Serum metabolomics analysis revealed metabolic disorders in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is by now the second of the most prevalent neurodegenerative diseases in the world, and its incidence is increasing rapidly as the global population ages, with 14.2 million PD patients expected worldwide by 2040. METHODS: We gathered a completion of 45 serum samples, including 15 of healthy controls and 30 from the PD group. We used non-targeted metabolomics analysis based on liquid chromatography-mass spectrometry to identify the molecular changes in PD patients, and conducted bioinformatics analysis on this basis to explore the possible pathogenesis of PD. RESULTS: We found significant metabolomics changes in the levels of 30 metabolites in PD patients compared with healthy controls. CONCLUSION: Lipids and lipid-like molecules accounted for the majority of the 30 differentially expressed metabolites. Also, pathway enrichment analysis showed significant enrichment in sphingolipid metabolic pathway. These assessments can improve our perception on the underlying mechanism of PD as well as facilitate a better targeting on therapeutic interventions.

[Transcutaneous auricular vagus nerve stimulation promotes gastric motility by up-rgulating α7nAChR and suppressing NF-κB p65 expression in duodenum in rats with functional dyspepsia].

OBJECTIVE: To study the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on gastric sensitivity and motility in rats with functional dyspepsia (FD), so as to explore its underlying mechanism in improving FD. METHODS: A total of 48 young SD rats were randomly divided into control (n=10), model (n=9), taVNS (n=9), subdiaphragmatic vagus nerve stimulation (SDVNS, n=9) and sham SDVNS (n=7) groups. The FD model was established by gavage of 0.1% iodoa-cetamide+2% glucose, once daily for 6 days. Rats in the taVNS group received taVNS (0.5 mA) of optopoint "Heart" and "Stomach" for 30 min, once daily for 14 days, while rats in the SDVNS group received subdiaphragmatic vagus nerve stimulation through the implanted electrode, and those of the sham SDVNS group received only application of the same electrodes without electrical stimulation. Electromyogram (EMG) of the cervical trapezius muscle (reflecting gastric sensitivity) was recorded before and after intragastric expansion via an air ballon and the gastric emptying rate was calculated for assessing the gastric motility. The contents of acetylcholine (ACh), nicotinic acetylcholine receptor α7 subunit (α7nAChR), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in the duodenum tissue were detected by enzyme-linked immunosorbent assay (ELISA). The expression of nuclear factor kappa B (NF-κB) p65 in the duodenum tissue was determined by Western blot. RESULTS: In comparison with the control group, the EMG change rate at intragastric pressure levels of 40, 60 and 80 mm Hg, expression of NF-κB p65 protein, and contents of IL-6, IL-1ß and TNF-α were significantly increased (P<0.05,P<0.01, P<0.001), while the gastric emptying rate, ACh and α7nAChR contents considerably decreased (P<0.05, P<0.001) in the model group. After interventions, the EMG change rate, contents of IL-6, IL-1ß and TNF-α, and expression of NF-κB p65 were notably decreased (P<0.05, P<0.01, P<0.001), and the gastric emptying rate, ACh and α7nAChR contents obviously increased (P<0.05, P<0.001) in both taVNS and SDVNS groups relevant to the model group. In comparison with the sham SDVNS group, the EMG change rate, contents of IL-6, IL-1ß and TNF-α, and expression of NF-κB p65 were notably decreased (P<0.01, P<0.05,P<0.001), and the gastric emptying rate, ACh and α7nAChR contents obviously increased (P<0.01, P<0.001) in the both SDVNS and taVNS groups. CONCLUSION: taVNS can reduce gastric sensitivity and promote gastric emptying in FD model rats, which may be closely related to its functions in up-regulating ACh and α7nAChR contents and inhibiting the activation of NF-κB p65 signaling in the duodenum.

Auricular Vagus Nerve Stimulation Ameliorates Functional Dyspepsia with Depressive-Like Behavior and Inhibits the Hypothalamus-Pituitary-Adrenal Axis in a Rat Model.

