A hypotensive protocol of inspiratory muscle strength training: Systematic review and meta-analysis with trial sequential analysis.

The aim of this study was to evaluate the hypotensive effect and optimal protocol of inspiratory muscle resistance training (IMST). Randomized controlled trials using IMST to lower blood pressure (BP) were retrieved from 12 databases as of July 2022. A meta-analysis of BP and heart rate variability (HRV) was performed and a trial sequence analysis was performed using trial sequential analysis (TSA) software. Twelve articles (n = 386 participants) from five countries were included, with a mean quality score of 5.83. IMST achieved significant results in reducing systolic, diastolic, and mean arterial pressure (-7.93 [-12.08, -3.78]; -3.80 [-6.08, -1.53]; -4.90 [-13.76, 3.96]). Furthermore, TSA has shown that the findings for systolic and diastolic BP are conclusive. Finally, considerable variation remained between studies when analyzing HRV. The overall hypotensive effect of IMST was demonstrated by the TSA and was well tolerated in different populations. Of these, two interventions, high resistance or low resistance combined with slow breathing, showed the best efficacy under an 8-week exercise intervention. In addition, the process of lowering BP by modulating sympathetic vagal activity has not been further confirmed in this study. Future long-term interventions, especially those over 3 months, are needed to observe the prolonged antihypertensive effects and modulatory mechanisms; controlling for variables such as respiratory rate and executing more rigorous studies to further explore antihypertensive options.

Patient-reported outcome measures in functional dyspepsia: a systematic review and COSMIN analysis.

BACKGROUND: Functional dyspepsia (FD) as a type of disorders of brain-gut interaction (DBGI), patient self-reporting of its symptoms becomes an important component of clinical outcome assessment. We performed a systematic review using Consensus Based Standards for the Selection of Health Measurement Instruments (COSMIN) guidelines to identify the best available patient-reported outcome measure (PROM) of FD. METHODS: The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched four databases with no date limit, looking for previously confirmed PROMs for evaluating FD symptoms. An overall rating was then assigned based upon COSMIN guidelines, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the level of evidence for psychometric properties of included PROMs. RESULTS: Thirty articles covering outcome indicators of 24 patient reports were included. The Leuven Postprandial Distress Scale (LPDS) showed adequate content validity and moderate quality evidence of adequate internal consistency to generate an A recommendation. CONCLUSION: LPDS is currently the most recommended PROM for patient self-reported FD symptoms. However, it fails to assess two important areas of cross-cultural validity/ measurement invariance and measurement error. Future research can be continuously improved on this basis.

Interventions for reducing blood pressure in prehypertension: A meta-analysis.

Background: We aimed to address which interventions best control blood pressure (BP) and delay disease progression in prehypertension and to give recommendations for the best option following a quality rating. Methods: A Bayesian network meta-analysis was used to assess the effect of the intervention on BP reduction, delaying hypertension progression and final outcome, with subgroup analyses for time and ethnicity. Recommendations for interventions were finally based on cumulative ranking probabilities and CINeMA. Results: From 22,559 relevant articles, 101 eligible randomized controlled trial articles (20,176 prehypertensive subjects) were included and 30 pharmacological and non-pharmacological interventions were evaluated. Moderate-quality evidence demonstrated that angiotensin II receptor blockers, aerobic exercise (AE), and dietary approaches to stop hypertension (DASH) lowered systolic blood pressure (SBP). For lowering diastolic blood pressure (DBP), AE combined with resistance exercise (RE) or AE alone provided high quality evidence, with calcium channel blockers, lifestyle modification (LSM) combined with drug providing moderate quality evidence. LSM produced the best BP lowering effect at 12 months and beyond of intervention. In Asians, TCD bubble was moderate quality evidence for lowering SBP and RE may have had a BP lowering effect in Caucasians. No recommendation can be given for delaying the progression of hypertension and reducing mortality outcomes because of low to very low quality of evidence. Conclusion: AE combined RE are preferentially recommended for BP control in prehypertension, followed by DASH. Long-term BP control is preferred to LSM. Asians and Caucasians add TCD bubble and RE to this list as potentially effective interventions. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022356302, identifier: CRD42022356302.

