BACKGROUND: : Tourette syndrome (TS) is a neuropsychiatric disorder with onset in childhood that warrants effective therapies. Gut microbiota can affect central physiology and function via the microbiota-gut-brain axis. Therefore, the gut microbiota plays an important role in some mental illnesses. A small clinical trial showed that fecal microbiota transplantation (FMT) may alleviate TS symptoms in children. Herein, FMT effects and mechanisms were explored in a TS mouse model. METHODS: : TS mice model (TSMO) (n = 80) were established with 3,3'-iminodipropionitrile, and 80 mice were used as controls. Mice were grouped into eight groups and were subjected to FMT with feces from children or mice with or without TS, or were given probiotics. Fecal specimens were collected 3 weeks after FMT. 16S rRNA sequencing, behavioral observation, and serum serotonin (5-HT) assay were performed. Differences between groups were analyzed using Mann-Whitney U test and Kolmogorov-Smirnov (KS) tests. RESULTS: : A total of 18 discriminative microbial signatures (linear discriminant analysis score > 3) that varied significantly between TS and healthy mice (CONH) were identified. A significant increase in Turicibacteraceae and Ruminococcaceae in TSMO after FMT was observed (P  < 0.05). Compared with non-transplanted TSMO, the symptoms of those transplanted with feces from CONH were alleviated (W = 336, P = 0.046). In the probiotic and FMT experiments, the serum 5-HT levels significantly increased in TSMO that received probiotics (KS = 1.423, P = 0.035) and in those transplanted with feces from CONH (W = 336.5, P = 0.046) compared with TSMO without transplantation. CONCLUSIONS : This study suggests that FMT may ameliorate TS by promoting 5-HT secretion, and it provides new insights into the underlying mechanisms of FMT as a treatment for TS.
Animals ; Disease Models, Animal ; Fecal Microbiota Transplantation ; Gastrointestinal Microbiome/physiology* ; Mice ; RNA, Ribosomal, 16S/genetics* ; Serotonin ; Tics ; Tourette Syndrome/therapy*

OBJECTIVE: To observe the clinical effect of chicken-claw needling at Xiaguan (ST 7) combined with intradermal needling on negative emotion in primary trigeminal neuralgia (PTN) of phlegm obstruction and blood stasis. METHODS: Sixty cases of patients with PTN of phlegm obstruction and blood stasis were randomly divided into an observation group and a control group, 30 cases in each group. The observation group was treated with chicken-claw needling at Xiaguan (ST 7) combined with intradermal needling (acupoints Sibai [ST 2], Yuyao [EX-HN 4], Hegu [LI 4], Taichong [LR 3] and auricular points Xin [CO₁₅], Shenmen [TF₄], Pizhixia [AT₄], etc.), once a day, 6 d as a course of treatment, rest 1 d between courses, a total of 2 courses of treatment; and the control group was given oral carbamazepine tablets for 13 days. Before and after treatment, the pain visual analogue scale (VAS), TCM syndromes, self-rating anxiety scale (SAS) scores and the contents of serum neurotransmitter (β-endorphin [β-EP], substance P [SP] and 5-hydroxytryptamine [5-HT]) were compared, and the clinical efficacy was evaluated. RESULTS: After treatment, the VAS, SAS, TCM syndrome scores and the contents of serum SP in the two groups were lower than those before treatment (P<0.05), and the above indexes in the observation group was lower than those in the control group (P<0.05). The contents of serum β-EP and 5-HT in the two groups were higher than those before treatment (P<0.05), and the above indexes in the observation group were higher than those in the control group (P<0.05). The total effective rate in the observation group was 93.3% (28/30), which was higher than 83.3% (25/30) in the control group (P<0.05). CONCLUSION Chicken-claw needling at Xiaguan (ST 7) combined with intradermal needling can relieve pain symptoms and negative emotions in patients with primary trigeminal neuralgia of phlegm obstruction and blood stasis, which may be related to the regulation of serum neurotransmitter levels.
Acupuncture Points ; Acupuncture Therapy ; Emotions ; Humans ; Pain ; Serotonin ; Syndrome ; Treatment Outcome ; Trigeminal Neuralgia/therapy*

