Effect of pulsed electromagnetic fields stimulation on ischemic skin model.

This study aimed to evaluate the effect of Pulsed Electromagnetic Fields (PEMF) in improving blood flow reduction and tissue necrosis of ischemic animal induced by skin flap. In each experiment, twenty rats (280-320 g) were randomly divided into control group (n = 10) and PEMF (n = 10) group. All of the rats were performed skin flap in back. In the PEMF group, PEMF (1 Hz, 10 mT) was performed in each experiment. In Experiment-1 (n = 20), PEMF was performed for 90 minutes. In Experiment-2 (n = 20), additionally, a blocking film was inserted, and suture was performed to induce necrosis. PEMF was performed for 30 minutes each day for 7 days. As a result of Speckle-Flow Index (SFI) analysis, in the control group, blood flow continued to decrease immediately after the procedure. In the PEMF group, blood flow was remained constant after 30 minutes and increased after 60 minutes. The blood flow in a specific region substantially increased from the initial state. As a result of skin necrosis analysis, the progression rate in the PEMF group was slower than that of the control group. The rate of necrosis in the PEMF group decreased dramatically from the 6th day, and there was a statistically significant difference between the two groups at the 7th day (p < .05). In this study, it was confirmed that PEMF (1 Hz, 10 mT) has a blood flow improvement and skin tissue necrosis alleviation in the ischemic flap animal model.

A Comparative Analysis of Clinical Screening Test and Language Specific Test in Language Delay Children.

The aim of this study was to investigate the usefulness of a clinical screening test [the Korean Infant and Child Developmental Test (KICDT)] compared to language specific tests: the sequenced language scale for infant (SELSI) and the Preschool Receptive-Expressive language Scale (PRES) in children with delayed language development. A retrospective chart review was conducted on 615 children who visited the Department of Pediatrics at Chonbuk National University Hospital from January 2013 to December 2016. All patients were evaluated with KICDT as a clinical screening test and SELSI or PRES as a language specific test. Language Developmental Quotients (LDQs) from the KICDT were compared with the Receptive Language Quotient (RLQ) and expressive language quotient (ELQ) from the SELSI or PRES. The sensitivity, specificity and predictive values of LDQ of KICDT were calculated by comparing with SELSI/PRES. Language DQs from the KICDT were significantly correlated with the RLQ (r=0.706), ELQ (r=0.768), and total language quotient (TLQ) (r=0.766) from the SELSI/PRES (p<0.05). In cross tabulation, the patients belonging to the retardation groups in both KICDT and SELSI/PRES were 417 (67.8%). Otherwise, patients belonging to the normal group in KICDT but not in SELSI/PRES were 151 (24.6%). Sensitivity and specificity of LDQ of KICDT relative to SELSI/PRES were 72.3% and 92.2% respectively (p<0.05). Our data suggests that clinical screening tests alone, not cumbersome language specific tests, can determine language developmental delays in children.

GZ-11608, a Vesicular Monoamine Transporter-2 Inhibitor, Decreases the Neurochemical and Behavioral Effects of Methamphetamine.