Bibliometric analysis of functional dyspepsia research trends over the past 20 years.

Background: Functional dyspepsia is one of the most common functional gastrointestinal disorders that affects the physical health and quality of life of many people. Its status as a chronic disease has received continued attention in the field of gastrointestinal research. Objective: Bibliometric methods using network analysis were used to identify developments and research trends in functional dyspepsia with a view to informing and orienting further in-depth research on functional dyspepsia. Method: Bibliometric methods were used to analyze the documents on functional dyspepsia published from 2002 to 2022 retrieved from Web of Science Core Collection on 1 July 2022, import literature data into Excel and VOSviewer, and extract relevant information to analyze and visualize the annual number of publications, authors, organizations, countries, journals published, citations, and keywords. Results: A total of 3,532 documents were retrieved, and the abstracts of each remaining documents were read one by one after four duplicate documents were removed, and 2,220 documents were included after screening, with a fluctuating growth trend. Tack J ranked first with 171 documents, followed by Talley NJ (n = 167). The top three organizations in terms of number of publications were Katholieke Universiteit Leuven (n = 131), Mayo Clinic (n = 127), and the University of Newcastle (n = 91). The most prolific country was the United States with 499 documents. The three journals with the highest number of publications are "Neurogastroenterology and Motility" (n = 218), "Alimentary pharmacology & therapeutics" (n = 101), and "Journal of Gastroenterology and Hepatology" (n = 90). The top three most cited documents were "Functional gastroduodenal disorders," "Childhood Functional Gastrointestinal Disorders: Child/Adolescent," and "The Serotonin Signaling System: From Basic Understanding to Drug Development for Functional GI Disorders." Frequency counts and network co-occurrences of keywords reveal trends in this field, including "gastric emptying," "anxiety," "acupuncture," and "ghrelin." Conclusion: The study of the mechanism of gut-brain interaction in functional dyspepsia and the combination of non-pharmacological treatment and pharmacological treatment may be the future research hotspots and trends. Our findings are helpful to comprehensively review the research history of FD and provide reference for researchers in this field to further study.

Moxibustion Regulates Gastrointestinal Motility via HCN1 in Functional Dyspepsia Rats.

BACKGROUND Moxibustion therapy has been found to ameliorate clinical symptoms of functional dyspepsia (FD). We aimed to examine the regulatory effect of moxibustion on the gastrointestinal (GI) motility in FD and explore the underlying mechanism based on the hyperpolarization-activated cyclic nucleotide-gated cation channel 1 (HCN1). MATERIAL AND METHODS Moxibustion therapy was used in FD rats induced by using classic tail-pinch and irregular feeding. Weight gain and food intake were recorded weekly, followed by detecting gastric residual rate (GRR) and small intestine propulsion rate (IPR). Next, western blotting was performed to determine the expression levels of HCN1 in the gastric antrum. qRT-PCR was used to detect HCN1 in the small intestine and hypothalamic satiety center. Double immunolabeling was used for HCN1 and ICCs in gastric antrum and small intestine. RESULTS The obtained results suggested that moxibustion treatment could increase weight gain and food intake in FD rats. The GRR and IPR were compared among the groups, which showed that moxibustion treatment could decrease GRR and increase IPR. Moxibustion increased the expression of HCN1 in the gastric antrum, small intestine, and hypothalamic satiety center. Histologically, the co-expressions of HCN1 and ICCs tended to increase in gastric antrum and small intestine. Meanwhile, HCN channel inhibitor ZD7288 prevented the above-mentioned therapeutic effects of moxibustion. CONCLUSIONS The results of the present study suggest that moxibustion can effectively improve the GI motility of FD rats, which may be related to the upregulation of HCN1 expression in gastric antrum, small intestine, and satiety center.

The Influence of the Different Repair Methods on the Electrical Properties of the Normally off p-GaN HEMT.

