE in bottled fresh Makgeolli, no significant difference in the pH, or the contents of total acids, ethanol, or methanol in the Makgeolli, were observed compared with control Makgeolli (with no GSE), during the preservation period (8 weeks) at 10 °C. In the Makgeolli with 0.1% and 0.2% GSE, the total bacterial counts decreased significantly by 4.9% (P < 0.01) and 11.2% (P < 0.001), respectively, versus the control. The decreases in yeast count were significantly lessened by 15.33% and 15.24% (both P < 0.001), respectively, after 8 weeks of storage, compared with the control. In the sensory evaluation of Makgeolli with 0.1% and 0.2% GSE, the refreshment and overall acceptability received significantly better scores than the control (P < 0.01), with no change in sweetness, bitterness, sourness, turbidity, color, or odor. These results suggest that GSE controls the growth of Makgeolli-brewing microorganisms and extends the shelf life (ca. 2 wk), without decreasing overall acceptance. PRACTICAL APPLICATION: A new preservation method for fresh Makgeolli by adding grapefruit seed extract (GSE) was developed. As fresh Makgeolli contains live microorganisms, the preservation period is 1 wk, which is relatively short. GSE controls the growth of Makgeolli-brewing and Makgeolli-spoiling microorganisms. 0.1% to 0.2% GSE is optimum for prolonging the shelf life (2 wk) of bottled fresh Makgeolli, and has no adverse effect on overall acceptability. We demonstrated that GSE is an effective natural additive that prolongs the shelf life of fresh Makgeolli with no significant loss in quality.

Seasonal variation of antibacterial activities in the green alga Ulva pertusa Kjellman.

The present study was performed to screen out the extracts of algae and assess the seasonal variation in antimicrobial activity of Ulva pertusa against Gardnerella vaginalis. Seasonal variation in antibacterial activity was observed, with the extracts showing no activity during summer and autumn, and showing antibacterial activity from early winter (December) to middle spring (April). The maximum value of antimicrobial activity (6.5 mm inhibition zone at 5 mg disk(-1)) of U. pertusa against G. vaginalis was observed in April. Otherwise, for both chlorophyll a and b, the highest content (2.87 mg g(-1) and 1.37 mg g(-1)) was observed in March 2009. These results may reflect variation in cellular chemical compositions such as secondary metabolite(s) rather than chlorophyll and biological activities according to season.

Single oral dose toxicity test of polycalcium, a mixed composition of polycan and calcium lactate-gluconate 1:9 (G/G) in SD rat.

The object of this study was to obtain acute oral toxicity information of Polycalcium, a mixed composition of Polycan and Calcium lactate-gluconate 1:9 (g/g), in Sprague-Dawely (SD) rats. In order to investigate the toxicity and identify target organs, Polycalcium were once orally administered to female and male SD rats at dose levels of 2000, 1000, 500 and 0 (control) mg/kg body weights. The mortality, changes on body weight and clinical signs were monitored during 14 days after treatment with gross observation, changes on the organ weights and histopathology of principle organs and treatment sites based on the recommendation of KFDA Guidelines [2009-116, 2009]. As the results of single oral treatment of Polycalcium, no treatment related mortalities were observed within 14 days after end of treatment up to 2000 mg/kg, the limited dosage of rodents in the both genders. In addition, no Polycalcium treatment related changes on the body and organ weights, clinical signs, necropsy and histopathological findings were detected. The results obtained in this study suggest that the Polycalcium is non-toxic in rats. The LD50 and approximate LD in rats after single oral dose of Polycalcium were considered over 2000 mg/kg in both female and male, respectively.

High glucose induces connective tissue growth factor expression and extracellular matrix accumulation in rat aorta vascular smooth muscle cells via extracellular signal-regulated kinase 1/2.

Connective tissue growth factor (CTGF) is a potent pro-fibrotic factor, which is implicated in fibrosis through extracellular matrix (ECM) induction in diabetic cardiovascular complications. It is an important downstream mediator in the fibrotic action of transforming growth factor ß (TGFß) and is potentially induced by hyperglycemia in human vascular smooth muscle cells (VSMCs). Therefore, the goal of this study is to identify the signaling pathways of CTGF effects on ECM accumulation and cell proliferation in VSMCs under hyperglycemia. We found that high glucose stimulated the levels of CTGF mRNA and protein and followed by VSMC proliferation and ECM components accumulation such as collagen type 1, collagen type 3 and fibronectin. By depleting endogenous CTGF we showed that CTGF is indispensable for the cell proliferation and ECM components accumulation in high glucose-stimulated VSMCs. In addition, pretreatment with the MEK1/2 specific inhibitors, PD98059 or U0126 potently inhibited the CTGF production and ECM components accumulation in high glucose-stimulated VSMCs. Furthermore, knockdown with ERK1/2 MAPK siRNA resulted in significantly down regulated of CTGF production, ECM components accumulation and cell proliferation in high glucose-stimulated VSMCs. Finally, ERK1/2 signaling regulated Egr-1 protein expression and treatment with recombinant CTGF reversed the Egr-1 expression in high glucose-induced VSMCs. It is conceivable that ERK1/2 MAPK signaling pathway plays an important role in regulating CTGF expression and suggests that blockade of CTGF through ERK1/2 MAPK signaling may be beneficial for therapeutic target of diabetic cardiovascular complication such as atherosclerosis.

