ABSTRACT
CT screening has markedly reduced the lung cancer mortality in high-risk population and increased the detection of early-stage pulmonary neoplasms, including multiple pulmonary nodules, especially those with a ground-glass appearance on CT. Multiple primary lung cancer (MPLC) constitutes a specific subtype of lung cancer with indolent biological behaviors, which is predominantly early-stage adenocarcinoma. Although MPLC progresses slowly with rare lymphatic metastasis, existence of synchronous lesions and distributed location of these nodules still pose difficulty for the management of such patients. One single operation is usually insufficient to eradicate all neoplastic lesions, whereas repeated surgical procedures bring about another dilemma: whether clinical benefits of surgical treatment outweigh loss of pulmonary function following multiple operations. Therefore, despite the anxiety for treatment among MPLC patients, whether and how to treat the patient should be assessed meticulously. Currently there is a heated discussion upon the timing of clinical intervention, operation mode and the application of local therapy in MPLC. Based on clinical experience of our multiple disciplinary team, we have summarized and commented on the evaluation, surgical treatment, non-surgical local treatment, targeted therapy and immunotherapy of MPLC in this article to provide further insight into this field.
Subject(s)
Adenocarcinoma , Lung Neoplasms , Multiple Pulmonary Nodules , Humans , Multiple Pulmonary Nodules/diagnostic imaging , Multiple Pulmonary Nodules/surgery , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/surgery , Adenocarcinoma/diagnostic imaging , Adenocarcinoma/surgery , Lung/pathology , Tomography, X-Ray ComputedABSTRACT
Objective: To summarize and analyse of literature on the susceptibility genes of noise induced hearing loss (NIHL) , and the key genes were screened and obtained by bioinformatics method, so as to provide reference for the prevention research of NIHL. Methods: In September 2021, Based on CNKI, NCBI Pubmed database and Web of Science database, this paper conducted bibliometric analysis and bioinformatics analysis on the genetic literature related to the susceptibility to noise-induced hearing loss from 1999 to 2020. Endnote X9 software and the WPS office software were used for bibliometric analysis, and online software STRING and Cytoscape software were used for bioinformatics analysis. Results: A total of 131 literatures were included in the study, involving 40 genes in total. Bibliometric analysis shows that 131 papers which included 36 Chinese articles and 95 English articles were published in 63 biomedical journals; the highest number of published articles was 19 in 2020. Bioinformatics analysis suggests that GAPDHãSOD2ãSOD1ãCATãCASP3ãIL6 and other genes play a key role in the interaction network. The involved pathways mainly include MAP2K and MAPK activations, PTEN regulation, P53-depardent G1 DNA damage response, signaoling by BRAF and RAF fusions and soon. Conclusion: The study of noise induced hearing loss involves multi gene biological information, and bioinformatics analysis is helpful to predict the occurrence and development of noise induced hearing loss.