The influence of the repair process on the electrical properties of the normally off p-GaN high-electron-mobility transistor (HEMT) is studied in detail in this paper. We find that the etching process will cause the two-dimensional electron gas (2DEG) and the mobility of the p-GaN HEMT to decrease. However, the repair process will gradually recover the electrical properties. We study different repair methods and different repair conditions, propose the best repair conditions, and further fabricate the p-GaN HEMTs devices. The threshold voltage of the fabricated device is 1.6 V, the maximum gate voltage is 7 V, and the on-resistance is 23 Ω·mm. The device has a good performance, which proves that the repair conditions can be successfully applied to the fabricate of the p-GaN HEMT devices.

The effects of tocotrienol supplementation on lipid profile: A meta-analysis of randomized controlled trials.

BACKGROUND & OBJECTIVE: Tocotrienol supplementation has been emerged as a potent candidate for the treatment of dyslipidemia. In the present study, a systematic review and meta-analysis of randomized controlled trials was performed with the aim of examining the effects of tocotrienol supplementation on the lipid profile. METHODS: Four databases (Scopus, PubMed/Medline, Web of Science and Embase) were used to accomplish the literature search up to November 2019. Clinical trials encompassing the impact of tocotrienol supplementation on lipid profile were extracted regardless of clinical condition, with studies included involving only adults patients. RESULTS: A total of 15 articles with 20 arms were eligible and included in the meta-analysis to estimate the pooled effect size. Overall results showed a significant effect of tocotrienol supplementation on increasing high-density lipoprotein cholesterol (HDL-C) levels (weight mean difference (WMD): 0.146 mmol/L, I2 = 85.9%) and a non-significant influence on total cholesterol (TC) (WMD: 0.010 mmol/L, I2 = 64.5%), low-density lipoprotein cholesterol (LDL-C) (WMD: 0.095 mmol/L, I2 = 87.4%), and triglycerides (TG) (WMD: -0.112 mmol/L, I2 = 67.4%) levels. Increment in HDL-C levels was significant greater for the tocotrienol dosage ≥ 200 mg/d (WMD: 0.202 mmol/L) and ≤8 weeks (WMD: 0.278 mmol/L). Moreover, studies that investigated tocotrienol dose ≥200 mg had no heterogeneity, while showing a significant decrease in TG levels (WMD: -0.177 mmol/L). CONCLUSION: The present meta-analysis demonstrated that supplementing with tocotrienols does not decrease the concentrations of LDL-C, TC and TG. However, tocotrienol supplementation was considered a candidate for increasing HDL-C levels.

Roles of polarization effects in InGaN/GaN solar cells and comparison of p-i-n and n-i-p structures.

The p-i-n and n-i-p InGaN/GaN solar cells (SCs) with Ga-face and N-face under different Indium composition were investigated and compared. From the charge distribution analysis, it can be deduced that if p-i-n was converted to n-i-p and the polarity of the SC was reversed simultaneously, or vice versa, the role of polarization effect (i.e. whether hinder or facilitate the photon-generated carriers transport) for the two SC structures would be resembling, though they had difference in degrees. The SC performance, energy band diagram at zero bias condition, recombination rate distribution and carrier concentration distribution of these SCs were analyzed, which suggested that although the polarization effect could facilitate the carrier transport both in p-i-n N-face SC and n-i-p Ga-face SC, the p-i-n N-face SC was apt to have better performance more or less if the barrier induced by band-offset at the hetero-interface would not block the carrier transport dominantly, e.g. when Indium content was less than or equal to 0.3. Besides, the high Indium content would result in the high band-offset barrier, and the barrier would affect the carrier transport in two ways, one was to hamper the carrier transport directly, and the other was to influence the electric field in i-region indirectly.

In Vitro Pharmacological Characterization and In Vivo Validation of LSN3172176 a Novel M1 Selective Muscarinic Receptor Agonist Tracer Molecule for Positron Emission Tomography.

