Inhibiting 5-hydroxytryptamine receptor 3 alleviates pathological changes of a mouse model of Alzheimer's disease

Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In this study,we found that 5-hydroxytryptamin receptor 3A subunit(HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice(an Alzheimer’s disease model) and patients with Alzheimer’s disease.To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques,we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model.Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons.These results suggest that HTR3A-positive interneurons may partially contribute to the generation of Aβ peptides.We treated 5.0-5.5-month-old model mice with tro pisetron,a HTR3 antagonist,for 8 consecutive weeks.We found that the cognitive deficit of mice was partially reversed,Aβ plaques and neuroinflammation we re remarkably reduced,the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice.These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reve rses the pathological changes of Alzheimer’s disease.

Bioassay-guided isolation of saikosaponins with agonistic activity on 5-hydroxytryptamine 2C receptor from Bupleurum chinense and their potential use for the treatment of obesity

5-Hydroxytryptamine 2C(5-HT2C) receptor is one of the major targets of anti-obesity agents, due to its role in regulation of appetite. In the present study, the 70% EtO H extract of the roots of Bupleurum chinense was revealed to have agonistic activity on 5-HT2 C receptor, and the subsequent bioassay-guided isolation led to identification of several saikosaponins as the active constituents with 5-HT2 C receptor agonistic activity in vitro and anti-obesity activity in vivo. The new compound, 22-oxosaikosaponin d(1), was determined by extensive spectroscopic analyses(HR-ESI-MS, IR, and 1D and 2D NMR). The primary structure-activity relationship study suggested that the intramolecular ether bond between C-13 and C-28 and the number of sugars at C-3 position were closely related to the 5-HT2 C receptor agonistic activity. Saikosaponin a(3), the main saponin in B. chinense, showed obviously agonistic activity on 5-HT2 C receptor with an EC50 value of 21.08 ± 0.33 μmol×L^(–1) in vitro and could reduce food intake by 39.1% and 69.2%, and weight gain by 13.6% and 16.4%, respectively, at 3.0 and 6.0 mg×kg^(–1) in vivo. This investigation provided valuable information for the potential use of B. chinense as anti-obesity agent.

Augmentative effect of tetrandrine on pentobarbital hypnosis mediated by 5-HT_(1A) and 5-HT_(2A/2C) receptors in mice

It has been reported that augmentative effect of tetrandrine on pentobarbital hypnosis in mice may be related to serotonergic system. The present study was undertaken to investigate the interaction of tetrandrine and different 5-HT receptors on pentobarbital-induced sleep by using the loss-of-righting reflex method. The results showed that augmentative effect of tetrandrine on pentobarbital hypnosis in mice were potentiated by the p-MPPI （5-HT1A receptor antagonist） （1 mg/kg, i.p.） and ketanserin （5-HT2A/2C receptor antagonist） （1.5 mg/kg, i.p.）, respectively. Pretreatment with either 8-OH-DPAT （5-HT1A receptor agonist） （0.1 mg/kg, s.c.） or DOI （5-HT2A/2C receptor agonist） （0.2 mg/kg, i.p.） significantly decreased pentobarbital-induced sleep time, and tetrandrine （60 mg/kg, i.g.） significantly reversed this effect. These results suggest that both the 5-HTLA and 5-HT2A/2C subfamily may be involved in the potentiating mechanism of tetrandrine＇s effects on pantobarbital hypnosis.

The 5-HT2c receptor gene Cys23Ser polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation

