25C-NBF, a new psychoactive substance, has addictive and neurotoxic potential in rodents.

The use of new psychoactive substances (NPSs) as a substitute for illegal drugs is increasing rapidly and is a serious threat to public health. 25C-NBF is a newly synthesized phenethylamine-type NPS that acts as a 5-hydroxyindoleacetic acid (5-HT) receptor agonist, but little is known about its pharmacological effects. Considering that NPSs have caused unexpected harmful effects leading to emergency and even death, scientific confirmation of the potential adverse effects of 25C-NBF is essential. In the present study, we investigated whether 25C-NBF has addictive and neurotoxic potential and causes neurochemical changes. In addictive potential assessments, high conditioned place preference (CPP) scores and stable self-administration (SA) were observed in the 25C-NBF groups (CPP [3 mg kg-1]; SA [0.01, 0.03, 0.1 mg kg-1]), suggesting the addictive liability of 25C-NBF. In neurotoxic potential assessments, 25C-NBF treatment (single super-high dose [1 × 15, 30, 40 mg kg-1]; repeated high dose [4 × 8, 15, 30 mg kg-1]) resulted in reduced motor activity (open field test), abnormal motor coordination (rota-rod test) and impaired recognition memory (novel object recognition test), suggesting that 25C-NBF is neurotoxic leading to motor impairment and memory deficits. Subsequently, immunohistochemistry showed that 25C-NBF treatment decreased tyrosine hydroxylase (TH) expression and increased ionized calcium-binding adapter molecule 1 (Iba-1) expression in the striatum. Taken together, our results clearly demonstrate the dangers of recreational use of 25C-NBF, and we suggest that people stop using 25C-NBF and other NPSs whose pharmacological effects are not precisely known.

Lespedeza bicolor Extract Improves Amyloid Beta25 - 35-Induced Memory Impairments by Upregulating BDNF and Activating Akt, ERK, and CREB Signaling in Mice.

Lespedeza bicolor, a traditional herbal medicine widely used in Australia, North America, and Eastern Asia, has various therapeutic effects on inflammation, nephritis, hyperpigmentation, and diuresis. In this study, to evaluate the effects of L. bicolor on cognitive function, we examined whether L. bicolor improved amyloid beta-induced memory impairment and assessed the possible mechanisms in mice. Catechin, rutin, daidzein, luteolin, naringenin, and genistein were identified in the powdered extract of L. bicolor by HPCL-DAD analyses. In behavioral experiments, L. bicolor (25 and 50 mg/kg, p. o.) significantly improved amyloid beta25 - 35 (6 nmol, intracerebroventricular)-induced cognitive dysfunction in the Y-maze, novel recognition, and passive avoidance tests. Our molecular studies showed L. bicolor (25 and 50 mg/kg, p. o.) significantly recovered the reduced glutathione content as well as increased thiobarbituric acid reactive substance and acetylcholinesterase activities in the hippocampus. Furthermore, we found that L. bicolor significantly increased the expression of brain-derived neurotrophic factor, and phospho-Akt, extracellular signal-regulated kinase, and cAMP response element binding caused by amyloid beta25 - 35 in the hippocampus. In conclusion, L. bicolor exerts a potent memory-enhancing effect on cognitive dysfunction induced by amyloid beta25 - 35 in mice.

Resveratrol Induces Mitochondrial Apoptosis and Inhibits Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma Cells.

OSCC is the most common malignant cancer of the head and neck. EMT is an essential cellular process critical to the morphogenesis and homeostasis of solid tissues. It is also involved in the initial stage of cancer metastasis and invasion in which cells lose epithelial characteristics. While cancer therapy protocols such as surgery, radiation, and chemotherapy are effective and useful, the drug tolerance and toxicity of OSCC patients remain a problem. Resveratrol is mainly produced in red grape skin and exhibits anti-oxidative, anti-inflammatory, anti-proliferative, and anti-cancer properties. This study was undertaken to investigate the underlying mechanisms giving rise to the induction of apoptosis by resveratrol in the human tongue squamous cell carcinoma cell line. Resveratrol treatment resulted in a time- and dose-dependent decrease in cell viability and increased the apoptotic cell ratio in CAL-27, SCC15, and SCC25 cells. Resveratrol treatment of CAL-27 cells showed that several lines of apoptotic manifestation and decreased cell migration, invasion, and EMT-inducing transcription factor. Taken together, our findings demonstrate the inhibitory effect of resveratrol in human OSCC cells via the mitochondrial pathway and that resveratrol is able to inhibit cell invasion and migration by inhibiting the EMT-inducing transcription factors.