Despite escalating methamphetamine use and high relapse rates, pharmacotherapeutics for methamphetamine use disorders are not available. Our iterative drug discovery program had found that R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), a selective vesicular monoamine transporter-2 (VMAT2) inhibitor, specifically decreased methamphetamine's behavioral effects. However, GZ-793A inhibited human-ether-a-go-go-related gene (hERG) channels, suggesting cardiotoxicity and prohibiting clinical development. The current study determined if replacement of GZ-793A's piperidine ring with a phenylalkyl group to yield S-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11608) diminished hERG interaction while retaining pharmacological efficacy. VMAT2 inhibition, target selectivity, and mechanism of GZ-11608-induced inhibition of methamphetamine-evoked vesicular dopamine release were determined. We used GZ-11608 doses that decreased methamphetamine-sensitized activity to evaluate the potential exacerbation of methamphetamine-induced dopaminergic neurotoxicity. GZ-11608-induced decreases in methamphetamine reinforcement and abuse liability were determined using self-administration, reinstatement, and substitution assays. Results show that GZ-11608 exhibited high affinity (Ki = 25 nM) and selectivity (92-1180-fold) for VMAT2 over nicotinic receptors, dopamine transporter, and hERG, suggesting low side-effects. GZ-11608 (EC50 = 620 nM) released vesicular dopamine 25-fold less potently than it inhibited VMAT2 dopamine uptake. GZ-11608 competitively inhibited methamphetamine-evoked vesicular dopamine release (Schild regression slope = 0.9 ± 0.13). GZ-11608 decreased methamphetamine sensitization without altering striatal dopamine content or exacerbating methamphetamine-induced dopamine depletion, revealing efficacy without neurotoxicity. GZ-11608 exhibited linear pharmacokinetics and rapid brain penetration. GZ-11608 decreased methamphetamine self-administration, and this effect was not surmounted by increasing methamphetamine unit doses. GZ-11608 reduced cue- and methamphetamine-induced reinstatement, suggesting potential to prevent relapse. GZ-11608 neither served as a reinforcer nor substituted for methamphetamine, suggesting low abuse liability. Thus, GZ-11608, a potent and selective VMAT2 inhibitor, shows promise as a therapeutic for methamphetamine use disorder. SIGNIFICANCE STATEMENT: GZ-11608 is a potent and selective vesicular monoamine transporter-2 inhibitor that decreases methamphetamine-induced dopamine release from isolated synaptic vesicles from brain dopaminergic neurons. Results from behavioral studies show that GZ-11608 specifically decreases methamphetamine-sensitized locomotor activity, methamphetamine self-administration, and reinstatement of methamphetamine-seeking behavior, without exhibiting abuse liability. Tolerance does not develop to the efficacy of GZ-11608 to decrease the behavioral effects of methamphetamine. In conclusion, GZ-11608 is an outstanding lead in our search for a therapeutic to treat methamphetamine use disorder.

Effectiveness of Low-Level Laser Therapy with a 915 Nm Wavelength Diode Laser on the Healing of Intraoral Mucosal Wound: An Animal Study and a Double-Blind Randomized Clinical Trial.

Background and objectives: Diode laser has been the most popular low-level laser therapy (LLLT) technique in dentistry due to its good tissue penetration, lower financial costs, small size for portable application, and convenience to use. A series of recent studies with 940 nm or 980 nm lasers demonstrated that LLLT showed positive effects after third molar extraction or periodontal flap surgery. However, the effects of LLLT on intraoral mucosal wound healing after surgical incision have not yet been determined in human clinical study. Materials and Methods: The present study was performed to determine the efficacy and safety of 915 nm wavelength low-level laser therapy (LLLT) in mucosal wound healing. A total of 108 Sprague-Dawley rats were used. They were divided into three groups: Abrasive wound group, immediate LLLT once group, and daily LLLT group. As a clinical study, a total of 16 patients with split-mouth design subjected to bilateral mandibular third molar extraction were allocated into the LLLT group and placebo group. The process of LLLT was performed on postoperative days 0, 1, and 7, and parameters related to wound healing were analyzed on days 1, 7, and 14. Results: Repeated laser irradiation promoted mucosal wound healing of the rats. In the clinical study, although there were no significant statistical differences between the LLLT and placebo groups in all inflammatory parameters, the early stage mucosal healing tendency of wound dehiscence was higher in the LLLT group than in the placebo group clinically on postoperative day 1. Conclusions: The present results showed that 915 nm LLLT could be applied safely as an auxiliary therapy for mucosal wound healing.

Muscarinic agonist, (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate: High affinity, but low subtype selectivity for human M1 - M5 muscarinic acetylcholine receptors.

Novel quinuclidinyl N-phenylcarbamate analogs were synthesized, and binding affinities at M1-M5 muscarinic acetylcholine receptor (mAChR) subtypes were determined using Chinese hamster ovary (CHO) cell membranes stably expressing one specific subtype of human mAChR. Although not subtype selective, the lead analog (±)-quinuclidin-3-yl-(4-fluorophenethyl)(phenyl)carbamate (3c) exhibited the highest affinity (Ki = 2.0, 13, 2.6, 2.2, 1.8 nM) at each of the M1-M5 mAChRs, respectively. Based on results from the [3H]dopamine release assay using rat striatal slices, 3c acted as an agonist at mAChRs. The effect of 3c was inhibited by the nonselective mAChR antagonist, scopolamine, and 3c augmented release evoked by oxotremorine. A potent analog from the same scaffold, (±)-quinuclidin-3-yl-(4-methoxyphenethyl)(phenyl)-carbamate (3b) exhibited the greatest selectivity (17-fold) at M3 over M2 mAChRs. These analogs could serve as leads for further discovery of novel subtype-selective muscarinic ligands with the goal of providing therapeutics for substance use disorders and chronic obstructive pulmonary disease.