In the search for improved symptomatic treatment options for neurodegenerative and neuropsychiatric diseases, muscarinic acetylcholine M1 receptors (M1 mAChRs) have received significant attention. Drug development efforts have identified a number of novel ligands, some of which have advanced to the clinic. However, a significant issue for progressing these therapeutics is the lack of robust, translatable, and validated biomarkers. One valuable approach to assessing target engagement is to use positron emission tomography (PET) tracers. In this study we describe the pharmacological characterization of a selective M1 agonist amenable for in vivo tracer studies. We used a novel direct binding assay to identify nonradiolabeled ligands, including LSN3172176, with the favorable characteristics required for a PET tracer. In vitro functional and radioligand binding experiments revealed that LSN3172176 was a potent partial agonist (EC50 2.4-7.0 nM, Emax 43%-73%), displaying binding selectivity for M1 mAChRs (Kd = 1.5 nM) that was conserved across species (native tissue Kd = 1.02, 2.66, 8, and 1.03 at mouse, rat, monkey, and human, respectively). Overall selectivity of LSN3172176 appeared to be a product of potency and stabilization of the high-affinity state of the M1 receptor, relative to other mAChR subtypes (M1 > M2, M4, M5 > M3). In vivo, use of wild-type and mAChR knockout mice further supported the M1-preferring selectivity profile of LSN3172176 for the M1 receptor (78% reduction in cortical occupancy in M1 KO mice). These findings support the development of LSN3172176 as a potential PET tracer for assessment of M1 mAChR target engagement in the clinic and to further elucidate the function of M1 mAChRs in health and disease.

Translational Pharmacology of the Metabotropic Glutamate 2 Receptor-Preferring Agonist LY2812223 in the Animal and Human Brain.

LY2812223 [(1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid] was identified via structure-activity studies arising from the potent metabotropic glutamate mGlu2/3 receptor agonist LY354740 [(+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid] as an mGlu2-preferring agonist. This pharmacology was determined using stably transfected cells containing either the human mGlu2 or mGlu3 receptor. We extended the pharmacological evaluation of LY2812223 to native brain tissues derived from relevant species used for preclinical drug development as well as human postmortem brain tissue. This analysis was conducted to ensure pharmacological translation from animals to human subjects in subsequent clinical studies. A guanosine 5'-O-(3-[35S]thio)triphosphate (GTPγS) functional binding assay, a method for measuring Gi-coupled signaling that is inherent to the group 2 mGlu receptors, was used to evaluate LY2812223 pharmacology of native mGlu receptors in mouse, rat, nonhuman primate, and human cortical brain tissue samples. In native tissue membranes, LY2812223 unexpectedly acted as a partial agonist across all species tested. Activity of LY2812223 was lost in cortical membranes collected from mGlu2 knockout mice, but not those from mGlu3 knockout mice, providing additional support for mGlu2-preferring activity. Other signal transduction assays were used for comparison with the GTP binding assay (cAMP, calcium mobilization, and dynamic mass redistribution). In ectopic cell line-based assays, LY2812223 displayed near maximal agonist responses at the mGlu2 receptor across all assay formats, while it showed no functional agonist activity at the mGlu3 receptor except in the cAMP assay. In native brain slices or membranes that express both mGlu2 and mGlu3 receptors, LY2812223 displayed unexpected partial agonist activity, which may suggest a functional interplay between these receptor subtypes in the brain.

Knowledge for unintentional injury and risky behavior among the school-age children in Changsha city of China.

OBJECTIVE: To investigate the current status on knowledge for unintentional injury and risky behavior among school-age children in Changsha, China, and to provide scientific evidence for the preventive strategies.
 METHODS: A cross-sectional study was conducted on 866 students who were between 6 and 12 years old in Changsha. Two primary schools were selected by stratified cluster random sampling from all primary schools of Changsha city to collect the information regarding knowledge for unintentional injury and risky behavior occurring in the 6-month period before the survey.
 RESULTS: The mean score for knowledge of unintentional injury was 11.83±2.38. The levels of knowledge for unintentional injury differed significantly in child's age, parents' education background and child's injury history (P<0.05). The child's knowledge level was correlated with child's age, mother's education, child's injury history. The mean score for risky behavior was 17.61±10.35. The levels of risky behavior differed significantly in child's gender, father's age to have the child, parents' marriage status, whom does/do child live with, child's injury history and medical history since the birthday (P<0.05). There was a linear regression relationship between risky behavior and child's injury history, parents' marriage status, child's gender. There was no significant correlation between knowledge and risky behavior (P>0.05).
 CONCLUSION: It is a common phenomenon in school-age children who are lack of the knowledge for unintentional injury and risky behavior. This study provides useful information on the risk factors for unintentional injury and risky behavior, which would be significant for prevention program.