The role of kaempferol-induced autophagy on differentiation and mineralization of osteoblastic MC3T3-E1 cells.

BACKGROUND: Kaempferol, a kind of flavonol, has been reported to possess various osteogenic biological activities, such as inhibiting bone resorption of osteoclasts and promoting the differentiation and mineralization of preosteoblasts. However, the precise cellular mechanism of action of kaempferol in osteogenesis is elusive. Autophagy is a major intracellular degradation system, which plays an important role in cell growth, survival, differentiation and homeostasis in mammals. Recent studies showed that autophagy appeared to be involved in the degradation of osteoclasts, osteoblasts and osteocytes, potentially pointing to a new pathogenic mechanism of bone homeostasis and bone marrow disease. The potential correlation between autophagy, osteogenesis and flavonoids is unclear. METHODS: The present study verified that kaempferol promoted osteogenic differentiation and mineralization and that it elevated osteogenic gene expression based on alkaline phosphatase (ALP) activity, alizarin red staining and quantitative PCR. And then we found that kaempferol induced autophagy by acridine orange (AO) and monodansylcadaverine (MDC) staining and autophagy-related protein expression. The correlation between kaempferol-induced autophagy and the osteogenic process was confirmed by the autophagy inhibitor 3-methyladenine (3-MA). RESULTS: Kaempferol promoted the proliferation, differentiation and mineralization of osteoblasts at a concentration of 10 µM. Kaempferol showed cytotoxic properties at concentrations above 50 µM. Concentrations above 10 µM decreased ALP activity, whereas those up to 10 µM increased ALP activity. Kaempferol at concentrations up to 10 µM also increased the expression of the osteoblast- activated factors RUNX-2, osterix, BMP-2 and collagen I according to RT-PCR analyses. 10 µM or less, the higher of the concentration and over time, kaempferol promoted the activity of osteoblasts. Kaempferol induced autophagy. It also increased the expression of the autophagy-related factors beclin-1, SQSTM1/p62 and the conversion of LC3-II from LC3-I. The application of 3-MA decreased the activity of ALP and the autophagy induced by kaempferol. In the RT-PCR analysis, the expression of RUNX-2, osterix, BMP-2 and collagen I was decreased. CONCLUSION: The present study showed that kaempferol stimulated the osteogenic differentiation of cultured osteoblasts by inducing autophagy.

Influences of Playfulness on Smartphone Dependency among Upper Grades of Korean Elementary Schoolers.

A paucity of research has addressed the relationship between each psychological construct of playfulness and smartphone dependency, and the purpose of this research is to understand how each psychological construct of playfulness, including physical animation, social engagement, mental spontaneity, emotional fluidity, and humorous perspective playfulness, influences smartphone dependency of the upper grades of elementary schoolers. For this purpose, a total of 278 questionnaires was analyzed for descriptive, correlation, and multiple regression analysis. The correlation analysis showed that respondents' age positively and parents' education levels negatively correlates to smartphone dependency. The multiple regression analyses showed that physical animation playfulness and emotional fluidity playfulness negatively and social engagement playfulness positively influence smartphone dependency of the respondents. The findings indicate that to reduce smartphone dependency among elementary schoolers, physical animation and emotional fluidity playfulness need to be promoted. The findings also suggest that each component of playfulness has distinctive advantages and disadvantages of developmental processes in childhood, and more future research endeavors need to be directed to understand the role of playfulness in children's behaviors and cognitive processes.