New Scaffold for Lead Compounds to Treat Methamphetamine Use Disorders.

Despite increased methamphetamine use worldwide, pharmacotherapies are not available to treat methamphetamine use disorder. The vesicular monoamine transporter-2 (VMAT2) is an important pharmacological target for discovery of treatments for methamphetamine use disorder. VMAT2 inhibition by the natural product, lobeline, reduced methamphetamine-evoked dopamine release, methamphetamine-induced hyperlocomotion, and methamphetamine self-administration in rats. Compared to lobeline, lobelane exhibited improved affinity and selectivity for VMAT2 over nicotinic acetylcholine receptors. Lobelane inhibited neurochemical and behavioral effects of methamphetamine, but tolerance developed to its behavioral efficacy in reducing methamphetamine self-administration, preventing further development. The lobelane analog, R-N-(1,2-dihydroxypropyl)-2,6-cis-di-(4-methoxyphenethyl)piperidine hydrochloride (GZ-793A), potently and selectively inhibited VMAT2 function and reduced neurochemical and behavioral effects of methamphetamine. However, GZ-793A exhibited potential to induce ventricular arrhythmias interacting with human-ether-a-go-go (hERG) channels. Herein, a new lead, R-3-(4-methoxyphenyl)-N-(1-phenylpropan-2-yl)propan-1-amine (GZ-11610), from the novel scaffold (N-alkyl(1-methyl-2-phenylethyl)amine) was evaluated as a VMAT2 inhibitor and potential therapeutic for methamphetamine use disorder. GZ-11610 was 290-fold selective for VMAT2 over dopamine transporters, suggesting that it may lack abuse liability. GZ-11610 was 640- to 3500-fold selective for VMAT2 over serotonin transporters and nicotinic acetylcholine receptors. GZ-11610 exhibited > 1000-fold selectivity for VMAT2 over hERG, representing a robust improvement relative to our previous VMAT2 inhibitors. GZ-11610 (3-30 mg/kg, s.c. or 56-300 mg/kg, oral) reduced methamphetamine-induced hyperactivity in methamphetamine-sensitized rats. Thus, GZ-11610 is a potent and selective inhibitor of VMAT2, may have low abuse liability and low cardiotoxicity, and after oral administration is effective and specific in inhibiting the locomotor stimulant effects of methamphetamine, suggesting further investigation as a potential therapeutic for methamphetamine use disorder.

Maximal strength and endurance scores of the tongue, lip, and cheek in healthy, normal Koreans.

OBJECTIVES: The purpose of this study was to establish normative data for healthy Korean adults by measuring the maximal strength and endurance scores of the tongue, lip, and cheek, and to examine correlations between these measurements. MATERIALS AND METHODS: This study included 120 subjects that were divided into three groups according to age: young (20-39 years), middle-aged (40-59 years), and older (over 60 years); and by gender. Measurements were taken using the Iowa Oral Performance Instrument (IOPI). RESULTS: The mean maximal tongue strengths were as follows: young men (46.7±10.2 kPa) and women (32.1±7.9 kPa), middle-aged men (40.9±9.3 kPa) and women (36.9±8.6 kPa), and older men (35.2±9.0 kPa) and women (34.5±6.9 kPa). The mean tongue endurance scores were: young men (28.8±12.6 seconds) and women (20.8±13.5 seconds), middle-aged men (17.0±8.5 seconds) and women (15.3±5.2 seconds), and older men (15.8±6.7 seconds) and women (17.9±8.1 seconds). The mean maximal lip strengths were: young men (11.6±3.0 kPa) and women (11.4±3.8 kPa), middle-aged men (11.4±4.2 kPa) and women (11.1±5.1 kPa), and older men (14.5±3.9 kPa) and women (11.7±2.6 kPa). The mean lip endurance scores were: young men (41.1±23.9 seconds) and women (22.4±21.7 seconds), middle-aged men (24.3±10.3 seconds) and women (30.5±13.4 seconds), and older men (24.9±11.0 seconds) and women (12.8±7.6 seconds). The mean maximal cheek strengths were: young men (24.5±4.6 kPa) and women (20.5±4.3 kPa), middle-aged men (25.2±6.4 kPa) and women (21.2±5.5 kPa), and older men (22.4±5.3 kPa) and women (18.0±4.8 kPa). The mean cheek endurance scores were: young men (47.8±24.4 seconds) and women (43.9±25.0 seconds), middle-aged men (27.3±11.3 seconds) and women (20.0±14.6 seconds), and older men (21.7±14.5 seconds) and women (17.2±11.4 seconds). CONCLUSION: The data collected in this study will provide an important database of standardized measurements for maximal strength and endurance scores of the tongue, lip and cheek in healthy, normal Koreans.