It has been postulated that the persistent short intravaginal ejaculation latency time （IELT） of men with lifelong premature ejaculation （LPE） is related to 5-hydroxytryptamine （HT）2c receptor functioning. The aim of this study was to investigate the relationship of Cys23Ser 5-HT2c receptor gene polymorphism and the duration of IELT in men with LPE. Therefore, a prospective study was conducted in 64 Dutch Caucasian men with LPE. Baseline IELT during coitus was assessed by stopwatch over a 1-month period. All men were genotyped for Cys23Ser 5-HT2c receptor gene polymorphism. Allele frequencies and genotypes of Cys and Ser variants of 5-HT2c receptor gene polymorphism were determined. Association between Cys/Cys and Ser/Ser genotypes and the natural logarithm of the IELT in men with LPE were.investigated. As a result, the geometric mean, median and natural mean IELT were 25.2, 27.0, 33.9s, respectively. Of all men, 20.0%, 10.8%, 23.1% and 41.5% ejaculated within 10, 10-20, 20-30 and 30-60s after vaginal penetration. Of the 64 men, the Cys/Cys and Ser/Ser genotype frequency for the Cys23Ser polymorphism of the 5-HT2c receptor gene was 81% and 19%, respectively. The geometric mean IELT of the wildtypes （Cys/Cys） is significantly lower （22.6s; 95% CI 18.3-27.8s） than in male homozygous mutants （Ser/Ser） （40.4s; 95% CI 20.3-80.4s） （P = 0.03）. It is concluded that Cys23Ser 5-HT2c receptor gene polymorphism is associated with the IELT in men with LPE. Men with Cys/Cys genotype have shorter IELTs than men with Ser/Ser genotypes.

Effects of Estradiol on 5-HTsA and 5-HT2c Receptor Immunolabeling in Rat Hippocampus

Steroid hormones participate in the modulation of serotonergic transmission, including the regulation of synthetic and metabolic enzyme production, as well as receptor and transporter activity. The changes of 5-HT5A and 5-HT2c immunolabeling induced by steroids in the hippocampus ofovariectomized rats were studied in this work. Densitometric analysis in rat hippocampi were carried out for adjacent brain coronal immunolabeled sections after treatment with subcutaneous injections of vehicle, estradiol, progesterone or the combination of both steroids in ovariectomized rats. Exposure to estradiol and the combination of estradiol and progesterone significantly reduced the 5-HT5A-like immunosignal in the CA 1 region while progesterone did not induce changes. On the other hand, exposure to the combination of estradiol and progesterone or estradiol alone increased the 5-HT2c immunosignal in the same region. These results indicate that estradiol is involved in the discrete regulation of serotonin receptors 5-HT5A and 5-HT2c in rat hippocampus.

5-羟色胺2C受体对形觉剥夺性成年弱视大鼠离体脑片初级视皮层长时程增强的影响

目的探讨5-羟色胺2C受体(5-HT2CR)对形觉剥夺性成年弱视大鼠离体脑片视皮层V1M区长时程增强(LTP)的影响。方法将16只2周龄Spargue Dawley大鼠随机分为正常对照组和单眼形觉剥夺组,每组8只。正常对照组大鼠不做任何处理;单眼形觉剥夺组大鼠行右侧眼睑缝合术制备单眼形觉剥夺性弱视模型,造模成功后饲养6周,然后处死2组大鼠,冠状切取400μm厚视皮层脑组织切片并孵育于人工脑脊液中。根据人工脑脊液中加入的药物不同,将正常对照组大鼠视皮层切片作为A组,将剥夺眼对侧视皮层切片分为B、C、D和E组,将剥夺眼同侧视皮层切片分为F、G、H和I组。A、B、F组人工脑脊液中不加任何药物,C、G组加生理盐水,D、H组加10μmol·L-15-羟色胺盐酸盐,E、I组加10μmol·L-1SB 242084和10μmol·L-15-羟色胺盐酸盐。采用细胞外微电极记录法对各组大鼠视皮层组织切片进行电生理学实验,记录离体组织切片视皮层V1M区LTP并计算神经元场突触后电位(f PSP)斜率。结果 A、B、C、D、E、F、G、H、I组大鼠视皮层f PSP斜率分别为(198.1±13.5)%、(106.3±8.3)%、(106.3±8.3)%、(157.1±9.7)%、(102.6±4.7)%、(144.5±2.9)%、(144.5±2.9)%、(192.2±8.6)%和(129.7±13.5)%。A、B、F组大鼠视皮层f PSP斜率两两比较差异均有统计学意义(P<0.001),其中A组大鼠视皮层f PSP斜率高于B、F组(P<0.001),B组大鼠视皮层f PSP斜率低于F组(P<0.001)。D组大鼠视皮层f PSP斜率高于C组(t=-10.833,P<0.001);H组大鼠视皮层f PSP斜率高于D、G组(t=-6.841、-10.616,P<0.001);E组大鼠视皮层f PSP斜率低于D、I组(t=11.872、-3.910,P<0.001,P<0.05);I组大鼠视皮层f PSP斜率低于H组(t=9.911,P<0.001)。结论单眼形觉剥夺可造成双侧视皮层神经元功能减退,5-羟色胺盐酸盐可通过5-HT2CR起到一定逆转作用。