[Influence of Electroacupuncture Intervention on Glutamic Acid and Ca2+ Contents and Expression of NMDA Receptor Protein in Hippocampus in Vascular Dementia Rats].

OBJECTIVE: To observe the influence of electroacupuncture (EA) intervention on hippocampal glutamate (Glu) and Ca2+ contents, and expression of Glu-N-methyl-D-aspartic acid receptor(NMDAR) and the learning-memory ability in vascular dementia (VD) rats, so as to reveal its mechanisms underlying improvement of VD. METHODS: SD rats were rando-mized into sham operation (sham) group (n=9), model group (n=11) and EA groups (n=10). The VD model was established by repeated bilateral common carotid arteries occlusion and reperfusion plus intraperitoneal injection of sodium nitroprusside. EA (2 Hz, 2 mA) was applied to "Baihui" (GV 20)-"Housanli" (ST 36) and "Geshu" (BL 17)-"Dazhui" (GV 14) for 10 min, once a day for 15 consecutive days. The neurological function was assessed by using stroke index (0-10 points) and neurological deficit scaling(0-10 points). The learning-memory ability was evaluated by using step-down tests. The contents of Glu and Ca2+ in the right hippocampal tissue were determined by using aspectrophotometer and the expression of NMDAR protein in the right hippocampus was detected by immunoblotting. RESULTS: Compared with the sham group, the stroke index and neurological deficit scores, and the reaction latency and the error times of step-down tests, as well as the contents of Glu and Ca2+ and the expression level of NMDAR in the right hippocampus were significantly increased in the model group (P<0.05, P<0.01), while the step-through latency was considerably decreased (P<0.01), suggesting a neurological disorder and a cognitive decline. After EA intervention, the reaction latency and error times of step-down tests, the contents of Glu and Ca2+ and the expression level of NMDAR in the right hippocampus were significantly down-regulated, and the step-through latency was notably increased in comparison with the model group (P<0.01). CONCLUSIONS: EA intervention is able to improve the cognitive ability of VD rats, which may be associated with its effects in reducing the excitatory neurotoxicity of hippocampal Glu-NMDAR and lowering cellular Ca2+ load to resist neuronal injury.

Value of triage early warning score for trauma patients in an emergency department.

OBJECTIVE: To evaluate the predictive accuracy of the triage early warning score (TEWS) in the prognosis and emergency treatment for trauma patients admitted to the emergency department (ED). METHODS: A total of 456 trauma patients (>12 years old) admitted to ED at an education and research hospital in approximately 4 months were prospectively studied. Th e TEWS was recorded in all patients. Th e primary end-point was during 28 days and the emergency responses (such as cardiopulmonary resuscitation/electrical defibrillation, mechanical ventilation) in the ED. RESULTS: Patients with TEWS less than or equal to 9, from 10 to 13, or greater or equal to 14 had mortality rates of 0.98%, 52.63%, or 80%, respectively. An increase in 1 point within the range of 17-point TEWS would be associated with an odds ratio (OR) of 2.14 for death [95% confidence interval (CI): 1.759 to 2.604]. In predicting mortality rates during 28 days, the cut-point was greater than 8, the sensitivity was 87.10% (95% CI: 70.2% to 96.4%), the specificity was 92.47% (95% CI: 89.5% to 94.8%), and the areas under the receiver operating characteristic curves (AUCROC) was 0.929 (95% CI: 0.902 to 0.951). Th e AUCROC of TEWS in predicting the emergency responses for CPR/electrical defibrillation application or mechanical ventilation was 0.969 (95% CI: 0.949 to 0.983) or 0.897 (95% CI: 0.865 to 0.923), respectively. CONCLUSION: TEWS is effective in predicting the prognosis and emergency treatment for trauma patients admitted to ED.

123I-iododexetimide preferentially binds to the muscarinic receptor subtype M1 in vivo.