Efficacy of loop electrosurgical excision procedure with cold coagulation for treating cervical intraepithelial neoplasia: A two center cohort study.

OBJECTIVE: To evaluate the efficacy of loop electrosurgical excision procedure (LEEP) combined with cold coagulation for treating cervical intraepithelial neoplasia (CIN). METHODS: We reviewed clinic-pathologic data of 498 patients treated with LEEP alone (n=354), and LEEP combined with cold coagulation (n=144) between January 2000 and December 2011. After LEEP, we followed up all patients by using Papanicolaou smear and human papillomavirus (HPV) test, and evaluated abnormal cervical cytology-free interval and high-risk HPV infection-free interval. Moreover, we investigated independent factors affecting abnormal cervical cytology or high-risk HPV infection after LEEP. RESULTS: Abnormal cervical cytology-free interval was longer in patients treated with LEEP combined with cold coagulation than in those treated with LEEP alone (mean, 92.4 vs. 84.4 months; P=0.01), and patients treated with LEEP combined with cold coagulation also showed longer high-risk HPV infection-free interval than those treated with LEEP alone (mean, 87.6 vs. 59.1 months; P=0.01). Moreover, CIN 3 and cold coagulation were factors affecting abnormal cervical cytology after LEEP (adjusted hazard ratios, 1.90 and 0.61; 95% confidence intervals, 1.27 to 2.84 and 0.39 to 0.96), and CIN 3, positive deep cervical margin and cold coagulation were also factors affecting high-risk HPV infection after LEEP (adjusted hazard ratios, 2.07, 4.11, and 0.64; 95% confidence intervals, 1.38 to 3.08, 1.63 to 10.39, and 0.43 to 0.96). When we performed subgroup analyses for patients with CIN 2 or CIN 3, the result were similar. CONCLUSION: LEEP combined with cold coagulation may be more effective for treating CIN than LEEP alone. Moreover, cold coagulation may decrease the risk of potential of recurrence after LEEP.