Subject(s)
Hearing Loss, Noise-Induced , Noise, Occupational , Humans , Hearing Loss, Noise-Induced/genetics , Hearing Loss, Noise-Induced/epidemiology , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Computational Biology , BibliometricsABSTRACT
Objective: To investigate the relationship between rs1053005 of signal conversion and transcription activator 3 (STAT3) and miR-452-3p, and the association between STAT3 gene polymorphism and noise-induced hearing loss (NIHL) . Methods: In December 2017, 1220 workers were selected from an automobile manufacturing factory, an energy company and a chemical fiber factory in Jiangsu Province who had occupational noise exposure and working age of more than 3 years. The workers with the mean hearing threshold of ≥26 dB (A) of the two ear high frequency (3000, 4000 and 6000 Hz) were defined as case group (n=609) , and the rest were control group (n=611) . Five single nucleotide polymorphism (SNP) sites of STAT3 (rs4796793, rs1053023, rs1053005, rs1053004 and rs3744483) were selected to explore the association between STAT3 gene polymorphism and NIHL by analyzing the points. The double luciferase reporter gene verified whether miR-452-3p was targeted to bind STAT3, and overexpressed miR-452-3p in HEI-OC1 cells to explore the mechanism of STAT3 expression regulation. Results: There was no significant difference in gender, age, smoking and drinking between the two groups (P>0.05) . Compared with the control group[ (15.58±4.76) dB], the mean hearing threshold of the case group [ (37.50±12.39) dB] was higher, and the difference were statistically significant (P<0.05) . Compared with the control group, the C alleles of rs1053023 and rs1053005 were higher in the case group (OR=1.367, 1.370, P<0.05) . The risk of NIHL in men with TC/CC genotype were 1.545 and 1.531 times higher than that in men with TT genotype (P<0.05) . Compared with the control group, the mRNA expression of STAT3 in the case group was significantly increased (P<0.05) . The STAT3 mRNA expression of miR-452-3p group cells was significantly decreased (P<0.05) . Conclusion: The rs1053023 and rs1053005 polymorphism of STAT3 are related to NIHL. The C alleles of rs1053023 and rs1053005 may be biomarkers of workers exposed to noise.
Subject(s)
Hearing Loss, Noise-Induced , MicroRNAs , Noise, Occupational , Case-Control Studies , Genetic Predisposition to Disease , Genotype , Humans , Male , Polymorphism, Single Nucleotide , STAT3 Transcription FactorABSTRACT
Low molecular weight heparins (LMWHs) and direct oral anticoagulants (DOACs) are among the recommended treatment options for cancer-associated thrombosis (CAT) in the 2019 National Comprehensive Care Network guidelines. Little is known about the current utilization of DOACs in CAT patients, particularly on the inpatient to outpatient therapy transition. This study assessed real-world treatment patterns of CAT in hospital/ED in adult cancer patients (≥ 18 years) diagnosed with CAT during a hospital visit in IQVIA's Hospital Charge Data Master database between July 1, 2015 and April 30, 2018, and followed their outpatient medical and pharmacy claims to evaluate the initial inpatient/ED and outpatient anticoagulants received within 3 months post-discharge. Results showed that LMWH and unfractionated heparin (UFH) were the most common initial inpatient/ED CAT treatments (35.2% and 27.4%, respectively), followed by DOACs (9.6%); 20.8% of patients received no anticoagulants. Most DOAC patients remained on DOACs from inpatient/ED to outpatient settings (71.4%), while 24.1%, 43.5%, and 0.1% of patients treated with LMWH, warfarin, or UFH respectively, remained on the same therapy after discharge. In addition, DOACs were the most common initial post-discharge outpatient therapy. Outpatient treatment persistence and adherence appeared higher in patients using DOACs or warfarin versus LMWH or UFH. This study shows that DOACs are used as an inpatient/ED treatment option for CAT, and are associated with less post-discharge treatment switching and higher persistence and adherence. Further research generating real-world evidence on the role of DOACs to help inform the complex CAT clinical treatment decisions is warranted.