UNLABELLED: The muscarinic M1 receptor (M1R) is highly involved in cognition, and selective M1 agonists have procognitive properties. Loss of M1R has been found in postmortem brain tissue for several neuropsychiatric disorders and may be related to symptoms of cognitive dysfunction. (123)I-iododexetimide is used for imaging muscarinic acetylcholine receptors (mAchRs). Considering its high brain uptake and intense binding in M1R-rich brain areas, (123)I-iododexetimide may be an attractive radiopharmaceutical to image M1R. To date, the binding affinity and selectivity of (123)I-iododexetimide for the mAchR subtypes has not been characterized, nor has its brain distribution been studied intensively. Therefore, this study aimed to address these topics. METHODS: The in vitro affinity and selectivity of (127)I-iododexetimide (cold-labeled iododexetimide), as well as its functional antagonist properties (guanosine 5'-[γ-(35)S-thio]triphosphate [GTPγ(35)S] assay), were assessed on recombinant human M1R-M5R. Distributions of (127)I-iododexetimide and (123)I-iododexetimide in the brain were evaluated using liquid chromatography-mass spectrometry and storage phosphor imaging, respectively, ex vivo in rats, wild-type mice, and M1-M5 knock-out (KO) mice. Inhibition of (127)I-iododexetimide and (123)I-iododexetimide binding in M1R-rich brain areas by the M1R/M4R agonist xanomeline, or the antipsychotics olanzapine (M1R antagonist) and haloperidol (low M1R affinity), was assessed in rats ex vivo. RESULTS: In vitro, (127)I-iododexetimide displayed high affinity for M1R (pM range), with modest selectivity over other mAchRs. In biodistribution studies on rats, ex vivo (127)I-iododexetimide binding was much higher in M1R-rich brain areas, such as the cortex and striatum, than in cerebellum (devoid of M1Rs). In M1 KO mice, but not M2-M5 KO mice, (127)I-iododexetimide binding was strongly reduced in the frontal cortex compared with wild-type mice. Finally, acute administration of both an M1R/M4R agonist xanomeline and the M1R antagonist olanzapine was able to inhibit (123)I-iododexetimide ex vivo, and (123)I-iododexetimide binding in M1-rich brain areas in rats, whereas administration of haloperidol had no effect. CONCLUSION: The current results suggest that (123)I-iododexetimide preferentially binds to M1R in vivo and can be displaced by M1R ligands. (123)I-iododexetimide may therefore be a useful imaging tool as a way to further evaluate M1R changes in neuropsychiatric disorders, as a potential stratifying biomarker, or as a clinical target engagement biomarker to assess M1R.

[Medication rule for treatment of functional dyspepsia: an analysis of traditional Chinese medicine literature based on China National Knowledge Internet].

By retrieving the clinical research literature of treatment functional dyspepsia by traditional Chinese medicine (TCM) from January 2004 to December 2014 based on China National Knowledge Internet (CNKI), we would establish a TCM decoction database for treating functional dyspepsia in this study. One hundred and sixty-four literature were included, involving 159 prescriptions, 377 medicines, in a total of 1 990 herbs. These herbs can be divided into 18 categories according to the effectiveness; and qi-regulating herbs, blood circulation herbs, and antipyretic herbs ranked top three ones according to the frequency of usage of the herbs, whose medicine usage frequency accounted for 51.81%. Usage frequency of 16 herbs was over 30, and Atractylodes, Radix, Poriaranked top three according to the usage frequency. Medicinal properties were divided into 9 kinds according to the frequency statistics, and the top three were warm, flat, and cold. Taste frequency statistics were classifiedinto 9 kinds, and the top three were acrid, sweet, and bitter. In frequency statistics of the meridian tropism of herbs, it was classifiedinto 11 kinds, and the top three were spleen, stomach, lung. The analysis can provide a reference for treatment and study of TCM of functional dyspepsia.