OBJECTIVE: To observe the effect of blistering moxibustion on the expression levels of 5-hydroxytyptamine (5-HT) and its receptors of the colon tissue in the mice with visceral hypersensitivity of irritable bowel syndrome (IBS), so as to explore the effect mechanism of blistering moxibustion in treatment of IBS. METHODS: Forty SPF-grade newborn Kunming mice were randomly divided into a normal group, a model group, an antagonist group and a blistering moxibustion group, 10 mice in each one. Before modeling, the injection with 0.2 mL parachlorophenylalanine (PCPA) was given on the lateral ventricle in the antagonist group. The endorectal glacial acetic acid stimulation combined with tail clipping was used to prepare the model of visceral hypersensitivity of IBS in the model group, the antagonist group and the blistering moxibustion group. After modeling, in the blistering moxibustion group, the intervention with blistering moxibustion was exerted at "Zhongwan" (CV 12), "Tianshu" (ST 25) and "Zusanli" (ST 36), once herbal irritant plaster at each acupoint, for 2 h each time, once a week, consecutively for 3 weeks. Abdominal withdrawal reflex (AWR) score and electromyographic (EMG) amplitude of abdominal muscles were adopted to evaluate the visceral hypersensitivity. HE staining was applied to observe the morphological changes in colon tissue, and immunohistochemistry was to determine the expression levels of 5-HT and its receptors. RESULTS: Compared with the normal group, EMG amplitude of abdominal muscles was increased under 20, 40 mm Hg (1 mm Hg=0.133 kPa) in the model group (P<0.05), AWR scores and EMG amplitude of abdominal muscles under 60, 80 mm Hg were all increased in the model group (P<0.05). In comparison with the model group, EMG amplitude of abdominal muscles was reduced under 20 mm Hg in the blistering moxibustion group (P<0.05), AWR scores were increased under 40 mm Hg in both the blistering moxibustion group and the antagonist group (P<0.05); AWR scores and EMG amplitude of abdominal muscles under 60, 80 mm Hg were all reduced in both the blistering moxibustion group and the antagonist group (P<0.05). Compared with the normal group, in the model group, the mucosa was slightly disturbed, while, the moderate inflammatory cells were visible in the submucosa. In comparison with the model group, the inherent glands of mucosa were regular in shape and a small number of inflammatory cells were visible in both the blistering moxibustion group and the antagonist group. In comparison with the normal group, the average positive staining area percentage (APSAP) of 5-HT and 5-HT₃R of the colon tissue was increased, while, APSAP of 5-HT₄R was reduced in the model group (P<0.05). Compared with the model group, APSAP of 5-HT and 5-HT₃R was reduced in both the blistering moxibustion group and the antagonist group (P<0.05). CONCLUSION Blistering moxibustion can relieve the visceral hypersensitivity of the mice with visceral hypersensitive IBS and the underlying mechanism is related to the regulation of the gut-brain axis mediated by 5-HT signaling pathway.
Animals ; Disease Models, Animal ; Hypersensitivity ; Irritable Bowel Syndrome/therapy* ; Mice ; Moxibustion ; Rats ; Rats, Sprague-Dawley ; Serotonin ; Signal Transduction

OBJECTIVE: To compare the curative effect on diarrhea-predominant irritable bowel syndrome (IBS-D) between acupuncture for regulating METHODS: A total of 231 patients with IBS-D were randomized into an acupuncture group (154 cases) and a western medication group (77 cases) at the ratio of 2 to 1. In the acupuncture group, acupuncture was applied to acupoint regimen for regulating RESULTS: After treatment and in follow-up, the total scores of IBS-SSS in the patients of the two groups were all reduced as compared with those before treatment ( CONCLUSION Acupuncture for regulating
Acupuncture Therapy ; Diarrhea/therapy* ; Humans ; Irritable Bowel Syndrome/therapy* ; Quality of Life ; Serotonin Plasma Membrane Transport Proteins/genetics* ; Spleen ; Treatment Outcome

