Diurnal variation of nicotine‐induced ACTH and cortisol secretion in non‐smoking healthy male volunteers

Most investigators have used either cigarette smoking or intravenous nicotine in order to try and study the effects of nicotine exposure on the hypothalamic–pituitary–adrenal (HPA) axis in man. Our two aims in this study were, firstly, to try and determine the effects of intra‐nasal nicotine on the HPA axis and, secondly, to see whether these effects were time‐dependent. Six male non‐smoking subjects were given either placebo or 1·0 mg of intranasal nicotine at 0900 h and at 1700 h. A one way analysis of variance and post hoc tests revealed significantly greater nicotine versus placebo‐induced δ cortisol values at 1700 h and at 0900 h (F=4·004, df=3, p<0·02). A one way analysis of variance and post hoc tests revealed that nicotine versus placebo‐induced δ ACTH values were significantly greater at both the 0900 h (p<0·05) and 1700 h test sessions (p<0·05); furthermore, nicotine‐induced δ ACTH values were significantly higher at 1700 h than at 0900 h (p<0·05) (F=199·04, df=3, p<0·0002). We have found that intra‐nasal nicotine is capable of stimulating the HPA axis and, furthermore, this activation is time dependent. Copyright © 1999 John Wiley & Sons, Ltd.     

Diethylstilbestrol impaired oogenesis of yellow catfish juveniles through disrupting hypothalamic–pituitary–gonadal axis and germ cell development

Diethylstilbestrol (DES), a non‐steroidal estrogen, has been found to cause altered germ cell development and disordered ovarian development in fish females. However, the mechanisms that might be involved are poorly understood. In this study, female juveniles of yellow catfish (Pelteobagrus fulvidraco) (120 days post‐hatching) were exposed to two doses (10 and 100 ng l^?1) of DES for 28 days. After the endpoint of exposure, decreased ovary weight and gonadosomatic index, as well as various ovarian impairments were observed in response to DES. Besides, DES elevated the mRNA levels of vitellogenin 1 (vtg 1) and estrogen receptor 1 (esr 1) in liver and decreased 17β‐estradiol level in plasma. Correspondingly, suppressed mRNA levels of the key genes in the hypothalamic–pituitary–gonadal axis (such as cyp19a1b, gnrh‐II, fshβ and lhβ in brain and fshr, lhr and cyp19a1a in ovary) after DES exposure were also observed. The declined level of plasma 17β‐estradiol and altered gene expressions of genes in the hypothalamic–pituitary–gonadal axis were thus supposed to be closely related to the disrupted oogenesis in DES‐treated fish. Analyses further demonstrated that, higher concentration of DES elevated the expression ratio of bax/bcl‐2, indicating the enhanced apoptosis occurred in ovary. Moreover, DES upregulated the expressions of genes involved in proliferation (cyclin d1 and pcna), meiotic entry (cyp26a1 and scp3) and meiotic maintenance (dmc1), resulting in arrested oogenesis in catfish. The present study greatly extended our understanding on the mechanisms underlying of reproductive toxicity of DES on fish oogenesis.     

Effect of acute hexavalent chromium exposure on pituitary–thyroid axis of a freshwater fish,Channa punctatus (Bloch)

Acute exposure to hexavalent chromium (10 mg L^?1, 20 mg L^?1, and 40 mg L^?1 potassium dichromate for 96 h) dose‐dependently affected the pituitary–thyroid axis of teleost, Channa punctatus. Significant hypertrophy of the thyroid follicle was observed in 20 mg L^?1 and 40 mg L^?1 groups; the follicular epithelium was however hypertrophied only in 40 mg L^?1 group. The colloid depletion in the lumen of thyroid follicle was evident in 20 mg L^?1 and 40 mg L^?1 groups. Serum thyroid hormones (thyroxine/T4 and triiodothyronine/T3) level increased significantly at both the higher doses. Increased immunointensity and significant hypertrophy of the pituitary thyrotrophs (anti TSHβ‐immunoreactive cells) was observed in both 20 mg L^?1 and 40 mg L^?1 chromium‐exposed fish. The increased thyroid hormones secretion observed in this study might be an adaptive response of the pituitary–thyroid axis under acute chromium‐induced stress condition to maintain homeostasis. The long‐term Cr(VI) exposures, however, may lead to attenuation/exhaustion of the pituitary–thyroid axis and pose serious threat to fish health and affect their population. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 621–627, 2015.     

Metoclopramide as pharmacological tool to assess vasopressinergic co-activation of the hypothalamus–pituitary–adrenal (HPA) axis: A study in healthy volunteers

The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus–pituitary–adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10 mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis.     