乳腺癌患者血清NR3C2和DNMT3A表达水平及其诊断价值研究

目的 探讨乳腺癌患者血清核受体亚家族C组成员2(nuclear receptor subfamily 3, group C, member 2,NR3C2),DNA甲基化转移酶-3A[DNA(cytosine-5)-methyltransferase 3A,DNMT3A]水平及其临床诊断价值。方法收集复旦大学附属华东医院2017年5月~2020年12月期间住院的94例乳腺癌患者为乳腺癌组,另选取同期健康体检者86例作为对照组。酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)检测两组血清NR3C2和DNMT3A水平,Pearson法分析乳腺癌患者血清NR3C2和DNMT3A表达水平相关性,多因素Logistic回归分析乳腺癌发生的影响因素,受试者工作特征(receiver operating characteristic,ROC)曲线评估NR3C2和DNMT3A对乳腺癌的诊断价值。结果 乳腺癌组患者血清NR3C2水平为317.84±33.47 ng/L,低于对照组(374.25±47.72ng/L),DNMT3A的表达水平为451.63±75.47μg/L,高于对照组(349.85±63.72μg/L),差异有统计学意义(t=9.243,9.729,均P<0.05)。Pearson分析结果显示,乳腺癌患者血清NR3C2与DNMT3A表达水平存在明显负相关(r=-0.501,P=0.000)。Logistic回归分析结果显示,NR3C2高水平为乳腺癌发生的保护因素(OR=0.563,95%CI:0.372~0.851,P=0.006),DNMT3A高水平是乳腺癌发生的危险因素(OR=1.834,95%CI:1.249~2.693,P=0.002)。ROC曲线结果发现,血清NR3C2与DNMT3A诊断乳腺癌的曲线下面积(area under the curve,AUC)分别为0.853(0.791~0.915),0.930(0.896~0.965),当两者联合时其AUC为0.969(0.949~0.990),高于两者单独检测(Z=3.460,1.894,P=0.000,0.034)。结论 乳腺癌患者血清NR3C2表达水平降低,DNMT3A表达水平升高,两者联合检测能够提高乳腺癌的诊断价值。

Synergistic interaction between C5a and NOD2 signaling in the regulation of chemokine expression in RAW 264.7 macrophages

The innate immune response is a complex process involving multiple pathogen-recognition receptors, including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors. Complement is also a critical component of innate immunity. While complement is known to interact with TLR-mediated signals, the interactions between NOD-like receptors and complement are not well understood. Here we report a synergistic interaction between C5a and Nod2 signaling in RAW 264.7 marophages. Long-term treatment with muramyl dipeptide (MDP), a NOD2 ligand, enhanced C5a-mediated expression of chemokine mRNAs in RAW 264.7 cells. This response was dependent on NOD2 expression and was associated with a decrease in expression of C5L2, a receptor for C5a which acts as a negative modulator of C5a receptor (C5aR) activity. MDP amplified C5a-mediated phosphorylation of p38 MAPK. Treatment of RAW264.7 cells with an inhibitor of p38 attenuated the synergistic effects of C5aon MDP-primed cells on MIP-2, but not MCP-1, mRNA. In contrast, inhibition of AKT prevented C5a stimulation of MCP-1, but not MIP-2, mRNA, in MDP-primed cells. Taken together, these data demonstrated a synergistic interaction between C5a and NOD2 in the regulation of chemokine expression in macrophages, associated with a down-regulation of C5L2, a negative regulator of C5a receptor activity.