Subject(s)
Ambulatory Care/trends , Anticoagulants/therapeutic use , Inpatients , Neoplasms/drug therapy , Practice Patterns, Physicians'/trends , Venous Thrombosis/drug therapy , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Databases, Factual , Drug Substitution/trends , Drug Utilization/trends , Factor Xa Inhibitors/therapeutic use , Female , Heparin/therapeutic use , Humans , Male , Medication Adherence , Middle Aged , Neoplasms/diagnosis , Neoplasms/epidemiology , Patient Discharge/trends , Retrospective Studies , Time Factors , Treatment Outcome , United States/epidemiology , Venous Thrombosis/diagnosis , Venous Thrombosis/epidemiology , Warfarin/therapeutic useABSTRACT
Objective: To investigate the health status of occupational mercury workers and reveal the effects of mercury exposure on the cardiovascular system. Methods: In June 2019, a total of 2651 mercury workers participated in the occupational health examination between 2016-2018 from a thermometer manufacturing plant and a fluorescent lamp manufacturing plant were included in this study. Then, they were divided into a high-level mercury exposure group (425 workers whose urine mercury concentration >35 µg/g creatinine) and a low-mercury mercury exposure group (2226 workers whose urinary mercury concentration <35 µg/g creatinine) . Mercury concentration in the workplace was also detected. Finally, the results of electrocardiogram (ECG) , blood routine, blood biochemistry and other physical examinations were analyzed. The measurement data of age and exposure years were analyzed by test. Urinary mercury and blood parameters were analyzed by Mann-Whitney nonparametric test. Chi-square test was used for the analyses of gender, ECG abnormality rate and other categorical data. Results: The 8-hour weighted average allowable concentration (CTWA) of mercury in the workplace of high-exposure group was 0.002 2-0.152 mg/m(3). The abnormal rate of ECG in the high-exposed group (29.6%) was higher than that in the low-exposure group (10.1%) in 2018 (P<0.01) . Compared with the low-exposure group, the WBC of the high-exposure group from 2016 to 2018 was increased, with statistically significance (P<0.05) ; the RBC of the high-exposure group in 2016 and 2017 was decreased, with statistically significance (P<0.01) ; the total bilirubin concentration in the high-exposure group was decreased from 2016 to 2018, with statistically significance (P<0.05) . Conclusion: Long-term exposure to high concentration of mercury in the workplace may influence cardiovascular system. Therefore, engineering protection and individual protection should be implemented well.
Subject(s)
Mercury/adverse effects , Occupational Exposure/adverse effects , China , Creatinine/blood , Electrocardiography , Humans , Mercury/urine , Occupational Exposure/statistics & numerical dataABSTRACT
Objective: To investigate the association between the single nucleotide polymorphisms of rs12212067 in FOXO3 gene and the susceptibility to occupational noise-induced deafness in a Chinese Han population. Methods: A total of 1 066 cases of noise exposure workers from a large chemical fiber factory in Jiangsu Province were selected as the study subjects. All subjects' basic data and field exposure data were collected through questionnaires and occupational health surveys. The subjects were divided into case group (531 persons, double ear high frequency average hearing threshold>25 dB) and control group (535 persons, double ear high frequency average hearing threshold≤25 dB) according to their results of pure tone hearing test .2ml fasting venous blood was collected for DNA extraction and genotyping was performed by TaqMan-PCR technique. Results: Genotyping results suggested that the GT+GG genotype is a risk factor for occupational noise-induced deafness, with an adjusted OR 95% confidence interval of 2.044 (1.51-2.78) . After the noise exposure intensity was stratified, the adjusted OR values and the 95% confidence intervals of noise intensity ≤85, 85-92 and>92 dB respectively 2.43 (1.52-3.90) , 2.17 (1.03-4.59) and 1.74 (1.07-2.83) . Conclusion: GT-GG genotype in rs12212067 of FOXO3 gene may be a risk factor for occupational noise-induced deafness.