Korean Red Ginseng inhibits methamphetamine addictive behaviors by regulating dopaminergic and NMDAergic system in rodents.

BACKGROUND: Methamphetamine (METH) is the most widely used psychostimulant and has been known to exhibit reinforcing effects even after long abstinence. We showed the inhibitory effect of Korean Red Ginseng extract (RGE) on METH-induced addictive behaviors in animal models mimicking the human drug-use pattern. METHODS: We first investigated the effect of RGE on the acquisition of METH-induced dependence using self-administration and conditioned place preference (CPP) tests. Additionally, further experiments such as METH-induced motivational behavior and seeking behavior were conducted. To study the underlying mechanism, dopamine receptor, dopamine transporter, and N-methyl-D-aspartate receptor were assessed through Western blot analysis. RESULTS: Treatment with RGE significantly reduced METH-induced self-administration on a fixed-ratio 1 schedule of reinforcement. It could be also decreased a progressive ratio schedule, and inhibited METH-primed reinstatement. In CPP, RGE significantly prevented the development of METH-induced CPP. Moreover, RGE not only shortened the withdrawal period clearly, but also prevented the reinstatement of CPP. RGE treatment also reversed METH-induced overexpression of dopamine transporter, dopamine receptor D1, and NMDA receptor in the nucleus accumbens. CONCLUSION: Our findings reflect that RGE has therapeutic potential to suppress METH-induced addictive behaviors by regulating dopaminergic and NMDAergic system.

Greater collagen deposition with the microneedle therapy system than with intense pulsed light.

BACKGROUND: Intense pulsed light (IPL) and the microneedle therapy system (MTS) are currently available for the treatment of scars. Greater collagen deposition has been proposed as a mechanism for the treatment of scars. OBJECTIVE: To compare the effects of IPL and MTS on collagen deposition. MATERIALS AND METHODS: Fifty-four imprinting control region mice were divided into three groups: untreated controls, treatment with IPL, and treatment with MTS. A single pass of IPL 10.5 J/cm(2) and five passes (total 15 strokes) of MTS were performed three times every 2 weeks. Four weeks after the last treatment, skin thickness measurements using a caliper, microscopic examination, Western blot analysis for type I collagen, and enzyme-linked immunosorbent assay for total collagen content were performed. RESULTS: Measured using calipers, MTS, resulted in greater skin thickness than IPL that paralleled the dermal thickness of the biopsied specimens. MTS also increased expression levels of type I collagen and total collagen content more than IPL. IPL effects were superior to control. CONCLUSION: MTS increased collagen deposition more than IPL, and MTS might be more effective than IPL for scar treatment. The authors have indicated no significant interest with commercial supporters.

Korean Red Ginseng reduces chronic social defeat stress-induced mood disorders via N-methyl-D-aspartate receptor modulation in mice.

BACKGROUND: A chronic social defeat stress (CSDS) model has been proposed as relevant to stress-induced behavioral change in humans. In this study, we examined the effect of Korean Red Ginseng (KRG) on CSDS-induced mood disorders and protein expression in an animal model. METHODS: To evaluate the effect of KRG on social defeat stress, test mice were exposed in the resident aggressor's home cage compartment for 14 days beginning 1 h after KRG treatment (10, 20, and 40 mg/kg, per oral (p.o.)). After the exposure, behavioral tests to measure anxiety, social interaction, and depression-like behavior were performed. To investigate the underlying mechanism, N-methyl-D-aspartate receptor expression levels in CSDS-induced mice were evaluated using Western blot analysis. RESULTS: CSDS induced anxiety-like behaviors by decreasing central activity in the open-field test and open-arm approach in the elevated plus maze test and led to social avoidance behavior in the social interaction test. CSDS mice showed upregulated NR1, NR2A, and NR2B expression in the hippocampus. KRG 20 and 40 mg/kg ameliorated anxiety-like activities and KRG 20 mg/kg alleviated social avoidance by decreasing time in the corner zone. KRG treatment recovered CSDS-induced NR1, NR2A, and NR2B protein levels in the hippocampus. CONCLUSION: These results indicate that KRG has a therapeutic effect on CSDS-induced mood disorder by alleviating N-methyl-D-aspartate receptor overexpression in the hippocampus.