Novel silicificated PVAc/POSS composite nanofibrous mat via facile electrospinning technique: potential scaffold for hard tissue engineering.

This study presents the fabrication of novel porous silicificated PVAc/POSS composite nanofibers by facile electrospinning technique and the interaction of synthesized mats with simulated body fluid (SBF). The physicochemical properties of the electrospun composites were determined by scanning electron microscopy, energy dispersive X-ray spectroscopy, transmission electron microscopy, electron probe micro-analysis, X-ray diffraction and thermogravimetry analysis. To examine the in vitro cytotoxicity, mouse myoblast C2C12 cells were treated with pristine and composite nanofibrous mats and the viability of cells was analyzed by cell counting kit-8 assay at regular time intervals. Our results indicated the enhanced nucleation and the formation of apatite-like structures at the surface of silicificated PVAc/POSS during the incubation of electrospun mats in SBF solution. Cytotoxicity experiments designated that the myoblasts could attach to the composite after being cultured. We observed in the present study that PVAc/POSS nanofibrous mat could support cell adhesion and guide the spreading behavior of myoblasts. We conclude that the new electrospun silicificated PVAc/POSS composite scaffold with unique porous morphology have excellent biocompatibility. Consequently, our investigation results showed that the as-spun porous PVAc/POSS composite nanofibrous scaffold could be a potential substrate for the proliferation and mineralization of osteoblasts, enhancing bone regeneration. The biocomposite mats represent a promising biomaterial to be exploited for various tissue engineering applications such as guided bone regeneration.

Inhibition of oral pathogens and collagenase activity by seaweed extracts.

Fifty-seven species of common seaweed from the Coast of Korea were screened for antimicrobial (i.e. inhibition of Prevotella intermedia and Porphyromonas gingivalis growth) activity. As a source of bioactive compounds, seaweeds can produce many secondary metabolites with a variety of activities. Using the agar diffusion method, only 17 species (29.8%) showed inhibitory activity. Of these, methanol extracts of Enteromorpha linza, Sargassum sagamianum, and Ulva pertusa showed strong inhibitory effects against both P. intermedia and P. gingivalis. The MIC values of E. linza, S. sagamianum, and U. pertusa extracts against P. intermedia were 625, 78 and 625 microg ml(-1) and those against P. gingivalis were 312, 156 and 625 microg ml(-1), respectively. When these three species' extracts were separated into five fractions according to their polarity, the main active agents were determined to be phenolic compounds. We then compared the antimicrobial activities of these phenolic compounds against various periodontal pathogens using a MIC test. Phenolic compound containing extracts at concentrations of 10 to 100 microg ml(-1) showed a moderate to significant inhibitory effect on collagenase 1,2 and 3 activity.

Higenamine reduces HMGB1 during hypoxia-induced brain injury by induction of heme oxygenase-1 through PI3K/Akt/Nrf-2 signal pathways.

Growing lines of evidence suggests that high mobility group box-1 (HMGB1) plays an important role for promoting inflammation and apoptosis in brain ischemia. Previously, we demonstrated that inducers of heme oxygenase-1 (HO-1) significantly reduce HMGB1 release in inflammatory conditions in vitro and in vivo. Thus, we tested our hypothesis that higenamine protects brain injury by inhibition of middle cerebral artery occlusion (MCAO)-mediated HMGB1 release in vivo, and glucose/glucose oxidase (GOX)-induced apoptosis in C6 cells in vitro due to HO-1 induction. Higenamine increased HO-1 expression in C6 cells in both hypoxia and normoxia, in which the former was much more significant than the latter. Higenamine increased Nrf-2 luciferase activity, translocated Nrf-2 to nucleus, and increased phosphorylation of Akt in C6 cells. Consistent with this, LY 294002, a PI3K inhibitor, inhibited HO-1 induction by higenamine and apoptosis induced by glucose/GOX in C6 cells was prevented by higenamine, which effect was reversed by LY 294002. Importantly, administration of higenamine (i.p) significantly reduced brain infarct size, mortality rate, MPO activity and tissue expression of HMGB1 in MCAO rats. In addition, recombinant high mobility group box 1 induced apoptosis in C6 cells by increasing ratio of Bax/bcl-2 and cleaved caspase c, which was inhibited by higenamine, and all of these effects were reversed by co-treatment with ZnPPIX. Therefore, we conclude that higenamine, at least in part, protects brain cells against hypoxic damages by up-regulation of HO-1. Thus, higenamine may be beneficial for the use of ischemic injuries such as stroke.