[Effect of electroacupuncture intervention on levels of SOD, GSH, GSH-Px, MDA, and apoptosis of dopaminergic neurons in substantia Nigra in rats with Parkinson's disease].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on superoxide (SOD), glutathione peroxidase (GSH-Px) activity, contents of glutathione (GSH) and malondiadehyde (MDA), and expression of tyrosine hydroxylase (TH) and apoptosis of Dopaminergic (DA) neurons in Substantia Nigra of rats with Parkinson's disease (PD). METHODS: Adult male Wistar rats were randomly divided into normal (10 rats), model (11 rats), EA (11 rats) and medication (11 rats) groups. The PD model was established by i.h. of Rotenone (0.8 mg/kg) for 28 days. EA stimulation (2 Hz/80 Hz, 2 mA) was applied at "Baihui" (GV 20), "Sanyinjiao" (SP 6) and "Taichong" (LR 3) acupoints for 10 min, once per day for 14 times. For rats in the medication group, Madopar suspension fluid (1.67 mg/kg) was given by gavage for 14 days. Xanthine oxidase method and colorimetric ana- lysis method were used to examine the SOD, GSH-Px activity and contents of GSH and MDA in the Substantia Nigra tissue of the right brain, respectively. Immunohistochemical technique was used to detect the TH positive neurons and TUNEL method was used to examine the apoptosis of DA neurons of the Substantia Nigra in the left brain. RESULTS: Following the intervention, the decreased SOD and GSH-Px activity, GSH contents, and the increased MDA content of the Substantia Nigra in PD rats were obviously reversed by EA intervention (P < 0.05) but not by medication except MDA content (P > 0.05). In comparison with the model group, the decreased TH immunoactivity, and the increased numbers of apoptotic cells of DA neurons were apparently suppressed in both EA and medication groups (P < 0.05), but without significant differences between the EA and the medication groups (P > 0.05). In addition, HE stain showed that EA intervention could improve PD-induced impairment of Substantia Nigra neurons (mild swelling of neurons with large nucleus and deranged fibers). CONCLUSION: EA intervention can reduce pathological changes of Substantial Nigra in PD rats, which is probably associated with its effects in up-regulating the SOD and GSH-Px activity, GSH contents, and down-regulating MDA level, and reducing the apoptosis of DA neurons of the Substantia Nigra, suggesting an anti-oxidative stress effect of EA therapy.

Characterization of the novel positive allosteric modulator, LY2119620, at the muscarinic M(2) and M(4) receptors.

The M(4) receptor is a compelling therapeutic target, as this receptor modulates neural circuits dysregulated in schizophrenia, and there is clinical evidence that muscarinic agonists possess both antipsychotic and procognitive efficacy. Recent efforts have shifted toward allosteric ligands to maximize receptor selectivity and manipulate endogenous cholinergic and dopaminergic signaling. In this study, we present the pharmacological characterization of LY2119620 (3-amino-5-chloro-N-cyclopropyl-4-methyl-6-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy] thieno[2,3-b]pyridine-2-carboxamide), a M(2)/M(4) receptor-selective positive allosteric modulator (PAM), chemically evolved from hits identified through a M4 allosteric functional screen. Although unsuitable as a therapeutic due to M(2) receptor cross-reactivity and, thus, potential cardiovascular liability, LY2119620 surpassed previous congeners in potency and PAM activity and broadens research capabilities through its development into a radiotracer. Characterization of LY2119620 revealed evidence of probe dependence in both binding and functional assays. Guanosine 5'-[γ-(35)S]-triphosphate assays displayed differential potentiation depending on the orthosteric-allosteric pairing, with the largest cooperativity observed for oxotremorine M (Oxo-M) LY2119620. Further [(3)H]Oxo-M saturation binding, including studies with guanosine-5'-[(ß,γ)-imido]triphosphate, suggests that both the orthosteric and allosteric ligands can alter the population of receptors in the active G protein-coupled state. Additionally, this work expands the characterization of the orthosteric agonist, iperoxo, at the M(4) receptor, and demonstrates that an allosteric ligand can positively modulate the binding and functional efficacy of this high efficacy ligand. Ultimately, it was the M(2) receptor pharmacology and PAM activity with iperoxo that made LY2119620 the most suitable allosteric partner for the M(2) active-state structure recently solved (Kruse et al., 2013), a structure that provides crucial insights into the mechanisms of orthosteric activation and allosteric modulation of muscarinic receptors.