Methoxphenidine (MXP) induced abnormalities: Addictive and schizophrenia-related behaviours based on an imbalance of neurochemicals in the brain.

BACKGROUND AND PURPOSE: Methoxphenidine is a dissociative-based novel psychoactive designer drug. Although fatal accidents from methoxphenidine abuse have been reported, recreational use of the drug continues. We aim to provide scientific supportfor legal regulation of recreational abuse of methoxphenidine by demonstrating its the pharmacological action. EXPERIMENTAL APPROACH: Addictive potential of methoxphenidine was examined using intravenous self-administration test with rats and conditioned place preference test with mice. Further, a series of behavioural tests (open field test, elevated plus maze test, novel object recognition test, social interaction test and tail suspension test) performed to assess whether methoxphenidine caused schizophrenia-related symptoms in mice. Additionally, neurotransmitter enzyme-linked immunosorbent assay and western blot were used to confirm methoxphenidine-induced neurochemical changes in specific brain regions related to abnormal behaviours. KEY RESULTS: Methoxphenidine caused addictive behaviours via reinforcing and rewarding effects. Consistently, methoxphenidine induced over-activation of dopamine pathways in the nuclear accumbens, indicating activation of the brain reward circuit. Also, methoxphenidine caused all categories of schizophrenia-related symptoms, including positive symptoms (hyperactivity, impulsivity), negative symptoms (anxiety, social withdrawal, depression) and cognitive impairment. Consistently, methoxphenidine led to the disruption of the hippocampal-prefrontal cortex pathway that is considered to be pathological involved in schizophrenia. CONCLUSIONS AND IMPLICATIONS: We demonastrate that methoxphenidine causes addictive and schizophrenia-like behaviours and induces neurochemical changes in brain regions associated with these behaviours. We propose that methoxphenidine could be used in developing useful animal disease models and that it also requires legal restrictions on its recreational use.

Prevalence of Low Testosterone According to Health Behavior in Older Adults Men.

Testosterone is a representative sex hormone for men, and low testosterone causes erectile dysfunction and cardiovascular disease. The purpose of this study was to investigate the association between low testosterone (LTT) and health behaviors, such as alcohol, smoking, and exercise habits. We included 2980 men aged 65 to 80. Total serum testosterone and body composition were measured. A testosterone level less than 300 ng/dL was defined as low testosterone. A questionnaire on smoking, alcohol, and exercise was included. The odds ratio (OR) of LTT was calculated through logistic regression. Model 1 only used age as the adjustment variable, whereas Model 2 adjusted for age, waist circumference, and smoking. The prevalence of LTT was 626 (21.0%). The prevalence of LTT was significant in fat mass (Model 1: OR, 2.133) and muscle mass (Model 1: medium OR, 2.130 and low OR, 3.022; Model 2: medium OR, 1.638 and low OR, 1.740). The prevalence of LTT was also different based on smoking (Model 1: OR, 1.590; Model 2: OR, 1.629) and strength exercise (Model 1: OR, 0.849; Model 2: OR, 0.923). In conclusion, high frequency strength exercise and smoking cessation lower the prevalence of low testosterone, and obesity and low muscle mass increase the prevalence of low testosterone.

Early Rehabilitation after Surgical Repair of Medial and Lateral Collateral Elbow Ligaments: A Report of Three Cases.