BACKGROUND: The hypothalamus-pituitary-adrenal axis is the most important endocrine system to control irritability response. Functional dyspepsia (FD) is closely related to irritability. This study aimed to preliminarily explore the corticotropin-releasing factor (CRF) mechanism of auricular vagus nerve stimulation (aVNS) for FD model rats. METHODS: Sprague-Dawley adult male rats were randomly divided into normal group, model group, aVNS group, and sham-aVNS group. Except for the normal rats, all other rats were induced into the FD model through tail-clamping stimulation for 3 weeks. Once the rat model was developed successfully, rats in the aVNS group and sham-aVNS group were intervened with aVNS or sham-aVNS for 2 weeks. No intervention was given to rats in the normal and model groups. The effect of aVNS was assessed. The expressions of hippocampal corticotropin-releasing hormone receptor 1 (CRHR1), hypothalamus CRF, adrenocorticotropic hormone (ACTH), and corticosterone in serum were assessed. RESULTS: 1. Compared with normal rats, model-developing rats showed FD-like behavior. 2. Compared with model rats, rats in the aVNS group showed an improved general condition score and gastric motility, and increased horizontal and vertical motion scores. 3. The release of corticosterone, ACTH in serum, and CRF in the hypothalamus all increased in model rats but decreased with aVNS instead of sham-aVNS. 4. The expression of hippocampus CRHR1 was lower in model rats but higher in the aVNS group. CONCLUSION: aVNS ameliorates gastric motility and improves the mental state in the FD-like rat, probably via inhibiting the CRF pathway.

Effects of transcutaneous auricular vagus nerve stimulation on brain functional connectivity of medial prefrontal cortex in patients with primary insomnia.

As a representative of acupuncture and nonpharmaceutical therapy, auricular acupuncture has been widely for the treatment of insomnia. Transcutaneous auricular vagus nerve stimulation (taVNS) is a combination of auricular point stimulation and vagus nerve stimulation. It can not only treat primary insomnia effectively, but also is noninvasive, painless, portable and economical. The medial prefrontal cortex (mPFC) is a core region of default mode network (DMN), which is important for maintenance of sleep. However, the mechanism of taVNS in alleviating primary insomnia (PI) remains to be clarified. In this study, we found that taVNS could not only effectively reduce the score of Pittsburgh Sleep Quality Index, but also decreased functional connection (FC) between the left mPFC and bilateral dorsal anterior cingulate gyrus as well as FC between the right mPFC and the occipital cortex in patients with PI. Furthermore, the decrease in FC was positively correlated with the decline of sleep index score. Therefore, we proposed that treatment with taVNS can improve sleep quality and prolong sleep duration in patients with PI by reducing FC within DMN, FC between DMN and salience network, as well as FC between DMN and the occipital cortex. This may be one of mechanisms of taVNS in treating PI.

[Effects of transcutaneous auricular vagus nerve stimulation on autonomic nervous function in rats with functional dyspepsia].