Hypericum treatment of mild–moderate depression in a placebo–controlled study. A prospective,double–blind,randomized, placebo–controlled,multicentre study

A prospective, randomized, multicentre, double-blind placebo controlled study is described which compares the efficacy and tolerability of hypericum administered as a concentrated ethanolic extract of St John's wort (ZE117) to patients with mild–moderate depression (ICD-10; F 32·0 mild; F 32·1 moderate). Patients on active medication received 250 mg extract tablets twice daily, corresponding to 1 mg hypericin daily, for 6 weeks. The primary efficacy variable was the 21 item Hamilton Depression Scale (HAMD); secondary variables were the risk-benefit Clinical Global Impression (CGI) scales I–III and a validated patient self-assessment on a Visual Analogue Scale (VAS). 162 patients entered the trial. 159 patients (80 on active medication) were evaluated in an intention-to-treat analysis; 136 patients (66 on active medication) in a protocol-compliant analysis. Patients in the two treatment groups did not differ with respect to the distribution of age, gender, weight and height. Based on differences in HAMD scores (p<0·001), both the intention-to-treat and protocol-compliant analyses demonstrate that ZE117 is clinically effective in the treatment of patients with mild to moderate depression following 6 weeks' treatment. Using the criteria of ≥50% reduction in HAMD score from baseline and/or an actual HAMD score ≤10 as evidence of a clinically relevant response, 56% patients treated with ZE117 were classified as responders, compared with 15% patients on placebo. The secondary efficacy variables data confirmed these findings. Compliance was high; using electronic devices within the medication containers, a therapeutic coverage of 81·7% was found. This was probably due, in part, to the low number of adverse events reported (11 total, 5 placebo, 6 active), the majority of which were transient, self-limiting and, in the case of active treatment, mostly non-specific gastrointestinal complaints. These results demonstrate that hypericum (ZE117) provides a safe and effective treatment for patients with mild to moderate depression. The good tolerability profile contributes to the high observed compliance, possibly conferring a clinical advantage in achieving efficacy over other antidepressants with less favourable side effect profiles. © 1998 John Wiley & Sons, Ltd.     

NMR structural characterization of cecropin A(1–8) – magainin 2(1–12) and cecropin A(1–8) – melittin(1–12) hybrid peptides

Abstract: In order to elucidate the structure–antibiotic activity relationships of the peptides, the three-dimensional structures of two hybrid peptides, CA(1–8) – MA(1–12) and CA(1–8) – ME(1–12) in trifluoroethanol-containing aqueous solution were investigated by NMR spectroscopy. Both CA(1–8) – MA(1–12) and CA(1–8) – ME(1–12) have strong antibacterial activity but only CA(1–8) – ME(1–12) has hemolytic activity against human erythrocytes. CA(1–8) – MA(1–12) has a hydrophobic 3₁₀-helix of only two turns combined with one short helix in the N-terminus with a flexible hinge section in between. CA(1–8) – MA(1–12) has a severely bent structure in the middle of the peptide. These structural features as well as the low hydrophobicity of CA(1–8) – MA(1–12) seem to be crucial for the selective lysis against the membrane of prokaryotic cells. CA(1–8) – ME(1–12) has an α-helical structure of about three turns in the melittin domain and a flexible structure with one turn in the cecropin domain connected with a flexible hinge section in between, and these might be the structural features required for membrane distruption against prokaryotic and eukaryotic cells. The central hinge region (Gly9-Ile10-Gly11) in an amphipathic antibacterial peptide is considered to play an important role in providing the conformational flexibility required for ion channel formation of the C-terminal hydrophobic α-helix on cell membrane.     

Antagonism of the Acute and Long–term Biochemical Effects of 4–Chloroamphetamine on the 5–HT Neurones in the Rat Brain by Inhibitors of the 5–Hydroxytryptamine Uptake

Abstract The effects of H 102/09 ((Z)–3–(4–bromophenyl)–N, N–dimethyl–3–(3–pyridyl)allylamine dihydrochloride) and chlorimipramine, two inhibitors of the membrane 5–hydroxytryptamine (5–HT) uptake, on the acute and long–term effects of 4–chloroamphetamine on the 5–HT neurones in rats were examined. The acute effect determined as the decrease in the brain level of 5–HT was antagonized by both compounds. The long–term effects determined as the decreases in 5–hydroxyindoles and the synaptosome accumulation of ¹⁴–C–5–HT were antagonized by a single injection of H 102/09 (20 mg/kg intraperitoneally) immediately before or shortly after the 4–chloroamphetamine administration. Chlorimipramine, 40 mg/kg intraperitoneally, had no antagonizing effect but on repeated injections of 40 mg/kg intraperitoneally before and four times with 3 hours' intervals after 4–chloroamphetamine, a partial antagonism of the longterm decrease in 5–HT was obtained. Combined with proadifen (SK & F 525 A) chlorimipramine partially antagonized the long–term effect. Two monoamine oxidase inhibitors (pheniprazine and clorgyline), pretreatment of the rats with p–chlorophenylalanine (2 × 300 mg/kg intraperitoneally) or proadifen alone (40 mg/kg intraperitoneally injected before and four times with 3 hours' interval) had no antagonistic effect on the long–term decrease in 5–HT. The accumulation of ³H–chloroamphetamine in synaptosomes of the hypothalamus midbrain region was slightly decreased by high concentrations of H 102/09 at 37° and 0°. H 102/09 decreased slightly but significantly the ratio between the ³H–chloramphetamine in the synaptosomal fraction and the supernatant as obtained when the rats were killed 2 hours after the injection. The increased efflux of ³H–5–HT from synaptosomes in vitro produced by 4–chloroamphetamine, ouabain and low external Na⁺ concentrations was in all cases inhibited by H 102/09 at 2.5 × 10^–6 M. Although the antagonism of the acute effect of 4–chloroamphetamine seems to be related to inhibition of the membrane 5–HT transport mechanism the antagonism of the long–term, irreversible effect produced by 4–chloroamphetamine may also involve an additional as yet unknown mechanism.     

