Time-dependent effect of inhaled cigarette smoke exposure in the bleomycin-induced lung injury rat model.

Cigarette smoke (CS) substances are known to induce diverse ailments such as cancer, decreased immunity, and lung diseases. Although some studies have been actively conducted to evaluate cigarette toxicity, the current animal exposure methods, that is, exposure of 28- or 90-days, require considerable research cost and lead to obscure results of the CS effects. In a previous study, we compared the effects of CS in a rat model of bleomycin (BLM) and lipopolysaccharide (LPS) induced lung disease. We determined that compared to the LPS-induced rat model, the BLM-induced rat model was more sensitive to alterations in secreting cytokines and total cell number. In the current study, we further confirmed the time-point of effective inhalation exposure by CS in the BLM-induced lung injury rat model. Using an automatic video instillator, rats were administered a single dose of 2.5 mg/kg BLM (day 1), and subsequently exposed to CS via inhalation (nose-only) 4 h/day, for 1, 2, 3, and 4 weeks. The bronchoalveolar lavage fluid (BALF) was obtained from the right lung lobes, total cell numbers were counted, and chemokine and cytokine expressions were evaluated using Enzyme-Linked Immunosorbent Assay. For the 1-week exposure, we observed a greater increase of neutrophils in the BLM + CS 300 µg/L group than in the BLM or CS 300 µg/L groups. Exposure of CS in the BLM-induced lung injury rat model enhanced the secretions of chemokines and cytokines, such as CCL2/MCP-1, CXCL2/MIP-2 and TNF-α, at 1 week. Immunohistochemistry and Hematoxylin and Eosin staining of lungs at 1-2 weeks after exposure clearly confirmed this tendency in the increased levels of CCL2/MCP-1 and TNF-α. Taken together, these results indicate that the rat model of BLM-induced lung injury is more sensitive to CS exposure than other rat models, and may be an appropriate model to evaluate the effect of CS exposure at 1-2 weeks.

Discovery of a novel highly potent broad-spectrum heterocyclic chemical series of arenavirus cell entry inhibitors.

We identified and explored the structure-activity relationship (SAR) of a novel heterocyclic chemical series of arenavirus cell entry inhibitors. Optimized lead compounds, including diphenyl-substituted imidazo[1,2-a]pyridines, benzimidazoles, and benzotriazoles exhibited low to sub-nanomolar potency against both pseudotyped and infectious Old and New World arenaviruses, attractive metabolic stability in human and most nonhuman liver microsomes as well as a lack of hERG K + channel or CYP enzyme inhibition. Moreover, the straightforward synthesis of several lead compounds (e.g., the simple high yield 3-step synthesis of imidazo[1,2-a]pyridine 37) could provide a cost-effective broad-spectrum arenavirus therapeutic that may help to minimize the cost-prohibitive burdens associated with treatments for emerging viruses in economically challenged geographical settings.

Carnosine Protects against Cerebral Ischemic Injury by Inhibiting Matrix-Metalloproteinases.

Stroke is one of the leading causes of death and disability worldwide. However, treatment options for ischemic stroke remain limited. Matrix-metalloproteinases (MMPs) contribute to brain damage during ischemic strokes by disrupting the blood-brain barrier (BBB) and causing brain edemas. Carnosine, an endogenous dipeptide, was found by us and others to be protective against ischemic brain injury. In this study, we investigated whether carnosine influences MMP activity. Brain MMP levels and activity were measured by gelatin zymography after permanent occlusion of the middle cerebral artery (pMCAO) in rats and in vitro enzyme assays. Carnosine significantly reduced infarct volume and edema. Gelatin zymography and in vitro enzyme assays showed that carnosine inhibited brain MMPs. We showed that carnosine inhibited both MMP-2 and MMP-9 activity by chelating zinc. Carnosine also reduced the ischemia-mediated degradation of the tight junction proteins that comprise the BBB. In summary, our findings show that carnosine inhibits MMP activity by chelating zinc, an essential MMP co-factor, resulting in the reduction of edema and brain injury. We believe that our findings shed new light on the neuroprotective mechanism of carnosine against ischemic brain damage.

Reproductive and developmental toxicity screening of polyhexamethylene guanidine phosphate by oral gavage in rats.