OBJECTIVE: To observe the effect of transcutaneous auricular vagus nerve stimulation (taVNS) on the autonomic nerve function in a rat model of functional dyspepsia (FD), so as to explore the mechanism of taVNS underlying regulation of FD. METHODS: SD rats were randomly divided into normal control group(n=8) and FD model group(n=26).The FD model was replicated with iodoacetamide gavage. The FD model rats were randomly divided into model, taVNS, sham-taVNS and Zusanli(ST36) groups, with 6 rats in each group. Rats in the taVNS group received electrical stimulation of auricular concha,while the sham-taVNS group received no electrical stimulation and rats in the ST36 group received stimulation at ST36 for 30 min once daily for 14 consecutive days. Cervical trapezius electromyography score and abdominal withdrawal reflex (AWR) score were used to evaluate gastric sensitivity. Histopathological changes of the gastric antrum tissue were observed under microscope after H.E. staining. Autonomic nerve function in rats was recorded and assessed by heart rate variability(HRV). The content of acetylcholine (Ach) and the expression of Ach receptor M3R in gastric antrum was detect by ELISA and Western blot, separately. RESULTS: Compared with the normal control group, the cervical trapezius electromyography and AWR scores of the model group increased (P<0.01, P<0.001), and there was no erosion in the gastric antral mucosa and muscle layer. The high-frequency power (HF) in HRV decreased (P<0.05), the ratio of low-frequency power/high-frequency power (LF/HF) increased (P<0.001), and the Ach content and its receptor M3R expression in gastric antrum tissue decreased (P<0.05). Following interventions, the cervical trapezius electromyography and AWR scores decreased (P<0.01,P<0.001, P<0.05), HF in HRV increased and LF/HF decreased(P<0.01，P<0.05,P<0.001), and the content of Ach in gastric antrum tissue and the expression of its receptor M3R increased (P<0.01, P<0.05) in both taVNS and ST36 groups relevant to the model group. CONCLUSION: taVNS can increase the activity of the vagus nerve and regulate the balance of the autonomic nerve function, which may be one of the mechanisms of taVNS in reducing the gastric sensitivity of rats with FD. In regulating the vagus nerve function, taVNS and acupuncture at ST36 acupoint have the similar effects.

Transcutaneous Auricular Vagus Nerve Stimulation: From Concept to Application.

Whether in the West or the East, the connection between the ear and the rest of the body has been explored for a long time. Especially in the past century or more, the relevant theoretical and applied research on the ear has greatly promoted the development of ear therapy, and finally the concept of transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed. The purpose of taVNS is to treat a disease non-invasively by applying electrical current to the cutaneous receptive field formed by the auricular branch of the vagus nerve in the outer ear. In the past two decades, taVNS has been a topic of basic, clinical, and transformation research. It has been applied as an alternative to drug treatment for a variety of diseases. Based on the rapid understanding of the application of taVNS to human health and disease, some limitations in the development of this field have also been gradually exposed. Here, we comprehensively review the origin and research status of the field.

[Instant adjustive effect of auricular electroacupuncture on brain default model network of patients with primary insomnia].

OBJECTIVE: To investigate the immediate brain effect of auricular electroacupuncture (EA) in the treatment of primary insomnia (PI). METHODS: In this study, 15 subjects with PI who were diagnosed according to Pitsburgh Sleep Quality Index (PSQI), and other 15 age- and gender-matched subjects without insomnia were recruited in the present study. The PI patients received EA (4 Hz/20 Hz, a tolerable electrical current strength) of auricular concha for 30 min, and their resting state functional magnetic resonance imaging (fMRI) data before and after treatment were collected. The healthy subjects received no any treatment and their resting state fMRI data were collected. The diffe-rence of default mode network functional connectivity between the patients and healthy subjects, and changes of the patient's brain functional connectivity after EA treatment were estimated by using seed-point-based analysis (SPBA). RESULTS: Analysis by taking the posterior cingulate gyrus as the seed-point showed that compared with the healthy participants before treatment, the patient's brain functional connectivity between the posterior cingulate gyrus and the right insula, or the inferior frontal gyrus of the right opercularis region, or the right rolandic operculum was increased. After 30 minutes' EA treatment, the functional connectivity between the posterior cingulate gyrus and the precuneus, the left angular gyrus, the left frontal superior gyrus, the left frontal middle cortex, the right temporalis inferior gyrus, the right temporalis middle gyrus or the left medial orbitofrontal cortex was decreased, while the functional connectivity between the posterior cingulate gyrus and the right lingual gyrus, or the cortex surrounding the right calcarine fissure was increased. CONCLUSION: EA of auricular concha has an instant effect in modulating the brain default mode network in PI patients, which may be its brain mechanism underlying improvement of PI.

Efficacy of Chinese Herbal Medicine for Diarrhea-Predominant Irritable Bowel Syndrome: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials.