Domesticated HERV-W env contributes to the activation of the small conductance Ca^(2+)-activated K^(+)type 2 channels via decreased 5-HT4 receptor in recent-onset schizophrenia

The human endogenous retroviruses type W family envelope(HERV-W env)gene is located on chromosome 7q21-22.Our previous studies show that HERV-W env is elevated in schizophrenia and HERV-W env can increase cal-cium influx.Additionally,the 5-HTergie system and particularly 5-hydroxytryptamine(5-HT)receptors play a prominent role in the pathogenesis and treatment of schizophrenia.5-hydroxytryptamine receptor 4(5-HT4R)agonist can block calcium channels.However,the underlying relationship between HERV-W env and 5-HT4R in the etiology of schizophrenia has not been revealed.Here,we used enzyme-linked immunosorbent assay to detect the concentration of HERV-W env and 5-HT4R in the plasma of patients with schizophrenia and we found that there were decreased levels of 5-HT4R and a negative correlation between 5-HT4R and HERV-W env in schizophrenia.Overexpression of HERV-W env decreased the transcription and protein levels of 5-HT4R but increased small conductance Ca^(2+)-activated K^(+)type 2 channels(SK2)expression levels.Further studies revealed that HERV-w env could interact with 5-HT4R.Additionally,luciferase assay showed that an essential region(-364 to-176 from the transcription start site)in the SK2 promoter was required for HERV-W env-induced SK2 expression.Importantly,5-HT4R participated in the regulation of SK2 expression and promoter activity.Electrophysiological recordings suggested that HERV-Wenv could increase SK2 channel currents and the increase of SK2 currents was inhibited by 5-HT4R.In condusion,HERV-W env could activate SK2 channels via decreased 5-HT4R,which might exhibit a novel mechanism for HERV-Wenv to influence neuronal activity in schizophrenia.

Effects of 5-hydroxytryptamine and 5-hydroxytryptamine 2A/2C agonist on the genioglossus activity and sleep apnea in rats

Background 5-hydroxytryptamine （5-HT） is a common neurotransmitter in the brain which plays an important role in the pathogenesis of sleep apnea.Dysfunction of 5-HT and 5-HT2 receptors may lead to the collapse of the upper airway and the instability of respiratory control, which in turn produce apnea.Genioglossus （GG） is one of the most important oropharyngeal muscles maintaining the upper airway open.The present study aimed to investigate the effects of 5-HT and 5-HT2 receptor on GG activity and the sleep apnea in Sprague-Dawley （SD） rats.Methods Microinjection probes were placed within the fourth ventricle of sixteen SD rats.After recovery for a week, the electromyogram （EMG） of GG was recorded in the anesthetized and vagotomized rats.The changes of GG activity before and after the microinjection of 5-HT or 5-HT2A/2c agonist -2,5-dimethoxy-4-iodoamphetamine hydrochloride （DOI）were observed.Probes were also laid in another eight SD rats.Electroencephalogram （EEG）, EMG of neck muscle and respiration were recorded at the same time a week later.The effects of DOI on the occurrence of sleep apnea were explored.Results Both 5-HT and DOI significantly enhanced the activity of GG just 3 minutes after the completion of injection.The effect of 5-HT disappeared quickly and the effect of DOI lasted for more than 27 minutes.DOI also significantly decreased the post-sigh apnea index in non-rapid-eye-movement （NREM） and rapid-eye-movement （REM） sleep and decreased the spontaneous apnea index only in NREM sleep （P 〈0.05, respectively）.Conclusion 5-HT and 5-HT2A/2c system correlated closely with the pathogenesis of the sleep apnea syndrome and 5-HT receptors may become the target of the drug treatment.

食管癌患者肿瘤组织CXCL5和CXCR2的表达与病情和预后的相关性分析

目的研究食管癌患者肿瘤组织CXC趋化因子5(CXCL5)和CXC趋化因子受体2(CXCR2)水平对食管癌病情及预后的影响,为食管癌临床诊断、治疗和评价预后提供新方向。方法选取2013年8月至2015年7月于徐州医科大学附属医院确诊且临床资料完整的126例未经放化疗的食管癌患者作为研究对象,通过免疫组织化学染色的方法检测食管癌组织CXCL5和CXCR2表达水平,探讨CXCL5和CXCR2表达水平与食管癌临床病理分型和生存预后的关系。结果食管癌组织CXCL5和CXCR2的表达阳性率显著高于癌旁组织(P<0.05),且两者存在相关性(P<0.05);食管癌组织CXCL5和CXCR2与食管癌TNM分期和淋巴结转移具有显著的相关性(P<0.05);生存曲线显示,食管癌组织CXCL5、CXCR2阳性的患者5年生存率和预期生存时间显著低于阴性者,差异有统计学意义(P<0.05);Cox多因素分析显示原发肿瘤部位、食管癌TNM分期、淋巴结转移和食管癌组织CXCL5、CXCR2水平为食管癌预后的独立危险因素(P<0.05)。结论食管癌患者肿瘤组织内CXCL5、CXCR2高表达,与食管癌病情相关,CXCL5、CXCR2是影响食管癌患者预后的独立危险因素。