Polyhexamethylene guanidine phosphate (PHMG-P) has effective antimicrobial activity against various microorganisms and has been widely used as a biocide in commercial products. However, its use as a humidifier disinfectant has provoked fatal idiopathic lung disease in South Korea, especially in pregnant or postpartum women and their young children. PHMG-P-related toxicological studies of reproduction and development in experimental animals have not been identified, and thus, we investigated the potential effects of early-stage oral exposure to PHMG-P by assessing its toxicological properties. PHMG-P was repeatedly administered by oral gavage at dose levels of 0, 13, 40 and 120 mg/kg to Sprague-Dawley rats during the pre-mating, mating, gestation and early lactation periods, and then general systemic and reproductive/developmental toxicities were investigated. At 120 mg/kg, PHMG-P-related toxicities including subdued behavior, thin appearance, decreased body weight, decreased food consumption and decreased F1 pup body weight were observed. Based on the results of this study, the no-observed-adverse-effect levels (NOAELs) of PHMG-P for both general systemic effects and development are considered to be 40 mg/kg/day.

Inhibitory Effects of a Novel Chrysin-Derivative, CPD 6, on Acute and Chronic Skin Inflammation.

The skin is an important physiological barrier against external stimuli, such as ultraviolet radiation (UV), xenobiotics, and bacteria. Dermal inflammatory reactions are associated with various skin disorders, including chemical-induced irritation and atopic dermatitis. Modulation of skin inflammatory response is a therapeutic strategy for skin diseases. Here, we synthesized chrysin-derivatives and identified the most potent derivative of Compound 6 (CPD 6). We evaluated its anti-inflammatory effects in vitro cells of macrophages and keratinocytes, and in vivo dermatitis mouse models. In murine macrophages stimulated by lipopolysaccharide (LPS), CPD 6 significantly attenuated the release of inflammatory mediators such as nitric oxide (NO) (IC50 for NO inhibition: 3.613 µM) and other cytokines. In cultured human keratinocytes, CPD 6 significantly attenuated the release of inflammatory cytokines induced by the combination of IFN-γ and TNF-α, UV irradiation, or chemical irritant stimulation. CPD 6 inhibited NFκB and JAK2/STAT1 signaling pathways, and activated Nrf2/HO-1 signaling. In vivo relevancy of anti-inflammatory effects of CPD 6 was observed in acute and chronic skin inflammation models in mice. CPD 6 showed significant anti-inflammatory properties both in vitro cells and in vivo dermatitis animal models, mediated by the inhibition of the NFκB and JAK2-STAT1 pathways and activation of Nrf2/HO-1 signaling. We propose that the novel chrysin-derivative CPD 6 may be a potential therapeutic agent for skin inflammation.

Methylglyoxal induced advanced glycation end products (AGE)/receptor for AGE (RAGE)-mediated angiogenic impairment in bone marrow-derived endothelial progenitor cells.

Endothelial cells (ECs) maintain the structure and function of blood vessels and are readily exposed to exogenous and endogenous toxic substances in the circulatory system. Bone marrow-derived endothelial progenitor cells (EPCs) circulate in the blood and differentiate to EC, which are known to participate in angiogenesis and regeneration of injured vessels. Dysfunction in EPC contributes to cardiovascular complications in patients with diabetes, but the precise molecular mechanisms underlying diabetic EPC abnormalities are not completely understood. The aim of this study was to investigate the mechanisms underlying diabetic EPC dysfunction using methylglyoxal (MG), an endogenous toxic diabetic metabolite. Data demonstrated that MG decreased cell viability and protein expression of vascular endothelial growth factor receptor (VEGFR)-2 associated with functional impairment of tube formation in EPC. The generation of advanced glycation end (AGE) products was increased in EPC following exposure to MG. Blockage of receptor for AGE (RAGE) by FPS-ZM1, a specific antagonist for RAGE, significantly reversed the decrease of VEGFR-2 protein expression and angiogenic dysfunction in MG-incubated EPC. Taken together, data demonstrated that MG induced angiogenic impairment in EPC via alterations in the AGE/RAGE-VEGFR-2 pathway which may be utilized in the development of potential therapeutic and preventive targets for diabetic vascular complications.

Effect of mirror use on lower extremity muscle strength of patients with chronic stroke.

[Purpose] This study examines the effect on muscle strength of lower extremity muscle strength exercise while using a mirror on the non-paretic side in patients with chronic stroke. [Subjects and Methods] Subjects were randomly assigned to a non-mirror lower extremity exercise group (n=10), a mirror lower extremity exercise group (n=10), or a mirror lower extremity muscle strength exercise group (n=10). Subjects were asked to do the exercise assigned to their group (5 sets 30 times a day, 5 times weekly for 4 weeks) with general physical therapy in the hospital. Muscle strength in the knee extensor and flexor of paretic and non-paretic side were measured using electrical muscle testing device before and after the intervention. [Results] Muscle strength significantly increased within each group after intervention. No significant differences were found among the three groups. [Conclusion] This study showed that the lower extremity muscle strength exercise of the non-paretic side using a mirror has a positive effect on muscle strength in patient with chronic stroke.