Topical treatments of Saussurea costus root and Thuja orientalis L. synergistically alleviate atopic dermatitis-like skin lesions by inhibiting protease-activated receptor-2 and NF-κB signaling in HaCaT cells and Nc/Nga mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The root of Saussurea costus (Aucklandia lappa Decne, Aucklandiae Radix, SC) and Thuja orientalis L. (TOL) have been traditionally used as anti-inflammatory agents in Korea. However, they have not been studied for the efficacy of atopic dermatitis (AD) treatment, a chronic inflammatory skin disease. We investigated the efficacy of topical applications with 1,3-butyleneglycol extracts of SC and TOL to alleviate the symptoms of AD. MATERIALS AND METHODS: HaCaT cells and the dorsal skin of Nc/Nga mice had a local exposure of house mite extracts and 2,4-dinitrochlorobenzene (DNCB), respectively. After lesions developed, we topically applied 1,3-butylen glycol (vehicle; control), SC (30%), TOL (30%), or SC (15%)+TOL (15%) to the skin lesions for 5 weeks. The normal-control was not exposed to DNCB. The skin thickness, mast cell infiltration, serum immunoglobulin E (IgE) and IgG1 and gene expressions of interleukin (IL)-4, IL-13, and IFN-γ in the dorsal skin and HaCaT cells were measured. RESULTS: Chlorogenic acid (129.6±10.2µg/g) for SC and catechin and apigenin (93.4±13.2 and 16.9±1.3µg/g, respectively) for TOL were used as indicator compounds for the strength of the extracts. SC+TOL decreased the expression of protease-activated receptor-2 and ICAM-1 and the release of TNF-α and IL-6 in HaCaT cells activated by 3µg/mL house mite extracts in comparison to either of SC or TOL alone. In Nc/Nga mice challenged with DNCB, SC+TOL synergistically attenuated clinical symptoms of AD such as erythema, hemorrhage, edema, excoriation and dryness in the dorsal skin better than either SC or TOL alone. Histological analysis of the dorsal skin also showed that SC+TOL treatment significantly and additively decreased the inflammatory cellular infiltrate, including mast cells and eosinophils in comparison to either of SC or TOL. SC+TOL also decreased serum IgE and IgG1 levels and the expression of IFN-γ, IL-4, and IL-13 mRNA in dorsal skin in DNCB-treated Nc/Nga mice. CONCLUSION: SC+TOL relieved the symptoms of AD by reducing pro-inflammatory activity and over-activated immune responses. These data suggest that SC+TOL may be an effective alternative intervention for the management of AD.

In vitro fertilization outcomes in women with surgery induced diminished ovarian reserve after endometrioma operation: Comparison with diminished ovarian reserve without ovarian surgery.

OBJECTIVE: To compare the in vitro fertilization (IVF) outcomes between women with diminished ovarian reserve (DOR) after endometrioma operation and women with DOR without ovarian surgery. METHODS: This retrospective case-control study included 124 women aged under 40 and had DOR (serum anti-Müllerian hormone level <1.1 ng/mL or antral follicle count ≤6). They participated in fresh first and/or second IVF cycles between March in 2010 and December in 2015. Basal characteristics and IVF outcomes were compared between 47 cycles (32 women) with surgery-induced DOR and 119 cycles (92 women) with DOR without ovarian surgery. RESULTS: Basal characteristics were similar in both groups except that the median ages were lower in the surgery-induced DOR group compared to the DOR group without ovarian surgery. The data regarding the controlled ovarian stimulation and IVF cycle outcomes showed similar result in both groups. Also, clinical pregnancy and live birth rate were not different significantly between two groups. CONCLUSION: In the same condition of DOR, clinical pregnancy and live birth rate were not different significantly between two groups regarding etiology of DOR.

Comparison of the Effects of Manual Acupuncture, Laser Acupuncture, and Electromagnetic Field Stimulation at Acupuncture Point BL15 on Heart Rate Variability.

The aim of this study was to compare the influences of manual acupuncture, laser acupuncture, and electromagnetic field stimulation on the autonomic nervous system. We monitored the heart rate variability before and after stimulation to check the influence on the autonomic nervous system. The heart rate variabilities at low frequency (LF; 0.04-0.15 Hz) and high frequency (HF; 0.15-0.4 Hz) were analyzed to acquire LF/HF ratio. Xinshu (BL15) was selected as the stimulation point. Methods included manual acupuncture with a 1-cm depth and laser acupuncture at a wavelength of 660 nm and output power of 50 mW. An electromagnetic field of 2 Hz and 460 gauss (46 mT) was chosen. The LF and the LF/HF ratio were found to be lower in the manual acupuncture and the electromagnetic field groups, but to be higher in the laser acupuncture group. The HF was found to be lower in the laser acupuncture group, but higher in the manual acupuncture and the electromagnetic field groups. In conclusion, we found that manual acupuncture and electromagnetic field stimulation at BL15 activated the parasympathetic nervous system, whereas laser acupuncture at BL15 activated the sympathetic nervous system.

TRPV1 Gene Polymorphisms Are Associated with Type 2 Diabetes by Their Interaction with Fat Consumption in the Korean Genome Epidemiology Study.