Elbow ligament injuries are commonly caused by overuse; degeneration; and trauma; such as from a fall or collision. The purpose of this study was to present the results of three cases involving patients undergoing early rehabilitation after surgical treatment for complex injury of the elbow medial collateral ligament (MCL) and lateral collateral ligament (LCL). Two patients were non-athlete middle-aged women and one was a recreational judo player. Surgery was performed through open incision or arthroscopically. Rehabilitation consisted of range of motion (ROM) exercise; muscle strength restoration; and neuromuscular training. Passive ROM exercise and isometric strength exercise began at 7 days; isotonic strength training at 6 weeks; and neuromuscular training at 3 months after operation. Center- and home-based methods of exercise participation were combined. Center-based exercises were performed 1-2 times per week for the first 6 months and 1-2 times per month for the next 6 months. Patients also performed home-based and self-monitoring exercise. Examinations included ROM using a goniometer; muscle strength test using isokinetic equipment; and Oxford elbow score. In the six months after surgery; flexion ROM was 130° for Case A (health side 145°), 110° for Case B (health side 145°), and 135° for Case C (health side 135°); grip strength was restored to 13 kg (health side 28 kg), 16 kg (health side 25 kg), and 38 kg (health side 52 kg); and isokinetic flexion strength was improved to 30 Nm (health side 58 Nm), 21 Nm (health side 50 Nm), and 72 Nm (health side 80 Nm), respectively. In conclusion; patients who underwent early rehabilitation recovered ROM and muscle strength and returned to daily activity without any side effects. This study showed that patients with elbow MCL and LCL injuries took approximately 3 months to recover meaningful ROM; approximately 6 months to recover muscle strength; and 4-8 months to play light recreational sports. In addition; it took patients 6 weeks to return to their daily activities and 6 months to improve questionnaire scores in their function and pain during daily activity. In follow-up two years after surgery; all three patients had full ROM and muscle strength within 10% of the healthy side.

Copper-Catalyzed Oxidative Cleavage of the C-C Bonds of ß-Alkoxy Alcohols and ß-1 Compounds.

Copper-catalyzed aerobic oxidation conditions were employed to promote the C-C bond cleavage of ß-alkoxy alcohols and ß-1 compounds (lignin model compounds). Besides these compounds, various 1,2 and 1,3-diols were successfully converted to aldehydes. We propose the Cu(I)-catalyzed mechanism explaining the C-C cleavage of these 1,2 and 1,3-dihydroxy compounds and ß-alkoxy alcohols based on XPS data. Although our reaction conditions do not include large excess of bases and elaborated ligand-modified catalysts, copper salts with/without Me-TBD show good catalytic activities for C-C bond cleavage of various lignin model compounds.

Protective effects of 6,7,4'-trihydroxyisoflavone, a major metabolite of daidzein, on 6-hydroxydopamine-induced neuronal cell death in SH-SY5Y human neuroblastoma cells.

Daidzein, one of the important isoflavones, is extensively metabolized in the human body following consumption. In particular, 6,7,4'-trihydroxyisoflavone (THIF), a major metabolite of daidzein, has been the focus of recent investigations due to its various health benefits, such as anti-cancer and anti-obesity effects. However, the protective effects of 6,7,4'-THIF have not yet been studied in models of Parkinson's disease (PD). Therefore, the present study aimed to investigate the protective activity of 6,7,4'-THIF on 6-hydroxydopamine (OHDA)-induced neurotoxicity in SH-SY5Y human neuroblastoma cells. Pretreatment of SH-SY5Y cells with 6,7,4'-THIF significantly inhibited 6-OHDA-induced neuronal cell death, lactate dehydrogenase release, and reactive oxygen species production. In addition, 6,7,4'-THIF significantly attenuated reductions in 6-OHDA-induced superoxide dismutase activity and glutathione content. Moreover, 6,7,4'-THIF attenuated alterations in Bax and Bcl-2 expression and caspase-3 activity in 6-OHDA-induced SH-SY5Y cells. Furthermore, 6,7,4'-THIF significantly reduced 6-OHDA-induced phosphorylation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase 1/2. Additionally, 6,7,4'-THIF effectively prevented 6-OHDA-induced loss of tyrosine hydroxylase. Taken together, these results suggest that 6,7,4'-THIF, a major metabolite of daidzein, may be an attractive option for treating and/or preventing neurodegenerative disorders such as PD.

A novel designer drug, 25N-NBOMe, exhibits abuse potential via the dopaminergic system in rodents.