Subject(s)
Deafness/etiology , Forkhead Box Protein O3/genetics , Hearing Loss, Noise-Induced/genetics , Noise, Occupational/adverse effects , Occupational Exposure/adverse effects , Case-Control Studies , Genetic Predisposition to Disease , Hearing Loss, Noise-Induced/epidemiology , Humans , Polymorphism, Single NucleotideABSTRACT
OBJECTIVE: To understand the current status and changing tendency of human hookworm infections in Anhui Province. METHODS: According to the unified national survey scheme, a total of 48 survey sites were sampled from 16 counties (cities) in 4 ecological regions of Anhui Province using a stratified cluster random sampling method from 2014 to 2015. The hookworm eggs were detected in the fecal samples from permanent residents at ages of over one year living in the survey sites using a modified Kato-Katz thick smear method, and the subjects'health knowledge and behaviors were investigated using questionnaire survey. RESULTS: A total of 12 300 persons were examined in the 48 survey sites from 4 ecological regions of Anhui Province between 2014 and 2015, and 259 subjects were identified with hookworm infections, with a mean prevalence of 2.11%. Among the four ecological regions, the North China Plain had the highest prevalence of human hookworm infections (3.02%) and in all survey sites, Linquan County had the highest prevalence (7.03%). Ancylostoma duodenale was the predominant hookworm species identified (62.16%), and 65.64% had mild infections. The prevalence of human hookworm infections was significantly greater in women than in men (χ2 = 4.16, P < 0.05), and showed a tendency towards a rise with ages (χ2trend = 113.36, P < 0.01). In addition, the prevalence of human hookworm infections varied in occupations (χ2 = 159.41, P < 0.01) and education levels (χ2 = 34.95, P < 0.01). Questionnaire survey showed low prevalence of human hookworm infections in subjects knowing the question"how hookworm infection occurs"and denying"using fresh stools for fertilization"(χ2 = 15.05, P < 0.01; χ2 = 4.19, P < 0.05). CONCLUSIONS: The prevalence of human hookworm infections has greatly decreased in Anhui Province; however, the prevalence remains relatively high in some regions and populations. The North China Plain should be regarded as the key area for hookworm disease prevention and control, and housewives and populations with advanced ages and low educational levels are key targeted populations in Anhui Province.
Subject(s)
Ancylostomatoidea , Hookworm Infections , Age Factors , Ancylostomatoidea/physiology , Animals , China/epidemiology , Feces/parasitology , Female , Hookworm Infections/epidemiology , Humans , Male , Prevalence , Sex Factors , Surveys and QuestionnairesABSTRACT
A series of stable aryl gallium(I) terphenyl derivatives was synthesized and characterized spectroscopically, structurally and by density functional calculations. Dimeric structures with trans-bent planar CGaGaC core arrangements were observed for [(GaAr*-4-tBu)(2)] (7, Ar*-4-tBu = C(6)H(2)-2,6(C(6)H(2)-2,4,6-iPr(3))(2)-4-tBu) and [(GaAr*-4-CF(3))(2)] (8, Ar*-4-CF(3) = C(6)H(2)-2,6(C(6)H(2)-2,4,6-iPr(3))(2)-4-CF(3)), whereas monomeric structures featuring one coordinate gallium were observed for the more crowded complexes [:GaAr*-3,5-iPr(2)] (10, Ar*-3,5-iPr(2) = C(6)H-2,6(C(6)H(2)-2,4-6-iPr(3))(2)-3,5-iPr(2)) and [GaAr'-3,5-iPr(2)] (11, Ar'-3,5-iPr(2) = C(6)H-2,6(C(6)H(3)-2,6-iPr(2))(2)-3,5-iPr(2)). Complexes 7 and 8 dissociate to monomers in hydrocarbon solution and their electronic spectra closely resemble those of 10 and 11 as well as those of [Ar'GaGaAr'] (Ar' = C(6)H(3)-2,6(C(6)H(3)-2,6-iPr(3))(2)) and [(GaAr*)(n)] (Ar* = C(6)H(3)-2,6(C(6)H(2)-2,4,6-iPr(3))(2)). The calculations showed that the binding energies of the compounds are weak, resemble closed-shell interactions and average approximately 5 kcal mol(-1), as in [Ar*GaGaAr*] with a lowest value of approximately -2 kcal mol(-1) for monomeric 10 and a highest value approximately 9 kcal mol(-1) for the least crowded species [Ar'GaGaAr']. The weak bonding in the complexes supports the view that the GaGa bonding in the previously published doubly reduced Na(2)[Ar*GaGaAr*] and Na(2)[Ar'GaGaAr'] is also weak and is consistent with approximate single bonding.