Switching-on of serotonergic calcium signaling in activated hepatic stellate cells

AIM:To investigate serotonergic Ca 2+ signaling and the expression of 5-hydroxytryptamine(5-HT) receptors,as well as Ca 2+ transporting proteins,in hepatic stellate cells(HSCs) . METHODS:The intracellular Ca 2+ concentration([Ca 2+ ]i) of isolated rat HSCs was measured with a fluorescence microscopic imaging system.Quantitative PCR was per-formed to determine the transcriptional levels of 5-HT receptors and endoplasmic reticulum(ER) proteins involved in Ca 2+ storage and release in cultured rat HSCs. RESULTS:Distinct from quiescent cells,activated HSCs exhibited[Ca 2+ ]i transients following treatment with 5-HT,which was abolished by U-73122,a phospholipase C inhibitor.Upregulation of 5-HT2A and 5-HT2B receptors,but not 5-HT3,was prominent during trans-differentiation of HSCs.Pretreatment with ritanserin,a 5-HT2 antagonist,inhibited[Ca 2+ ]i changes upon application of 5-HT.Expression of type 1 inositol-5'-triphosphate receptor and type 2 sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase were also increased during activation of HSCs and serve as the major isotypes for ER Ca 2+ storage and release in activated HSCs.Ca 2+ binding chaperone proteins of the ER,including calreticulin,calnexin and calsequestrin,were up-regulated following activation of HSCs. CONCLUSION:The appearance of 5-HT-induced[Ca 2+ ]i response accompanied by upregulation of metabotropic 5-HT2 receptors and Ca 2+ transporting/chaperone ER proteins may participate in the activating process of HSCs.

Neurotoxicity of prenatal alcohol exposure on medullary pre-B?tzinger complex neurons in neonatal rats

Prenatal alcohol exposure disrupts the development of normal fetal respiratory function, but whether it perturbs respiratory rhythmical discharge activity is unclear. Furthermore, it is unknown whether the 5-hydroxytryptamine 2A receptor（5-HT2AR） is involved in the effects of prenatal alcohol exposure. In the present study, pregnant female rats received drinking water containing alcohol at concentrations of 0%, 1%, 2%, 4%, 8% or 10%（v/v） throughout the gestation period. Slices of the medulla from 2-day-old neonatal rats were obtained to record respiratory rhythmical discharge activity. 5-HT2 AR protein and m RNA levels in the pre-B？tzinger complex of the respiratory center were measured by western blot analysis and quantitative RT-PCR, respectively. Compared with the 0% alcohol group, respiratory rhythmical discharge activity in medullary slices in the 4%, 8% and 10% alcohol groups was decreased, and the reduction was greatest in the 8% alcohol group. Respiratory rhythmical discharge activity in the 10% alcohol group was irregular. Thus, 8% was the most effective alcohol concentration at attenuating respiratory rhythmical discharge activity. These findings suggest that prenatal alcohol exposure attenuates respiratory rhythmical discharge activity in neonatal rats by downregulating 5-HT2 AR protein and m RNA levels.