Study on the design development of a multi joint ankle foot orthosis.

[Purpose] The purpose of this study was to investigate the effects of a newly designed multi joint ankle-foot orthosis on the gait and dynamic balance of stroke patients having foot drop. [Participants and Methods] This study was investigated 10 participants who were diagnosed with stroke. Patients were evaluated based on a 10-meter walk test, timed up and go test and Berg balance scale after each participant wore a plastic ankle-foot orthosis and a multi joint ankle-foot orthosis (AFO) that consisted of orthosis joints (having poster-stop joint and Klenzak joint functions). [Results] The 10-meter walk test, timed up and go test and Berg balance scale showed significant differences in the orthosis with the Klenzak joint function. [Conclusion] The appropriate use of Klenzak AFO of the newly designed multi joint AFO is expected to have a positive effect on improving the gait and balancing ability of stroke patients having foot drop.

The relationship between anterior pelvic tilt and gait, balance in patient with chronic stroke.

[Purpose] The aim of this study is to find out the association between anterior pelvic tilt and gait and balance in chronic stroke. [Subjects and Methods] Fourteen chronic stroke patients were included in this study. A palpation meter was employed to measure the anterior inclination of the pelvis. A GAITRite system automates measuring temporal and spatial gait parameters. A 10-Meter Walk test was used to measure gait speed. The Timed Up and Go test was used to measure the dynamic balance ability and gait ability of the participants. A BioRescue was used to assess balance by measuring the moving distance and area of the center of pressure. [Results] There were significant negative correlations between pelvic anterior tilt and velocity, step length, and stride. There were significant positive correlations between velocity and cadence, step length, and stride length. There were significant negative correlations between velocity and cycle time, H-H base, TUG, and 10MWT. There was significant negative correlation between cadence and cycle time and H-H base. [Conclusion] This study showed a negative correlation between pelvic anterior tilt and gait function including gait speed and step length.

Selenium-binding protein 1: a sensitive urinary biomarker to detect heavy metal-induced nephrotoxicity.

Identifying novel biomarkers to detect nephrotoxicity is clinically important. Here, we attempted to identify new biomarkers for mercury-induced nephrotoxicity and compared their sensitivity to that of traditional biomarkers in animal models. Comparative proteomics analysis was performed in kidney tissues of Sprague-Dawley rats after oral treatment with HgCl2 (0.1, 1, or 5 mg/kg/day) for 21 days. Kidney cortex tissues were analyzed by two-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization, and differentially expressed proteins were identified. The corresponding spots were quantitated by RT-PCR. Selenium-binding protein 1 (SBP1) was found to be the most markedly upregulated protein in the kidney cortex of rats after HgCl2 administration. However, blood urea nitrogen, serum creatinine, and glucose levels increased significantly only in the 1 or 5 mg/kg HgCl2-treated groups. A number of urinary excretion proteins, including kidney injury molecule-1, clusterin, monocyte chemoattractant protein-1, and ß-microglobulin, increased dose-dependently. Histopathological examination revealed severe proximal tubular damage in high-dose (5 mg/kg) HgCl2-exposed groups. In addition, urinary excretion of SBP1 significantly increased in a dose-dependent manner. To confirm the critical role of SBP1 as a biomarker for nephrotoxicity, normal kidney proximal tubular cells were treated with HgCl2, CdCl2, or cisplatin for 24 h. SBP1 levels significantly increased in conditioned media exposed to nephrotoxicants, but decreased in cell lysates. Our investigations suggest that SBP1 may play a critical role in the pathological processes underlying chemical-induced nephrotoxicity. Thus, urinary excretion of SBP1 might be a sensitive and specific biomarker to detect early stages of kidney injury.

Immediate Effects of Ankle Balance Taping with Kinesiology Tape for Amateur Soccer Players with Lateral Ankle Sprain: A Randomized Cross-Over Design.

BACKGROUND The objective of this study was to investigate the immediate effect on gait function when ankle balance taping is applied to amateur soccer players with lateral ankle sprain. MATERIAL AND METHODS A cross-over randomized design was used. Twenty-two soccer players with an ankle sprain underwent 3 interventions in a random order. Subjects were randomly assigned to ankle balance taping, placebo taping, and no taping groups. The assessment was performed using the GAITRite portable walkway system, which records the location and timing of each footfall during ambulation. RESULTS Significant differences were found in the velocity, step length, stride length, and H-H base support among the 3 different taping methods (p<0.05). The ankle balance taping group showed significantly greater velocity, step length, and stride length in comparison to the placebo and no taping group. The ankle balance taping group showed a statistically significant decrease (p<0.05) in the H-H base support compared to the placebo and no taping groups, and the placebo group showed significantly greater velocity in comparison to the no taping group (p<0.05). CONCLUSIONS We conclude that ankle balance taping that uses kinesiology tape instantly increased the walking ability of amateur soccer players with lateral ankle sprain. Therefore, ankle balance taping is a useful alternative to prevent and treat ankle sprain of soccer players.