OBJECTIVES: Severe complications of tramadol overdose have been reported; however, few large-scale studies have investigated this issue. Therefore, this study aimed to explore the presentation and complications of tramadol overdose in patients admitted to an intoxication referral center in northwestern Iran.METHODS: Patients with tramadol overdose admitted to Sina Teaching Hospital in Tabriz, Iran during 2013-2017 were included. For each patient, the following data were collected: demographics, previous drug or medication overdose, whether the patient was in the process of quitting drug use, ingested dose of tramadol and co-ingestants, Glasgow Coma Scale (GCS) score, clinical symptoms at the time of admission, and admission characteristics. Serotonin toxicity was diagnosed in patients who fit the Hunter criteria. Multiple logistic regression was performed to identify variables associated with the incidence of severe complications of tramadol overdose.RESULTS: In total, 512 cases of tramadol overdose were evaluated, of which 359 patients were included, with a median age of 41 years (range, 16-69) and a median tramadol dose of 1,500 mg (range, 500-4,000). The most frequent complications associated with tramadol overdose were hypertension (38.4%), tachycardia (24.8%), and seizure (14.5%). No serotonin toxicity was detected in patients. Having a GCS score <15, having taken a tramadol dose of >1,000 mg, being in the process of quitting drug use, being 30-49 years old, and male sex were significantly related to the incidence of severe complications of tramadol overdose.CONCLUSIONS: Although seizure was prevalent among Iranian patients with tramadol poisoning, serotonin toxicity and cardiogenic shock were rare findings.
Demography ; Glasgow Coma Scale ; Hospitals, Teaching ; Humans ; Hypertension ; Incidence ; Iran ; Logistic Models ; Male ; Poisoning ; Referral and Consultation ; Seizures ; Serotonin ; Serotonin Syndrome ; Shock, Cardiogenic ; Tachycardia ; Tramadol

OBJECTIVES: Severe complications of tramadol overdose have been reported; however, few large-scale studies have investigated this issue. Therefore, this study aimed to explore the presentation and complications of tramadol overdose in patients admitted to an intoxication referral center in northwestern Iran. METHODS: Patients with tramadol overdose admitted to Sina Teaching Hospital in Tabriz, Iran during 2013-2017 were included. For each patient, the following data were collected: demographics, previous drug or medication overdose, whether the patient was in the process of quitting drug use, ingested dose of tramadol and co-ingestants, Glasgow Coma Scale (GCS) score, clinical symptoms at the time of admission, and admission characteristics. Serotonin toxicity was diagnosed in patients who fit the Hunter criteria. Multiple logistic regression was performed to identify variables associated with the incidence of severe complications of tramadol overdose. RESULTS: In total, 512 cases of tramadol overdose were evaluated, of which 359 patients were included, with a median age of 41 years (range, 16-69) and a median tramadol dose of 1,500 mg (range, 500-4,000). The most frequent complications associated with tramadol overdose were hypertension (38.4%), tachycardia (24.8%), and seizure (14.5%). No serotonin toxicity was detected in patients. Having a GCS score <15, having taken a tramadol dose of >1,000 mg, being in the process of quitting drug use, being 30-49 years old, and male sex were significantly related to the incidence of severe complications of tramadol overdose. CONCLUSIONS: Although seizure was prevalent among Iranian patients with tramadol poisoning, serotonin toxicity and cardiogenic shock were rare findings.
Demography ; Glasgow Coma Scale ; Hospitals, Teaching ; Humans ; Hypertension ; Incidence ; Iran ; Logistic Models ; Male ; Poisoning ; Referral and Consultation ; Seizures ; Serotonin ; Serotonin Syndrome ; Shock, Cardiogenic ; Tachycardia ; Tramadol