Indigo carmine enhances phenylephrine-induced contractions in an isolated rat aorta.

BACKGROUND: The intravenous administration of indigo carmine has been reported to produce transiently increased blood pressure in patients. The goal of this in vitro study was to examine the effect of indigo carmine on phenylephrine-induced contractions in an isolated rat aorta and to determine the associated cellular mechanism with particular focus on the endothelium-derived vasodilators. METHODS: The concentration-response curves for phenylephrine were generated in the presence or absence of indigo carmine. Phenylephrine concentration-response curves were generated for the endothelium-intact rings pretreated independently with a nitric oxide synthase inhibitor, N(ω)-nitro-L-arginine methyl ester (L-NAME), a cyclooxygenase inhibitor, indomethacin, and a low-molecular-weight superoxide anion scavenger, tiron, in the presence or absence of indigo carmine. The fluorescence of oxidized dichlorofluorescein was measured in rat aortic vascular smooth muscle cells cultured in the control, indigo carmine alone and tiron plus indigo carmine. RESULTS: Indigo carmine (10(-5) M) increased the phenylephrine-induced maximum contraction in the endothelium-intact rings with or without indomethacin, whereas indigo carmine produced a slight leftward shift in the phenylephrine concentration-response curves in the endothelium-denuded rings and L-NAME-pretreated endothelium-intact rings. In the endothelium-intact rings pretreated with tiron (10(-2) M), indigo carmine did not alter phenylephrine concentration-response curves significantly. Indigo carmine (10(-5) M) increased the fluorescence of oxidized dichlorofluorescein in the vascular smooth muscle cells, whereas tiron abolished the indigo carmine-induced increase in oxidized dichlorofluorescein fluorescence. CONCLUSIONS: Indigo carmine increases the phenylephrine-induced contraction mainly through an endothelium-dependent mechanism involving the inactivation of nitric oxide caused by the increased production of reactive oxygen species.

ß1-adrenergic receptor-mediated HO-1 induction, via PI3K and p38 MAPK, by isoproterenol in RAW 264.7 cells leads to inhibition of HMGB1 release in LPS-activated RAW 264.7 cells and increases in survival rate of CLP-induced septic mice.

High mobility group box (HMGB)-1 plays an important role in sepsis-associated death in experimental studies. Heme oxygenase-1 (HO-1) inducers were reported to reduce HMGB1 release in experimental sepsis. Previously, we reported on the importance of the ß1-adrenergic receptor and protein kinase A pathway in the regulation of HO-1 expression by isoproterenol (ISO) in RAW 264.7 cells. We investigated whether ISO reduces HMGB1 release in LPS-activated RAW 264.7 cells and improves survival rate in septic mice due to HO-1 induction. ISO concentration-dependently increased HO-1 via Nrf-2 translocation and inhibited release of HMGB1 through the ß1-adrenergic receptor (ß1-AR) in LPS-activated RAW 264.7 cells. This conclusion was supported by the finding that dobutamine but not salbutamol increased HO-1 expression in both RAW 264.7 cells. ISO failed to inhibit HMGB1 release when HO-1 expression was suppressed by ZnPPIX, an HO-1 inhibitor in RAW 264.7 cells. ISO significantly inhibited phosphorylation of IκB-α and NF-κB-driven luciferase activity in LPS-activated RAW 264.7 cells. In addition, LY294002, a PI3K inhibitor, and SB203580, a p38 MAPK inhibitor, significantly inhibited not only HO-1 induction but also HMGB1 release by ISO. Importantly, ISO increased HO-1 protein expression in heart and lung tissues, reduced HMGB1 in plasma and increased survival rate in CLP-treated septic mice, which was significantly reversed by co-treatment with ZnPPIX. Taken together, we conclude that inhibition of HMGB1 release during sepsis via ß1-AR-mediated HO-1 induction is a novel mechanism for the beneficial effects of ISO in the treatment of sepsis.