ABSTRACT
At the interface between monolayer FeSe films and SrTiO3 substrates the superconducting transition temperature (Tc) is unexpectedly high, triggering a surge of excitement. The mechanism for the Tc enhancement has been the central question, as it may present a new strategy for seeking out higher Tc materials. To reveal this enigmatic mechanism, by combining advances in high quality interface growth, 16O [Formula: see text] 18O isotope substitution, and extensive data from angle resolved photoemission spectroscopy, we provide striking evidence that the high Tc in FeSe/SrTiO3 is the cooperative effect of the intrinsic pairing mechanism in the FeSe and interactions between the FeSe electrons and SrTiO3 phonons. Furthermore, our results point to the promising prospect that similar cooperation between different Cooper pairing channels may be a general framework to understand and design high-temperature superconductors.
ABSTRACT
Reactions of an anionic heavy ruthenocene with CCl4, MeI, EtBr and Me3SiCl afforded the first stannole monoanion complexes. Surprisingly, coordination modes of the stannole rings are highly dependent on the substituents on the tin atom. The chloro derivative exhibits a η(4)-fashion-like coordination mode with a bent stannole ring, whereas the trimethylsilyl derivative adopts the conventional η(5)-coordination mode. Coordination modes of the alkyl derivatives are in between the two types. Cyclic voltammograms for these complexes reveal that the electron-donating character of the stannole ligand becomes stronger as the stannole ring becomes planar. Theoretical calculations elucidate that the different coordination modes originate from both electronegativity of an adjacent atom to the tin atom and bulkiness of a substituent on the tin atom.
ABSTRACT
Spinal cord injury (SCI) represents a severe health problem worldwide usually associated with severe disability and reduced quality of life. The aim of this work was to investigate the role of prohibitin 1 (PHB1) in the progression of SCI in rats. Firstly, we observed that expression of PHB1 was downregulated following SCI in rats. Then, we hypothesized that PHB1 overexpression by delivery of Ad-PHB1 could result in neuroprotection and promote functional recovery following SCI. Briefly, Wistar rats received a 35-g clip-compression injury and were administered Ad-PHB1 or Ad immediately following SCI. It was found that Ad-PHB1 administration significantly improved locomotor function and increased pain tolerance in rats with SCI. Furthermore, Ad-PHB1 administration following SCI attenuated axonal degradation and increased neuron sparing. Ad-PHB1 administration following SCI reduced apoptosis through inhibiting the Bcl-2/Bax/caspase-3 pathway. Ad-PHB1 administration following SCI suppressed endoplasmic reticulum stress, evidenced by reduced mRNA levels of CCAAT enhancer binding protein homologous protein, chaperone-ucose-regulated protein 78, and X-box protein 1. Ad-PHB1 administration following SCI restored mitochondrial adenosine triphosphate formation, reduced reactive oxygen species formation, and improved mitochondrial respiration rates. Finally, Ad-PHB1 administration following SCI activated downstream signals including phosphatidylinositol-3-kinase (PI3K)/Akt, extracellular signal-regulated kinase (ERK1/2), and nuclear factor-kappaB. These data indicate that the PHB1 plays an important role in the development of SCI and might provide a therapeutic target to promote recovery from SCI.