BACKGROUND/AIMS: Patients with irritable bowel syndrome (IBS) often report poor sleep quality. Whether poor sleep is associated with tryptophan (Trp) metabolites is unknown. We compared serum Trp metabolites in women with IBS and healthy controls (HCs) using targeted liquid chromatography mass spectrometry (LC-MS)-based profiling. In IBS only, we explored whether Trp metabolites are associated with IBS symptoms and subjective and objective sleep indices, serum cortisol, plasma adrenocorticotropic hormone (ACTH), and cortisol/ACTH levels. METHODS: Blood samples were obtained every 80 minutes in 21 HCs and 38 IBS subjects following an anticipation-of-public-speaking stressor during a sleep laboratory protocol. Subjects completed symptom diaries for 28 days. Adjacent values of metabolites were averaged to represent 4 time-periods: awake, early sleep, mid-sleep, and mid-to-late sleep. Thirteen of 20 targeted Trp metabolites were identified. RESULTS: Ten of 13 Trp metabolites decreased across the night, while nicotinamide increased in both groups. A MANOVA omnibus test performed after principal component analysis showed a significant difference in these 13 principal component (P = 0.014) between groups. Compared to HCs, nicotinamide levels were higher and indole-3-lactic acid levels lower in the IBS group. Melatonin and indole-3-acetic acid levels were associated with several subjective/objective sleep measures; decreased stool consistency/frequency and abdominal pain were positively associated with melatonin and serotonin in the IBS group. The kynurenine and kynurenic acid were associated with ACTH (positively) and cortisol/ACTH (negatively). CONCLUSIONS: Nighttime Trp metabolites may provide clues to poor sleep and stress with IBS. Further study of the mechanism of metabolite action is warranted.
Abdominal Pain ; Adrenocorticotropic Hormone ; Chromatography, Liquid ; Female ; Humans ; Hydrocortisone ; Irritable Bowel Syndrome ; Kynurenic Acid ; Kynurenine ; Mass Spectrometry ; Melatonin ; Niacinamide ; Plasma ; Principal Component Analysis ; Serotonin ; Tryptophan

K⁺ channels are key components of the primary and secondary basolateral Cl- pump systems, which are important for secretion from the salivary glands. Paroxetine is a selective serotonin reuptake inhibitor (SSRI) for psychiatric disorders that can induce QT prolongation, which may lead to torsades de pointes. We studied the effects of paroxetine on a human K⁺ channel, human ether-a-go-go-related gene (hERG), expressed in Xenopus oocytes and on action potential in guinea pig ventricular myocytes. The hERG encodes the pore-forming subunits of the rapidly-activating delayed rectifier K⁺ channel (I(Kr)) in the heart. Mutations in hERG reduce I(Kr) and cause type 2 long QT syndrome (LQT2), a disorder that predisposes individuals to life-threatening arrhythmias. Paroxetine induced concentration-dependent decreases in the current amplitude at the end of the voltage steps and hERG tail currents. The inhibition was concentration-dependent and time-dependent, but voltage-independent during each voltage pulse. In guinea pig ventricular myocytes held at 36℃, treatment with 0.4 µM paroxetine for 5 min decreased the action potential duration at 90% of repolarization (APD₉₀) by 4.3%. Our results suggest that paroxetine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects of clinical administration of paroxetine.
Action Potentials ; Animals ; Arrhythmias, Cardiac ; Guinea Pigs ; Heart ; Humans ; Long QT Syndrome ; Muscle Cells ; Oocytes ; Paroxetine ; Salivary Glands ; Serotonin ; Tail ; Torsades de Pointes ; Xenopus