New psychoactive substances that have been modified and developed to mimic the effects of already prohibited drugs are an increasingly global problem. Among them, 2-(2,5-dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine (25 N-NBOMe) belonging to the N-methoxybenzyl-phenethylamines (NBOMes) class has recently emerged as a new psychoactive substance. However, the rewarding effects of 25 N-NBOMe have not yet been studied. Here, we investigated the addictive potential of 25 N-NBOMe using conditioned place preference and self-administration in rodents. We also evaluated the effects of 25 N-NBOMe on the dopaminergic system using Western blot analysis. We found that 25 N-NBOMe at 3 mg/kg significantly increased conditioned place preference in mice and 25 N-NBOMe at 0.01 mg/kg/infusion significantly enhanced self-administration in rats. In addition, repeated administration of 25 N-NBOMe did not affect the expression of the dopamine 1 receptor but significantly reduced the expression of the dopamine 2 receptor in both the nucleus accumbens (NAc) and the dorsal striatum (DSt). We also found that 25 N-NBOMe significantly decreased the expression of the dopamine transporter only in the NAc, while increasing the expression of the phosphorylated dopamine transporter in both the NAc and the DSt. Furthermore, 25 N-NBOMe significantly reduced the expression of tyrosine hydroxylase in the NAc but not in the DSt. Taken together, these findings suggest that 25 N-NBOMe has abuse potential via dopaminergic system.

Segmentally distributed neurofibromatosis associated with adenocarcinoma of the colon.

Neurofibromatosis can be associated with various malignancies, but an association with adenocarcinoma is extremely rare. A 61-year-old man who had been diagnosed with adenocarcinoma of the hepatic flexure of the colon was referred for segmentally located, multiple café-au-lait spots and tumors on his back and axillary freckles for 40 years. Histopathologic examination of the tumor was consistent with the neurofibromatosis. We report an unusual case of type I neurofibromatosis associated with adenocarcinoma of the colon that was clinically similar to segmental neurofibromatosis.

The usability of the upper eyelid crease approach for correction of medial orbital wall blowout fracture.

BACKGROUND: There are many approaches to the medial orbital wall. However, most of them have problems with limitation of exposure, scarring, and postoperative inflammatory symptoms related to the eye. The authors used an upper eyelid crease approach to overcome these problems and investigate the usefulness of this approach. METHODS: Between 2009 and 2011, the authors used this approach in 22 patients with medial orbital wall fractures. Incisions were performed on the medial one-third of the crease and a 2- to 3-mm superomedial extension along a relaxed skin tension line. RESULTS: Postoperative computed tomographic scans demonstrated complete reduction and accurate reconstitution of the bony defect in all cases. The initial two cases had revision to correct the implant position. Follow-up ranged from 8 to 28 months, with an average of 12 months. Complications related to the operation were not observed. Diplopia and limitation of eye movement resolved in most cases. Two patients had persistent diplopia for more than 6 months that decreased with time. Enophthalmos of more than 2 mm was not observed in any orbit. The operative scar was inconspicuous. CONCLUSIONS: This approach provides several advantages, including ease of exposure, and is more familiar to the plastic surgeon than the transconjunctival approach. There is little need to retract the globe laterally, thus minimizing postoperative inflammatory symptoms related to the eye. Therefore, the authors suggest that this method should be considered as a natural and useful surgical approach to medial orbital blowout fractures.

Pretibial epidermolysis bullosa: is this case a new subtype with loss of types IV and VII collagen?

Pretibial epidermolysis bullosa (PEB) is an extremely rare subtype of dominant dystrophic epidermolysis bullosa (DDEB), in which recurrent blistering with scarring predominantly involves the pretibial skin. Nail dystrophy, albopapuloid lesions, and hypertrophic scars may also occur. In PEB, immunohistochemical and electron microscopic studies demonstrate the complete or partial loss of the anchoring fibril (AF) in the basement membrane zone, suggesting disturbed synthesis or excessive degradation of collagen VII, the main component of AF. Interestingly, we report a case of PEB with unusual results of joint loss of types IV and VII collagen.