Subject(s)
Neuroprotective Agents/metabolism , Neuroprotective Agents/therapeutic use , Recovery of Function/drug effects , Repressor Proteins/metabolism , Repressor Proteins/therapeutic use , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/metabolism , Adenoviridae , Animals , Apoptosis/drug effects , Disease Progression , Endoplasmic Reticulum Stress/drug effects , Female , Genetic Vectors , Hyperalgesia/drug therapy , Locomotion/drug effects , Neurons/drug effects , Neurons/metabolism , Prohibitins , Rats , Rats, Wistar , Repressor Proteins/genetics , Signal Transduction/drug effects , Spinal Cord Injuries/geneticsABSTRACT
The bed nucleus of the stria terminalis (BNST) plays a critical role in regulating the behavioral response to stress. Stressors that activate the BNST also activate serotonergic (5-HT) systems. Hence, maladaptive changes of 5-HT receptor expression may contribute to stress-induced anxiety disorders. The BNST contains three neuronal types, Type I-III neurons. However, little is known about 5-HT receptor subtypes mRNA expression in these neurons, or whether it can be modulated by stress. Whole-cell patch clamp recording from Type I-III neurons was used in conjunction with single cell reverse transcriptase polymerase chain reaction (RT-PCR) to characterize 5-HT receptor mRNA expression, and examine the effects of stress on this expression. We report that Type I neurons expressed mRNA transcripts predominantly for 5-HT(1A) and 5-HT(7) receptors. Type II neurons expressed transcripts for every 5-HT receptor except the 5-HT(2C) receptor. Type II neurons were divided into three sub-populations: Type IIA in which transcripts for 5-HT(3) and 5-HT(7) receptors predominate, Type IIB that mainly express 5-HT(1B) and 5-HT(4) receptor transcripts, and Type IIC in which transcripts for 5-HT(1A) and 5-HT(2A) receptors predominate. Type III neurons were also subdivided into two sub-populations; one that predominantly expressed transcripts for 5-HT(1A), 5-HT(1B) and 5-HT(2A) receptors, and another that mainly expressed transcripts for 5-HT(2C) receptor. Unpredictable shock stress (USS) caused a long-lasting increase in anxiety-like behavior, and a concomitant decrease in 5-HT(1A) transcript expression in Type I-III neurons, as well as an up-regulation of a transcriptional repressor of 5-HT(1A) gene expression, deformed epidermal autoregulatory factor 1 (Deaf-1). Significantly USS decreased 5-HT(1A) protein level, and increased the level of Deaf-1. USS also increased 5-HT(1B) transcript expression in Type III neurons, as well as 5-HT(7) expression in Type I and II neurons. These data suggest that cell type-specific disruption of 5-HT receptor expression in BNST(ALG) neurons may contribute to stress-induced anxiety disorders.
Subject(s)
Gene Expression Regulation/physiology , Neurons/metabolism , Receptors, Serotonin/classification , Receptors, Serotonin/metabolism , Septal Nuclei/pathology , Stress, Psychological/pathology , Acoustic Stimulation/adverse effects , Animals , Electric Stimulation/adverse effects , Male , Neurons/classification , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Patch-Clamp Techniques , Psychoacoustics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Reaction Time/physiology , Receptors, Serotonin/genetics , Sensory Gating/physiology , Stress, Psychological/metabolism , Transcription FactorsABSTRACT
Activation of neurons in the bed nucleus of the stria terminalis (BNST) plays a critical role in stress and anxiety-related behaviors. Previously, we have shown that serotonin (5-HT) can directly modulate BNST neuronal excitability by an action at postsynaptic receptors. In this study we built upon that work to examine the effects of 5-HT on excitatory neurotransmission in an in vitro rat BNST slice preparation. Bath application of 5-HT reversibly reduced the amplitude of evoked excitatory postsynaptic currents (eEPSCs). These effects were mimicked by the 5-HT(1B/D) receptor agonist, sumatriptan, and by the 5-HT(1B) receptor selective agonist, CP93129. Conversely, the effects of 5-HT and sumatriptan could be blocked by the 5-HT(1B) receptor-selective antagonist, GR55562. In contrast, the 5-HT(1A) receptor agonist 8-OH DPAT or antagonist WAY 100635 could not mimic or block the effect of 5-HT on eEPSCs. Together, these data suggest that the 5-HT-induced attenuation of eEPSCs was mediated by 5-HT(1B) receptor activation. Moreover, sumatriptan had no effect on the amplitude of the postsynaptic current elicited by pressure applied AMPA, suggesting a possible presynaptic locus for the 5-HT(1B) receptor. Furthermore, 5-HT, sumatriptan and CP93129 all increased the paired pulse ratio of eEPSCs while they concomitantly decreased the amplitude of eEPSCs, suggesting that these agonists act to reduce glutamate release probability at presynaptic locus. Consistent with this observation, sumatriptan decreased the frequency of miniature EPSCs, but had no effect on their amplitude. Taken together, these results suggest that 5-HT suppresses glutamatergic neurotransmission in the BNST by activating presynaptic 5-HT(1B) receptors to decrease glutamate release from presynaptic terminals. This study illustrates a new pathway by which the activity of BNST neurons can be indirectly modulated by 5-HT, and suggests a potential new target for the development of novel treatments for depression and anxiety disorders.