BACKGROUND: Different transient receptor potential vanilloid 1 (TRPV1) variants may be differently activated by noxious stimuli. AIM: We investigated how TRPV1 variants modulated the prevalence of type 2 diabetes and specific gene-nutrient interactions. METHODS: Among 8,842 adults aged 40-69 years in the Korean Genome Epidemiology Study, the associations between TRPV1 genotypes and the prevalence of type 2 diabetes as well as their gene-nutrient interactions were investigated after adjusting for the covariates of age, gender, residence area, body mass index, daily energy intake, and total activity. RESULTS: The TRPV1 rs161364 and rs8065080 minor alleles lowered HOMA-IR and the risk of type 2 diabetes after adjusting for covariates. There were gene-nutrient interactions between TRPV1 variants rs161364 and rs8065080 and preference for oily taste, intake of oily foods, and fat intake after adjusting for covariates. Among subjects with the minor alleles of TRPV1 rs161364 and rs8065080, the group with a high preference for oily foods had a lower odds ratio for type 2 diabetes. Consistent with the preference for taste, among subjects with the minor alleles, the group with high fat intake from oily foods also exhibited a lower risk of type 2 diabetes than subjects with the major alleles. CONCLUSIONS: People with the minor alleles of the TRPV1 single nucleotide polymorphisms rs161364 and rs8065080 have a lower risk of diabetes with a high-fat diet, but people with the major alleles are at a higher risk of type 2 diabetes when consuming high-fat diets. The majority of people should be careful about a high fat intake.

Synthesis of O- and N-alkylated products of 1,2,3,4-tetrahydrobenzo[c][2,7]naphthyrin-5(6H)-one.

Efficient syntheses of O- and N-alkylated products of 1,2,3,4-tetrahydrobenzo[c][2,7]naphthyrin-5(6H)-one are presented. The O-alkylated analogues were synthesized through a reduction-cyclization cascade and a selective O-alkylation reaction; whereas the N-alkylated analogues were obtained through a key Buchwald coupling.

Muscarinic acetylcholine receptor binding affinities of pethidine analogs.

A series of pethidine analogs were synthesized and their affinities for the [(3)H]N-methyl-scopolamine (NMS) binding site on muscarinic acetylcholine receptors (mAChRs) were determined using M1, M3 or M5 human mAChRs expressed by Chinese hamster ovary (CHO) cell membranes. Compound 6b showed the highest binding affinities at M1, M3 and M5 mAChRs (Ki=0.67, 0.37, and 0.38 µM, respectively).

IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarthritis. Numerous agents with varying mechanisms are used in the treatment of RA, including non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and some biological agents. Studies to uncover the cause of RA have recently ended up scrutinizing the importance of pro-inflammatory cytokine such as tumor necrosis factor α (TNF-α) and interleukin (IL)-6 in the pathogenesis of RA. TNF-α inhibitors are increasingly used to treat RA patients who are non-responsive to conventional anti-arthritis drugs. Despite its effectiveness in a large patient population, up to two thirds of RA patients are found to be partially responsive to anti-TNF therapy. Therefore, agents targeting IL-6 such as tocilizumab (TCZ) attracted significant attention as a promising agent in RA treatment. In this article, we review the mechanism of anti-IL-6 in the treatment of RA, provide the key efficacy and safety data from clinical trials of approved anti-IL-6, TCZ, as well as six candidate IL-6 blockers including sarilumab, ALX-0061, sirukumab, MEDI5117, clazakizumab, and olokizumab, and their future perspectives in the treatment of RA.

Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening.

We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.

Electromagnetic acupuncture to enhance the effects of manual acupuncture on recovery from muscle fatigue of the quadriceps.

The aim of this study was to investigate a new method of manual acupuncture that used a magnetic field to stimulate only one acupoint vertically. We developed an eight-channel electromagnetic acupuncture (EMA) system that uses a solenoid-type electrode to insert the manual acupuncture needle into a hole in an electrode. We used a manual acupuncture needle for magnetic induction in order to penetrate vertically and deeply into tissues. In order to confirm the usefulness of EMA, we investigated the effects of treatment on muscle fatigue after strenuous knee extension/flexion exercises that had been performed by three groups: the nonstimulation, the manual acupuncture, and the EMA groups. Electromyograms showed that the median frequency (MF) in the EMA group had rapidly recovered after 4 minutes (p = 0.608), but that the peak torque had not recovered to the normal state (p < 0.05). Thus, we confirmed that compared with manual acupuncture, EMA resulted in better recovery from muscle fatigue.