Effects of the Bad Ragaz Ring Method on muscle activation of the lower limbs and balance ability in chronic stroke: A randomised controlled trial.

BACKGROUND: Recovery of balance and walking abilities is important for the rehabilitation of stroke patients. OBJECTIVES: To evaluate the effects of the Bad Ragaz Ring method on functional recovery in chronic stroke patients. METHODS: Twenty-two chronic stroke patients were randomly assigned to two groups: a Bad Ragaz Ring method group (the experimental group) or a control group. Stroke patients in the experimental group underwent Bad Ragaz Ring exercise and comprehensive rehabilitation therapy, whereas patients in the control group underwent comprehensive rehabilitation therapy alone. The participants in both groups received therapy 3 days per week for 6 weeks. Muscle activations, balance indices, and Timed Up and Go test results were assessed before and after the 6-week therapy period. RESULTS: The experimental group showed significant improvements in activations of tibialis anterior and gastrocnemius muscles, balance index, and Timed Up and Go test results as compared with preintervention results (p < 0.05), whereas the control group showed significant improvement in Timed Up and Go test (p < 0.05). Significant differences in posttraining gains in the activations of tibialis anterior and gastrocnemius muscles and in balance index were observed between the experimental and control groups (p < 0.05). Effect sizes for gains in the experimental and control groups were strong for tibialis anterior and gastrocnemius muscles (effect sizes, 1.04 and 1.45 respectively). CONCLUSION: The Bad Ragaz Ring method may be beneficial for improving balance and leg muscle activation of chronic stroke patients.

Immediate effect of ankle balance taping on dynamic and static balance of soccer players with acute ankle sprain.

[Purpose] This study aimed to evaluate the immediate effect of ankle balance taping on balance ability of soccer players with acute ankle sprain. [Subjects and Methods] This study was conducted with 16 subjects who were diagnosed with ankle sprain. A cross-over randomized design was used. Each subject performed three interventions in a random order. Subjects were randomly assigned to an ankle balance taping, placebo taping, and no taping. For dynamic and static balance, ability was measured using BIORescue (RM Ingenierie, Rodes, France). Limit of stability, sway length and sway speed for one minute were measured. [Results] The Limit of Stability, Sway length and Sway speed differed significantly among the three different taping methods. [Conclusion] In this study, we found that ankle balance taping was effective in terms of improving balance ability of soccer players with an ankle sprain.

The effect of newly designed multi joint ankle foot orthosis on the gait and dynamic balance of stroke patients with foot drop.

[Purpose] The purpose of this study is to investigate the effect of the newly designed multi joint ankle-foot orthosis on the gait and dynamic balance of stroke patients having foot drop. [Subjects and Methods] This study was conducted with 15 subjects who were diagnosed with stroke. 10-meter walk test, functional reaching test and timed up and go test were measured after each subjects wore a plastic ankle-foot orthosis and a multi joint ankle-foot orthosis that consists of orthosis joints (having free joint, anterior-stop joint, poster-stop joint, and Klenzak joint functions). In the case of the newly developed multi joint ankle-foot orthosis, the experiments were performed using posterior-stop joint and Klenzak joint. [Results] 10-meter walk test, functional reaching test and timed up and go test showed significant differences in the orthosis using posterior joint-stop function and Klenzak joint function. [Conclusion] The appropriate use of the four functions of the newly designed multi joint ankle-foot orthosis is expected to have a positive effect on improving the gait and balancing ability of stroke patients having foot drop.

Immediate effects of ankle eversion taping on dynamic and static balance of chronic stroke patients with foot drop.

[Purpose] This study evaluates the immediate effect of ankle eversion taping on dynamic and static balance of chronic stroke patients with foot drop. [Subjects and Methods] This study was conducted with nine subjects who were diagnosed with stroke. A cross-over randomized design was used. Each subject performed three interventions in a random order. Subjects were randomly assigned to an ankle everion taping, placebo taping, and no taping. For dynamic and static balance, ability was measured using BIO Rescue. Limit of stability, sway length and sway speed for one minute were measured. [Results] The Limit of Stability, Sway length and Sway speed differed significantly among the three different taping methods. [Conclusion] We conclude that ankle eversion taping that uses kinesiology tape instantly increases the dynamic and static balance ability of chronic stroke patients with foot drop.