BACKGROUND/AIMS: Irritable bowel syndrome (IBS) is a multifaceted disorder that afflicts millions of individuals worldwide. IBS is currently diagnosed based on the presence/duration of symptoms and systematic exclusion of other conditions. A more direct manner to identify IBS is needed to reduce healthcare costs and the time required for accurate diagnosis. The overarching objective of this work is to identify gene expression-based biological signatures and biomarkers of IBS. METHODS: Gene transcripts from 24 tissue biopsy samples were hybridized to microarrays for gene expression profiling. A combination of multiple statistical analyses was utilized to narrow the raw microarray data to the top 200 differentially expressed genes between IBS versus control subjects. In addition, quantitative polymerase chain reaction was employed for validation of the DNA microarray data. Gene ontology/pathway enrichment analysis was performed to investigate gene expression patterns in biochemical pathways. Finally, since vitamin D has been shown to modulate serotonin production in some models, the relationship between serum vitamin D and IBS was investigated via 25-hydroxyvitamin D (25[OH]D) chemiluminescence immunoassay. RESULTS: A total of 858 genetic features were identified with differential expression levels between IBS and asymptomatic populations. Gene ontology enrichment analysis revealed the serotonergic pathway as most prevalent among the differentially expressed genes. Further analysis via real-time polymerase chain reaction suggested that IBS patient-derived RNA exhibited lower levels of tryptophan hydroxylase-1 expression, the enzyme that catalyzes the rate-limiting step in serotonin biosynthesis. Finally, mean values for 25(OH)D were lower in IBS patients relative to non-IBS controls. CONCLUSIONS: Values for serum 25(OH)D concentrations exhibited a trend towards lower vitamin D levels within the IBS cohort. In addition, the expression of select IBS genetic biomarkers, including tryptophan hydroxylase 1, was modulated by vitamin D. Strikingly, the direction of gene regulation elicited by vitamin D in colonic cells is “opposite” to the gene expression profile observed in IBS patients, suggesting that vitamin D may help “reverse” the pathological direction of biomarker gene expression in IBS. Thus, our results intimate that IBS pathogenesis and pathophysiology may involve dysregulated serotonin production and/or vitamin D insufficiency.
Biomarkers ; Biopsy ; Cohort Studies ; Colon ; Diagnosis ; Gene Expression Profiling ; Gene Expression ; Gene Ontology ; Health Care Costs ; Humans ; Immunoassay ; Irritable Bowel Syndrome ; Luminescence ; Oligonucleotide Array Sequence Analysis ; Polymerase Chain Reaction ; Real-Time Polymerase Chain Reaction ; RNA ; Serotonin ; Transcriptome ; Tryptophan ; Tryptophan Hydroxylase ; Vitamin D ; Vitamins

BACKGROUND/AIMS: MicroRNAs (miRNAs) were reported to be responsible for intestinal permeability in diarrhea-predominant irritable bowel syndrome (IBS-D) rats in our previous study. However, whether and how miRNAs regulate visceral hypersensitivity in IBS-D remains largely unknown. METHODS: We established the IBS-D rat model and evaluated it using the nociceptive visceral hypersensitivity test, myeloperoxidase activity assay, restraint stress-induced defecation, and electromyographic (EMG) activity. The distal colon was subjected to miRNA microarray analysis followed by isolation and culture of colonic epithelial cells (CECs). Bioinformatic analysis and further experiments, including dual luciferase assays, quantitative real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay, were used to detect the expression of miRNAs and how it regulates visceral hypersensitivity in IBS-D rats. RESULTS: The IBS-D rat model was successfully established. A total of 24 miRNAs were differentially expressed in the distal colon of IBS-D rats; 9 were upregulated and 15 were downregulated. Among them, the most significant upregulation was miR-200a, accompanied by downregulation of cannabinoid receptor 1 (CNR1) and serotonin transporter (SERT). MiR-200a mimic markedly inhibited the expression of CNR1/SERT. Bioinformatic analysis and luciferase assay confirmed that CNR1/SERT are direct targets of miR-200a. Rescue experiments that overexpressed CNR1/SERT significantly abolished the inhibitory effect of miR-200a on the IBS-D rats CECs. CONCLUSIONS: This study suggests that miR-200a could induce visceral hyperalgesia by targeting the downregulation of CNR1 and SERT, aggravating or leading to the development and progression of IBS-D. MiR-200a may be a regulator of visceral hypersensitivity, which provides potential targets for the treatment of IBS-D.
Animals ; Blotting, Western ; Colon ; Computational Biology ; Defecation ; Diarrhea ; Down-Regulation ; Enzyme-Linked Immunosorbent Assay ; Epithelial Cells ; Hyperalgesia ; Hypersensitivity ; Irritable Bowel Syndrome ; Luciferases ; Microarray Analysis ; MicroRNAs ; Models, Animal ; Permeability ; Peroxidase ; Rats ; Real-Time Polymerase Chain Reaction ; Receptors, Cannabinoid ; Serotonin Plasma Membrane Transport Proteins ; Serotonin ; Up-Regulation