Objective. To explore the efficacy of Chinese herbal medicine in treating diarrhea-predominant irritable bowel syndrome (D-IBS). Methods. Four English and four Chinese databases were searched through November, 2015. Randomized, double-blind and placebo-controlled trials were selected. Data extraction and quality evaluation were performed by two authors independently. RevMan 5.2.0 software was applied to analyze the data of included trials. Results. A total of 14 trials involving 1551 patients were included. Meta-analysis demonstrated superior global symptom improvement (RR = 1.62; 95% CI 1.31, 2.00; P < 0.00001; number needed to treat = 3.6), abdominal pain improvement (RR = 1.95; 95% CI 1.61, 2.35; P < 0.00001), diarrhea improvement (RR = 1.87; 95% CI 1.60, 2.20; P < 0.00001), pain threshold assessment (MD = 54.53; 95% CI 38.76, 70.30; P < 0.00001), and lower IBS Symptom Severity Score (SMD = -1.01; 95% CI -1.72, -0.30; P = 0.005), when compared with placebo, while for defecation threshold assessment, quality of life, and adverse events, no differences were found between treatment groups and controlled groups. Conclusion. This meta-analysis shows that Chinese herbal medicine is an effective and safe treatment for D-IBS. However, due to the small sample size and high heterogeneity, further studies are required.

Self-Assembly of Ferritin Nanoparticles into an Enzyme Nanocomposite with Tunable Size for Ultrasensitive Immunoassay.

The self-assembly of nanoparticles into larger superstructures is a powerful strategy to develop novel functional nanomaterials, as these superstructures display collective properties that are different to those displayed by individual nanoparticles or bulk samples. However, there are increasing bottlenecks in terms of size control and multifunctionalization of nanoparticle assemblies. In this study, we developed a self-assembly strategy for construction of multifunctional nanoparticle assemblies of tunable size, through rational regulation of the number of self-assembling interaction sites on each nanoparticle. As proof-of-principle, a size-controlled enzyme nanocomposite (ENC) was constructed by self-assembly of streptavidin-labeled horseradish peroxidase (SA-HRP) and autobiotinylated ferritin nanoparticles (bFNP). Our ENC integrates a large number of enzyme molecules, together with a streptavidin-coated surface, allowing for a drastic increase in enzymatic signal when the SA is bound to a biotinylated target molecule. As result, a 10 000-fold increase in sensitivity over conventional enzyme-linked immunosorbent assays (ELISA) methods was achieved in a cardiac troponin immunoassay. Our method presented here should provide a feasible approach for constructing elaborate multifunctional superstructures of tunable size useful for a broad range of biomedical applications.

Effects of dexamethasone on aquaporin-4 expression in brain tissue of rat with bacterial meningitis.

Aquaporin-4 (AQP4) is the most popular water channel protein expressed in brain tissue and plays a very important role in regulating the water balance in and outside of brain parenchyma. To investigate the expression of aquaporin-4 in the rat brain tissue after dexamethasone therapy of meningitis induced by Streptococcus pneumonia, total 40 of 3-week old Sprague-Dawley rats were divided into infection group (n=30) and normal control group (n=10). The meningitis groups were infected with 1×10(7) cfu/ml of Streptococcus pneumoniae and then randomized into no treatment (untreated group, n=10), treatment with ceftriaxone (CTRX group, n=10) and treatment with dexamethasone combined ceftriaxone (CTRX+DEXA group, n=10). The normal control group was established by using saline. The rats were euthanized when they reached terminal illness or five days after infection, followed by detection of AQP4 through using immunohistochemistry and Western blot methods. Data has showed that expression of AQP4 in model group remained higher than the control and treatment group (P<0.05). AQP4 expression in CTRX+DEXA group was lower than that in CTRX group (P<0.05). There was no statistical difference between CTRX+DEXA group and the control group (P>0.05). These data suggested that Dexamethasone could down-regulate the expression of AQP4 in the brain tissue of rats with meningitis and provides evidence for the mechanism of protective effect of Dexamethasone on central neurosystem.