Genes in the serotonin pathway are associated with bipolar affective disorder in a Han Chinese population

Serotonin plays an important role in mood regulation, but the involvement of serotonin pathway genes in the development of bipolar I disorder. （BP-I）, a mood disorder, is not clear. We selected 21 single- nucleotide polymorphisms （SNPs） within the HTR2A gene, 8 within the SLC6A4 gene and 23 within the TPH2 gene for genotyping using the GoldenGate genotyping assay. A total of 375 patients with BP-I and 475 normal controls were recruited. Two out of 21 SNPs （rs1475196 and rs9567747） in the HTR2A gene and 1/23 SNPs （rs17110566） in the TPH2 gene were significantly associated with BP-I, both genotype-wise and allele-wise. Furthermore, a specific haplotype in the HTR2A gene showed a significant association with BP-I. Our results indicate that the HTR2A and TPH2 genes in the serotonin pathway play important roles in susceptibility to BP-I.

Analgesic effects of JCM-16021 on neonatal maternal separation-induced visceral pain in rats

AIM:To investigate the pharmacological effect of JCM-16021,a Chinese herbal formula,and its underlying mechanisms.METHODS:JCM-16021 is composed of seven herbal plant materials.All raw materials of the formula were examined according to the quality control criteria listed in the Chinese Pharmacopeia(2005).In a neonatal maternal separation(NMS)model,male SpragueDawley rats were submitted to daily maternal separation from postnatal day 2 to day 14,or no specific handling(NH).Starting from postnatal day 60,rats were administered JCM-16021(2,4,8 g/kg per day)orally twice a day for 28 d.Pain threshold pressure and electromyographic activities of external oblique muscles in response to colorectal distention recorded with a Power Lab System(AD Instruments International),were tested as pain indices.Changes in serotonin(5-HT)and 5-hydroxyindoleacetic acid(5-HIAA)concentrations in the colon of rats were analyzed;the enterochromaffin cell numbers and serotonin transporter in the colon of rats were also evaluated with an immunohistochemistry method.RESULTS:NMS treatment significantly reduced pain threshold pressure(37.4±1.4 mmHg),as compared to that of NH rats(57.7±1.9 mmHg,P<0.05).After JCM-16021 treatment,the pain threshold pressure significantly increased when compared to that before treatment(34.2±0.9 mmHg vs 52.8±2.3 mmHg in the high dose group,40.2±1.6 mmHg vs 46.5±1.3 mmHg in the middle dose group,and 39.3±0.7 mmHg vs 46.5±1.6 mmHg in the low dose group,P<0.05).Also JCM-16021 significantly and dose-dependently decreased electromyographic activity to the graded colorectal distension(CRD),(the meanΔAUC values were:0.17±0.03,0.53±0.15,1.06±0.18,1.22±0.24 in the high dose group;0.23±0.04,0.68±0.17,1.27 ±0.26,1.8±0.3 in the middle dose group;and 0.29 ±0.06,0.8±0.16,1.53±0.24,2.1±0.21 in the low dose group for the pressures 20,40,60,80 mmHg),as compared to the NMS vehicle group.The meanΔAUC values were:0.57±0.12,1.33±0.18,2.57±0.37,3.08±0.37 for the pressures 20,40,60,80 mmHg(P <0.05).JCM-16021 treatment significantly reduced the 5-HT concentrations(from high,middle and low dosage groups:60.25±5.98 ng/100 mg,60.32±4.22 ng/100 mg,73.31±7.65 ng/100 mg),as compared to the NMS vehicle groups(93.11±9.85 ng/100 mg,P<0.05);and increased the 5-HIAA concentrations(after treatment,from high,middle and low dosage groups:54.24±3.27 ng/100 mg,50.34±1.26 ng/100 mg,51.37±2.13 ng/100 mg)when compared to that in the NMS vehicle group(51.75±1.98 ng/100 mg,P <0.05);but did not change the enterochromaffin cell numbers in the colon of rats.In addition,NMS rats had higher SERT expression(n=10)than NH rats(n=8,P<0.05).JCM-16021 treatment significantly decreased SERT expression when compared to the NMS group(P <0.01-0.001).CONCLUSION:JCM-16021 can attenuate visceral hypersensitivity,and this analgesic effect may be mediated through the serotonin signaling pathway in the colon of rats.

Melatonin shapes bacterial clearance function of porcine macrophages during enterotoxigenic Escherichia coli infection

Due to the immature gastrointestinal immune system,weaning piglets are highly susceptible to pathogens,e.g.,enterotoxigenic Escherichia coli(ETEC).Generally,pathogens activate the immune cells(e.g.,macrophages)and shape intracellular metabolism(including amino acid metabolism);nevertheless,the metabolic cues of tryptophan(especially melatonin pathway)in directing porcine macrophage function during ETEC infection remain unclear.Therefore,this study aimed to investigate the changes in the serotonin pathway of porcine macrophages during ETEC infection and the effect of melatonin on porcine macrophage functions.Porcine macrophages(3D4/21 cells)were infected with ETEC,and the change of serotonin pathway was analysed by reverse transcription PCR and metabolomic analysis.The effect of melatonin on porcine macrophage function was also studied with proteomic analysis.In order to investigate the effect of melatonin on bacterial clearance function of porcine macrophages during ETEC infection,methods such as bacterial counting,reverse transcription PCR and western blotting were used to detect the corresponding indicators.The results showed that ETEC infection blocked melatonin production in porcine macrophages(P<0.05)which is largely associated with the heat-stable enterotoxin b(STb)of ETEC(P<0.05).Interestingly,melatonin altered porcine macrophage functions,including bacteriostatic and bactericidal activities based on proteomic analysis.In addition,melatonin pretreatment significantly reduced extracellular lactate dehydrogenase(LDH)activity(P<0.05),indicating that melatonin also attenuated ETEC-triggered macrophage death.Moreover,melatonin pretreatment resulted in the decrease of viable ETEC in 3D4/21 cells(P<0.05),suggesting that melatonin enhances bacterial clearance of porcine macrophages.These results suggest that melatonin is particularly important in shaping porcine macrophage function during ETEC infection.