Follicular helper T lymphocytes in health and disease

A correct antibody response requires the participation of both B and T lymphocytes and antigen presenting cells. In this review we address the role of follicular helper T lymphocytes(T FH) in this reaction. We shall focus on the regulation of their development and function in health and disease. T FH can be characterized on the basis of their phenotype and the pattern of secretion of cytokines. This fact is useful to study their participation in the generation of antibody deficiency in primary immunodeficiency diseases such as common variable immunodeficiency, X-linked hyper Ig M syndrome orX-linked lymphoproliferative disease. Increased numbers of T FH have been demonstrated in several autoimmune diseases and are thought to play a role in the development of autoantibodies. In chronic viral infections caused by the human immunodeficiency virus, hepatitis B or C virus, increased circulating T FH have been observed, but their role in the protective immune response to these agents is under discussion. Likewise, an important role of T FH in the control of some experimental protozoan infections has been proposed, and it will be important to assess their relevance in order to design effective vaccination strategies.

Dissecting the novel abilities of aripiprazole: The generation of anti-colorectal cancer effects by targeting Gαq via HTR2B

Colorectal cancer(CRC)is a type of malignant tumor that seriously threatens human health and life,and its treatment has always been a difficulty and hotspot in research.Herein,this study for the first time reports that antipsychotic aripiprazole(Ari)against the proliferation of CRC cells both in vitro and in vivo,but with less damage in normal colon cells.Mechanistically,the results showed that5-hydroxytryptamine 2B receptor(HTR2B)and its coupling protein G protein subunit alpha q(Gaq)were highly distributed in CRC cells.Ari had a strong affinity with HTR2B and inhibited HTR2B downstream signaling.Blockade of HTR2B signaling suppressed the growth of CRC cells,but HTR2B was not found to have independent anticancer activity.Interestingly,the binding of Gaq to HTR2B was decreased after Ari treatment.Knockdown of Gaq not only restricted CRC cell growth,but also directly affected the antiCRC efficacy of Ari.Moreover,an interaction between Ari and Gaq was found in that the mutation at amino acid 190 of Gaq reduced the efficacy of Ari.Thus,these results confirm that Gaq coupled to HTR2B was a potential target of Ari in mediating CRC proliferation.Collectively,this study provides a novel effective strategy for CRC therapy and favorable evidence for promoting Ari as an anticancer agent.

Effects of Ginseng Fruit Saponins on Serotonin System in Sprague-Dawley Rats with Myocardial Infarction, Depression, and Myocardial Infarction Complicated with Depression

Background： Our previous studies have demonstrated that the levels of 5-hydroxytryptamine （5-HT） and 5-HT 2A receptor （5-HT2AR） in serum and platelet were associated with depression and myocardial infarction （MI）, and pretreatment with ginseng fruit saponins （GFS） before MI and depression had an effect on the 5-HT system. In this study, the effects of GFS on the 5-HT system in the Sprague-Dawley （SD） rats with MI, depression, and MI ＋ depression were evaluated. Methods： A total of eighty SD rats were allocated to four groups： MI, depression, MI ＋ depression, and control groups （n = 20 in each group）. Each group included two subgroups （n = 10 in each subgroup）： Saline treatment subgroup and GFS treatment subgroup. The levels of 5-HT, 5-HT2AR, and serotonin transporter （SERT） were quantified in serum, platelet lysate, and brain tissue through the enzyme-linked immunosorbent assay method, respectively. Results： Compared with those in the saline treatment subgroups, the levels of 5-HT in serum and platelet lysate statistically significantly increased in the GFS treatment subgroups of MI, depression, and MI ＋ depression groups （serum： all P = 0.000; platelet lysate： P = 0.002, 0.000, 0.000, respectively）. However, the 5-HT levels in brain homogenate significantly decreased in the GFS treatment subgroups compared with those in the saline treatment subgroups in MI and depression groups （P = 0.025 and 0.044 respectively）, and no significant difference was observed between saline and GFS treatment subgroups in MI ＋ depression group （P = 0.663）. Compared with that in GFS treatment subgroup of control group, the 5-HT2AR levels in the platelet lysate significantly decreased in GFS treatment subgroups of MI, depression, and MI ＋ depression groups （all P = 0.000）. Compared to those in the saline treatment subgroups, the serum SERT levels significantly decreased in the GFS treatment subgroups in MI, depression, and MI ＋ depression groups （P = 0.009, 0.038, and P = 0.001, respectively）, while the SERT levels of platelet lysate significantly decreased in GFS treatment subgroup of MI group （P = 0.000）, significantly increased in GFS treatment subgroup of depression group （P = 0.019）, and slightly changed in GFS treatment subgroup of MI ＋ depression group （P = 0.219）. No significant changes for SERT levels in brain homogenate could be found between the saline and GFS treatment subgroups in MI, depression, and MI ＋ depression groups （P = 0.421, 0.076 and P = 0.642）. Conclusions： This study indicated that GFS might inhibit the reuptake of 5-HT from serum to platelet according to decreased 5-HT2AR in platelet and SERT in serum and platelet. The change of 5-HT in serum after GFS treatment was inconsistent with that in the brain. It seemed that GFS could not pass through the blood-brain barrier to affect the central serotonergic system.