The effects of visual biofeedback using ultrasonograpy on deep trunk muscle activation.

[Purpose] The objective of this study is to investigate the effect of visual biofeedback using ulatrasonography on the functional improvement of deep trunk muscle. [Subjects and Methods] This study selected ten healthy people without orthopedic history and information on the study. The average ages, heights, and weights were 22.70 ± 2.06 years old, 171.15 ± 9.18 cm, and 66.86 ± 8.88 kg in the experimental group, respectively. The abdominal drawing-in maneuver were executed for subjects through monitoring the status of muscle contraction using ultrasonic waves. And motor control exercises were performed during 6 weeks, 20 minutes/day and three times/week. We collected the data using electromyography MP150 system (BIOPAC system Inc., CA, USA) in order to measure trunk muscle activation. [Results] The subjects showed significant improvements in Internal oblique abdominis and lumbar multifidus muscle after intervention. [Conclusion] Visual biofeedback training using ultrasonography might be effective in improving function of the deep trunk muscle.

Immediate effects of forearm elastic and nonelastic taping on wrist flexor muscle and grip strength of normal adults.

[Purpose] The purpose of this study was to examine the effects of forearm elastic taping on grip and wrist flexor muscle strength. [Subjects and Methods] This was a single-blind, crossover study. This study selected 40 healthy subjects with no history of orthopedic disorders and was conducted after consent to participate was obtained. Grip and wrist flexor muscle strength of subjects were assessed by a handheld dynamometer and a Commander Muscle Tester, respectively, with forearm elastic taping or nonelastic taping. [Results] After application of forearm elastic taping, grip strength and wrist flexor muscle strength significantly increased compared with the nonelastic taping group. [Conclusion] Application of forearm elastic taping is considered to have positive effects on improving wrist and grip strength.

Effects of lumbopelvic sling and abdominal drawing-in exercises on lung capacity in healthy adults.

[Purpose] To examine the effects of lumbopelvic sling and abdominal drawing-in exercises on the lung capacities of healthy subjects. [Subjects and Methods] Twenty-nine healthy subjects with no orthopedic history of the back were recruited. Subjects were randomly assigned to a experimental group and control group. Subjects were allocated to one of two groups; an experimental group that underwent lumbopelvic sling and abdominal drawing-in exercises and a control group that underwent treadmill and abdominal drawing-in exercises. Lung capacities were evaluated 4 weeks after exercises. [Results] The experimental group showed significant increments in EV, ERV, IRV, VT vs. pre-intervention results, and the control group showed significant increments in the EVC and IRV. Significant intergroup differences were observed in terms of post-training gains in EVC, IRV, and VT. [Conclusion] Combined application of lumbopelvic sling and abdominal drawing-in exercises were found to have a positive effect on lung capacity.

Discovery of a new series of potent prostacyclin receptor agonists with in vivo activity in rat.

The design and synthesis of two closely related series of prostacyclin receptor agonist compounds that showed excellent human IP receptor potency and efficacy is described. Compounds from this series showed in vivo activity after SC dosing in the monocrotaline model of PAH in rat.

Protective activity of Dendropanax morbifera against cisplatin-induced acute kidney injury.

BACKGROUND/AIMS: Drug-induced acute kidney injury (AKI) has been a severe threat to hospitalized patients, raising the urgent needs to develop strategies to reduce AKI. We investigated the protective activity of Dendropanax morbifera (DP), a medicinal plant which has been widely used to treat infectious and pain diseases, on acute kidney injury (AKI) using cisplatin-induced nephropathic models. METHODS: Both in vitro renal tubular cells (NRK-52E) and in vivo rat models were used to demonstrate the nephroprotective effect of DP. RESULTS: Methanolic extract from DP significantly reduced cisplatin-induced toxicity in renal tubular cells. Through successive liquid extraction, the extract of DP was separated into n-hexane, CHCl3, EtOAc, n-BuOH, and H2O fractions. Among these, the CHCl3 fraction (DPCF) was found to be most potent. The protective activity of DPCF was found to be mediated through anti-oxidant, mitochondrial protective, and anti-apoptotic activities. In in vivo rat models of AKI, treatment with DPCF significantly reversed the cisplatin-induced increase in blood urea nitrogen and serum creatinine and histopathologic damage, recovered the level of anti-oxidant enzymes, and inhibited renal apoptosis. CONCLUSION: We demonstrated that DP extracts decreased cisplatin-induced renal toxicity, indicating its potential to ameliorate drug-associated acute kidney damage.