Development of a radioligand, [(3)H]LY2119620, to probe the human M(2) and M(4) muscarinic receptor allosteric binding sites.

In this study, we characterized a muscarinic acetylcholine receptor (mAChR) potentiator, LY2119620 (3-amino-5-chloro-N-cyclopropyl-4-methyl-6-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]thieno[2,3-b]pyridine-2-carboxamide) as a novel probe of the human M2 and M4 allosteric binding sites. Since the discovery of allosteric binding sites on G protein-coupled receptors, compounds targeting these novel sites have been starting to emerge. For example, LY2033298 (3-amino-5-chloro-6-methoxy-4-methyl-thieno(2,3-b)pyridine-2-carboxylic acid cyclopropylamid) and a derivative of this chemical scaffold, VU152100 (3-amino-N-(4-methoxybenzyl)-4,6-dim​ethylthieno[2,3-b]pyridine carboxamide), bind to the human M4 mAChR allosteric pocket. In the current study, we characterized LY2119620, a compound similar in structure to LY2033298 and binds to the same allosteric site on the human M4 mAChRs. However, LY2119620 also binds to an allosteric site on the human M2 subtype. [(3)H]NMS ([(3)H]N-methylscopolamine) binding experiments confirm that LY2119620 does not compete for the orthosteric binding pocket at any of the five muscarinic receptor subtypes. Dissociation kinetic studies using [(3)H]NMS further support that LY2119620 binds allosterically to the M2 and M4 mAChRs and was positively cooperative with muscarinic orthosteric agonists. To probe directly the allosteric sites on M2 and M4, we radiolabeled LY2119620. Cooperativity binding of [(3)H]LY2119620 with mAChR orthosteric agonists detects significant changes in Bmax values with little change in Kd, suggesting a G protein-dependent process. Furthermore, [(3)H]LY2119620 was displaced by compounds of similar chemical structure but not by previously described mAChR allosteric compounds such as gallamine or WIN 62,577 (17-ß-hydroxy-17-α-ethynyl-δ-4-androstano[3,2-b]pyrimido[1,2-a]benzimidazole). Our results therefore demonstrate the development of a radioligand, [(3)H]LY2119620 to probe specifically the human M2 and M4 muscarinic receptor allosteric binding sites.

Effect of electroacupuncture on brain-derived neurotrophic factor mRNA expression in mouse hippocampus following cerebral ischemia-reperfusion injury.

OBJECTIVE: This work aims to observe the effects of electroacupuncture on brain-derived neurotrophic factor (BDNF) mRNA expression in mouse hippocampus following cerebral ischemia-reperfusion injury. METHODS: The models of mouse cerebral ischemia-reperfusion injury were established. A total of 96 healthy mice were randomly assigned into 4 groups, namely, the sham surgery, model, model + electroacupuncture, and mode + hydergine groups. Mice in the model + electroacupuncture group were treated through electroacupuncture at the Shenshu (BL 23), Geshu (BL 17), and Baihui (GV 20) acupoints. Mice in the model+hydergine group were intragastrically administered with hydergine (0.77 mg/kg(-1) x day(-1)). The levels of BDNF mRNA expressions in the hippocampus were ana lyzed through a semi-quantitative reverse transcription-polymerase chain reaction assay on days 1 and 7 after the surgeries. RESULTS: BDNF mRNA expressions in the mouse hippocampus of the model group on days 1 and 7 after the surgery were higher than those of the sham surgery group (both P < 0.01). On days 1 and 7 of the electroacupuncture treatment, BDNF mRNA expression in the mouse hippocampus of the model + electroacupuncture group was significantly elevated compared with the model group (both P < 0.01) or the model + hydergine group (both P < 0.01). On days 1 and 7 of the hydergine treatment, BDNF mRNA expression in the mouse hippocampus of the model + hydergine group tended to increase compared with the model group; however, statistical significance was not achieved (both P > 0.05). CONCLUSION: Electroacupuncture treatment enhances endogenous BDNF expression, which may improve the survival environment for intracerebral neurons and inhibit the apoptosis of hippocampal cells.