Antibody drug conjugate development in gastrointestinal cancers:hopes and hurdles from clinical trials

Gastrointestinal(GI)cancers represent the leading cause of cancer-related mortality worldwide.Antibody drug conjugates(ADCs)are a rapidly growing new class of anti-cancer agents which may improve GI cancer patient survival.ADCs combine tumour-antigen specific antibodies with cytotoxic drugs to deliver tumour cell specific chemotherapy.Currently,only two ADCs[brentuximab vedotin and trastuzumab emtansine(T-DM1)]have been Food and Drug Administration approved for the treatment of lymphoma and metastatic breast cancer,respectively.Clinical research evaluating ADCs in GI cancers has shown limited success.In this review,we will retrace the relevant clinical trials investigating ADCs in GI cancers,especially ADCs targeting human epidermal growth receptor 2,mesothelin,guanylyl cyclase C,carcinogenic antigen-related cell adhesion molecule 5(also known as CEACAM5)and other GI malignancy specific targets.We will review potential hurdles for their success and provide new perspective for future treatment.

电针足三里对严重烫伤致大鼠急性肺损伤的影响

目的 探讨电针足三里对严重烫伤致大鼠急性肺损伤的影响.方法 雄性SD大鼠40只,体重200～250 g,随机分为5组（n=8）：对照组、烫伤组、足三里组、非经非穴组和α-银环蛇毒素组（α-BGT组）.对照组尾静脉注射生理盐水1 ml.烫伤组、足三里组、非经非穴组和α-BGT组先制备30%总体表面积Ⅲ度烫伤模型,然后烫伤组尾静脉注射生理盐水1 ml;足三里组于双侧足三里穴垂直进针7 mm,给予脉冲电流（电压3V,电流2ms,频率3 Hz）持续刺激12 mim,间隔8 h刺激1次,持续2 d;非经非穴组于双侧足三里穴旁5mm处给予脉冲刺激,方法同足三里组;α-BGT组尾静脉注射α-BGT 1.0 μg/kg,再于双侧足三里穴给予脉冲刺激,方法同足三里组.各组处理结束后,处死大鼠,取肺组织,光镜下观察病理学结果,电镜下观察超微结构,采用ELISA法测定肺组织高迁移率族蛋白B1（HMGBl）含量,采用免疫组化法测定HMGBl蛋白表达,采用RT-PCR法测定HMGBl mRNA表达.结果 烫伤组肺组织光镜下可见肺泡壁崩解,泡内大量渗出液,间质水肿、肥厚和增生,伴大量炎性细胞浸润;电镜下可见细胞核形态不规则,核膜僵硬,部分凸凹不平和核溶解,胞质内板层小体明显减少,肺组织病理损伤程度较对照组减轻.与对照组比较,烫伤组、非经非穴组和α-BGT组肺组织HMGBl含量升高,HMGBl蛋白及其mRNA的表达上调（P〈0.05）,足三里组各指标差异无统计学意义（P〉0.05）;与烫伤组比较,足三里组肺组织HMGBl含量降低,HMGBl蛋白及其mRNA的表达下调,非经非穴组和α-BGT组肺组织HMGBl mRNA表达下调（P〈0.05）;与足三里组比较,非经非穴组和α-BGT组肺组织HMGBl含量升高,HMGBl蛋白及其mRNA的表达上调（P〈0.05）.结论 电针足三里可减轻严重烫伤致大鼠急性肺损伤,其机制与激活含α7亚基N型胆碱能受体介导的胆碱能抗炎通路,抑制肺组织HMGBl的表达有关.