Subject(s)
Glutamic Acid/metabolism , Presynaptic Terminals/physiology , Receptor, Serotonin, 5-HT1B/metabolism , Septal Nuclei/physiology , Serotonin/metabolism , Synaptic Transmission/physiology , Animals , Evoked Potentials/drug effects , Excitatory Postsynaptic Potentials/drug effects , In Vitro Techniques , Male , Membrane Potentials/drug effects , Neural Inhibition/drug effects , Neural Inhibition/physiology , Neurons/drug effects , Neurons/physiology , Presynaptic Terminals/drug effects , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT1D/metabolism , Septal Nuclei/drug effects , Serotonin 5-HT1 Receptor Agonists , Serotonin 5-HT1 Receptor Antagonists , Synapses/drug effects , Synapses/physiology , Synaptic Transmission/drug effects , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolismABSTRACT
Activation of neurons in the anterolateral bed nucleus of the stria terminalis (BNST(ALG)) plays an important role in mediating the behavioral response to stressful and anxiogenic stimuli. Application of 5-HT elicits complex postsynaptic responses in BNST(ALG) neurons, which includes (1) membrane hyperpolarization (5-HT(Hyp)), (2) hyperpolarization followed by depolarization (5-HT(Hyp-Dep)), (3) depolarization (5-HT(Dep)) or (4) no response (5-HT(NR)). We have shown that the inhibitory response is mediated by activation of postsynaptic 5-HT(1A) receptors. Here, we used a combination of in vitro whole-cell patch-clamp recording and single cell reverse transcriptase polymerase chain reaction (RT-PCR) to determine the pharmacological properties and molecular profile of 5-HT receptor subtypes mediating the excitatory response to 5-HT in BNST(ALG) neurons. We show that the depolarizing component of both the 5-HT(Hyp/Dep) and the 5-HT(Dep) response was mediated by activation of 5-HT(2A), 5-HT(2C) and/or 5-HT(7) receptors. Single cell RT-PCR data revealed that 5-HT(7) receptors (46%) and 5-HT(1A) receptors (41%) are the most prevalent receptor subtypes expressed in BNST(ALG) neurons. Moreover, 5-HT receptor subtypes are differentially expressed in type I-III BNST(ALG) neurons. Hence, 5-HT(2C) receptors are almost exclusively expressed by type III neurons, whereas 5-HT(7) receptors are expressed by type I and II neurons, but not type III neurons. Conversely, 5-HT(2A) receptors are found predominantly in type II neurons. Finally, bi-directional modulation of individual neurons occurs only in type I and II neurons. Significantly the distribution of 5-HT receptor subtypes in BNST(ALG) neurons predicted the observed expression pattern of 5-HT responses determined pharmacologically. Together, these results suggest that 5-HT can differentially modulate the excitability of type I-III neurons, and further suggest that bi-directional modulation of BNST(ALG) neurons occurs primarily through an interplay between 5-HT(1A) and 5-HT(7) receptors. Hence, modulation of 5-HT(7) receptor activity in the BNST(ALG) may offer a novel avenue for the design of anxiolytic medications.