DAMP molecules S100A9 and S100A8 activated by IL-17A and house-dust mites are increased in atopic dermatitis.

S100A9 and S100A8 are called damage-associated molecular pattern (DAMP) molecules because of their pro-inflammatory properties. Few studies have evaluated S100A9 and S100A8 function as DAMP molecules in atopic dermatitis (AD). We investigated how house-dust mites affect S100A9 and S100A8 expression in Th2 cytokine- and Th17 cytokine-treated keratinocytes, and how secretion of these molecules affects keratinocyte-derived cytokines. Finally, we evaluated expression of these DAMP molecules in AD patients. S100A9 expression and S100A8 expression were strongly induced in IL-17A- and Dermatophagoides (D.) farinae-treated keratinocytes, respectively. Furthermore, co-treatment with D. farinae and IL-17A strongly increased expression of S100A9 and S100A8 compared with D. farinae-Th2 cytokine co-treatment. The IL-33 mRNA level increased in a dose-dependent manner in S100A9-treated keratinocytes, but TSLP expression did not change. S100A8/A9 levels were also higher in the lesional skin and serum of AD patients, and correlated with disease severity. Taken together, S100A9 and S100A8 may be involved in inducing DAMP-mediated inflammation in AD triggered by IL-17A and house-dust mites.

Effects of ß2-adrenergic receptor gene polymorphisms on ritodrine therapy in pregnant women with preterm labor: prospective follow-up study.

This study aimed to evaluate the effects of ß2-adrenergic receptor (ADRB2) gene polymorphisms on ritodrine therapy outcomes in patients with preterm labor. Genotyping analysis of ADRB2 gene (rs1042713, rs1042714, rs1042717, rs1042718, and rs1042719) was performed on 137 patients with preterm labor. Survival analysis was conducted for the effects of SNPs on the median time to delivery as a primary outcome. The median time to delivery in the study patients was 349.3 h. Gestational age at admission and modified Bishop scores revealed significant effects on time to delivery (p<0.001). Among studied SNPs, rs1042717 and rs1042718 showed linkage disequilibrium in this population, and their effects on time to delivery were marginally significant (p<0.1). Patients with variant-homozygotes in the rs1042713 showed considerably shortened time to delivery compared to wild-allele carriers. The rs1042719 polymorphism significantly affected time to delivery in both univariate and multivariate analysis; the GC and CC carriers showed 64% decrease in time to delivery compared to the wild-type homozygote carriers. Based on the results, it was concluded that the gene polymorphisms of ADRB2 could affect ritodrine therapy in patients with preterm labor. However, given the single-center and the relatively small sample size, our hypothesis requires further independent validation using multi-center and large sample size.

Selective immunoproteasome inhibitors with non-peptide scaffolds identified from structure-based virtual screening.

As a major component of the crucial nonlysosomal protein degradation pathway in the cells, the proteasome has been implicated in many diseases such as Alzheimer's disease, Huntington's disease, inflammatory bowel diseases, autoimmune diseases, multiple myeloma (MM) and other cancers. There are two main proteasome subtypes: the constitutive proteasome which is expressed in all eukaryotic cells and the immunoproteasome which is expressed in immune cells and can be induced in other cell types. Majority of currently available proteasome inhibitors are peptide backbone-based, having short half-lives in the body. It is highly desirable to identify novel, immunoproteasome-selective inhibitors with non-peptide scaffolds for development of novel therapeutics. Through combined virtual screening and experimental studies targeting the immunoproteasome, we have identified a set of novel immunoproteasome inhibitors with diverse non-peptide scaffolds. Some of the identified inhibitors have significant selectivity for the immunoproteasome over the constitutive proteasome. Unlike most of the currently available proteasome inhibitors, these new inhibitors lacking electrophilic pharmacophores are not expected to form a covalent bond with proteasome after the binding. These non-peptide scaffolds may provide a new platform for future rational drug design and discovery targeting the immunoproteasome.