Subject(s)
Neurons/metabolism , Receptors, Serotonin/physiology , Septal Nuclei/metabolism , Serotonin/physiology , Animals , In Vitro Techniques , Male , Patch-Clamp Techniques , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2A/biosynthesis , Receptor, Serotonin, 5-HT2A/physiology , Receptor, Serotonin, 5-HT2C/biosynthesis , Receptor, Serotonin, 5-HT2C/physiology , Receptors, Serotonin/biosynthesis , Reverse Transcriptase Polymerase Chain Reaction , Serotonin Receptor Agonists/pharmacologyABSTRACT
In normal pregnancy the vasodilating actions of prostacyclin and the antioxidant activity of vitamin E are important for normal physiologic function. Thromboxane and lipid peroxides oppose these actions by promoting vasoconstriction and peroxidation reactions, respectively. An imbalance between thromboxane and prostacyclin and between lipid peroxides and antioxidant activity is implicated in pathologic states such as preeclampsia. We hypothesized that in normal pregnancy there would be a balance in the ratios of prostacyclin to thromboxane and of vitamin E to lipid peroxides that would favor prostacyclin and vitamin E. Blood samples were collected from normally pregnant women throughout gestation and analyzed for prostacyclin, thromboxane, vitamin E, and lipid peroxides. Serum levels of lipid peroxides remained relatively stable throughout gestation, but the levels of vitamin E progressively increased. Plasma levels of prostacyclin progressively increased with advancing gestation, whereas levels of thromboxane progressively decreased. Therefore the ratios of both prostacyclin/thromboxane, and vitamin E/lipid peroxides progressively increased during pregnancy. The increase in the ratios was highly correlated, r = 0.94. We conclude that the changes in the maternal concentrations of these compounds and the progressive increase in the ratios of prostacyclin/thromboxane and vitamin E/lipid peroxides suggest that the vasodilating actions of prostacyclin and the antioxidant activity of vitamin E are progressively favored with advancing gestation in normally pregnant women.
Subject(s)
Epoprostenol/blood , Lipid Peroxides/blood , Pregnancy/blood , Thromboxane B2/blood , 6-Ketoprostaglandin F1 alpha/blood , Adult , Female , Gestational Age , HumansABSTRACT
Preeclampsia is associated with an imbalance between thromboxane and prostacyclin. The cause of the imbalance is unknown. Preeclampsia sera contain cytotoxic factors that can damage endothelial cells. Lipid peroxides can damage cell membranes, so elevated levels in the mother's blood could be related to endothelial cell injury and decreased prostacyclin in preeclampsia. This study determined maternal plasma levels of thromboxane and prostacyclin and serum levels of lipid peroxides and vitamin E in women with normal pregnancy (n = 12), mild preeclampsia (n = 16), and severe preeclampsia (n = 19) between 36 and 40 weeks' gestation. In normal pregnancy the ratio of thromboxane to prostacyclin (0.63) favored prostacyclin, and the ratio of lipid peroxides to vitamin E (0.43) favored vitamin E. Prostacyclin was significantly decreased in both mild and severe preeclampsia. Thromboxane was not increased in mild preeclampsia but was significantly increased in severe preeclampsia. The ratio of thromboxane to prostacyclin was increased in mild preeclampsia (0.77) and greatly increased in severe preeclampsia (1.94). Lipid peroxides were significantly increased in mild preeclampsia and increased further in severe preelcampsia. Vitamin E levels were unaltered in mild preeclampsia but significantly decreased in severe preeclampsia. The ratio of lipid peroxides to vitamin E was increased in mild (0.52) and greatly increased in severe (1.09) preeclampsia. We concluded the following: (1) Maternal plasma prostacyclin is decreased in both mild and severe preeclampsia, but thromboxane is increased only in severe cases. (2) Lipid peroxides are significantly increased in both mild and severe preeclampsia and vitamin E is significantly decreased in severe preeclampsia. We speculate that this imbalance could result in endothelial and platelet cell damage and in decreased prostacyclin and increased thromboxane synthesis. (3) Preeclampsia is associated with an imbalance not only between thromboxane and prostacyclin but also between lipid peroxides and vitamin E in maternal blood. The imbalances progressively favor thromboxane and lipid peroxides with the increasing severity of preeclampsia, which is consistent with the clinical symptoms of this disorder.