The effects of sucrose on stability of human brain natriuretic peptide [hBNP (1–32)] and human parathyroid hormone [hPTH (1–34)]

Abstract: Although the effect of sucrose on the physical stability of proteins has been well documented, its impact on their chemical stability is largely unknown. The aim of this study was to investigate the potential effects of sucrose on the structural conformation of human brain natriuretic peptide [hBNP (1–32)] and the synthetic human parathyroid hormone [hPTH (1–34)], and link these effects to chemical degradation pathways of these peptides. The stability of hBNP (1–32) and hPTH (1–34) was studied at pH 5.5. Aggregation was monitored using size exclusion high‐performance liquid chromatography (SE‐HPLC), whereas oxidation and deamidation products were measured by reversed phase (RP) HPLC. Fourier transform infrared (FT‐IR) spectroscopy was used to study the peptides’ conformation. Sucrose retarded aggregation, deamidation, and oxidation of hBNP (1–32) and hPTH (1–34), with a maximum effect at relatively high concentrations (as much as 1 m ). FT‐IR spectroscopy indicated that sucrose maintained the native conformation of hBNP (1–32) and induced small conformation changes in the hPTH (1–34) structure. Sucrose enhanced the stability of hBNP (1–32) and hPTH (1–34) in liquid formulations. The stabilizing effect of sucrose was due to a large extent to retardation of oxidation and deamidation of hBNP (1–32) and hPTH (1–34).     

Synthesis,molecular modeling,in vivo study,and anticancer activity of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen

A new series of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen ( 7a–m ) was synthesized in this study. The structures of these compounds were characterized by spectral (Fourier‐transform infrared spectroscopy, ¹H‐nuclear magnetic resonance (NMR), ¹³C‐NMR, and high‐resolution electron ionization mass spectrometry) methods. Furthermore, molecular modeling of these compounds was studied on human methionine aminopeptidase‐2. All synthesized compounds were screened for anticancer activity against three prostate cancer cell lines (PC3, DU‐145, and LNCaP) using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium colorimetric method. Compound 7a showed the best activity against the PC3, DU‐145 and LNCaP cancer cell lines with IC₅₀ values of 26.0, 34.5, and 48.8 μM, respectively. Compounds 7b , 7k , and 7m showed anticancer activity against cancer cell lines PC3 and DU‐145 with IC₅₀ values of 43.0, 36.5, 29.3 μM and 49.8, 49.1, 31.6 μM, respectively. Compounds 7f and 7g showed anticancer activity against PC3 cells with IC₅₀ values of 43.4 and 34.5 μM, respectively. To assess the biodistribution in mice of IRDye800, dye‐labeled compound 7a or 100 μM of free dye was injected intravenously into the mice's tail. In vivo images were taken with in vivo imaging system spectrum device at 60, 120, 180, 240, 300, and 360 min after injection. At the end of 360 min, ex vivo studies were carried out to determine in which organs the dye was accumulated in the urogenital system. Ex vivo studies showed that the accumulation of compound 7a in the prostate is greater than that of the free dye, and it is concluded that compound 7a may be promising for the treatment of prostate cancer.     

Protective arms of the renin–angiotensin‐system in neurological disease

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Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with <Emphasis Type="Italic">S</Emphasis>-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response

Rationale A dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is a well-documented neurobiological finding in major depression. Moreover, clinically effective therapy with antidepressant drugs may normalize the HPA axis activity. Objective The aim of this study was to test whether citalopram (R/S-CIT) affects the function of the HPA axis in patients with major depression (DSM IV). Methods Twenty depressed patients (11 women and 9 men) were challenged with a combined dexamethasone (DEX) suppression and corticotropin-releasing hormone (CRH) stimulation test (DEX/CRH test) following a placebo week and after 2, 4, and 16 weeks of 40 mg/day R/S-CIT treatment. Results The results show a time-dependent reduction of adrenocorticotrophic hormone (ACTH) and cortisol response during the DEX/CRH test both in treatment responders and nonresponders within 16 weeks. There was a significant relationship between post-DEX baseline cortisol levels (measured before administration of CRH) and severity of depression at pretreatment baseline. Multiple linear regression analyses were performed to identify the impact of psychopathology and hormonal stress responsiveness and R/S-CIT concentrations in plasma and cerebrospinal fluid (CSF). The magnitude of decrease in cortisol responsivity from pretreatment baseline to week 4 on drug [delta-area under the curve (AUC) cortisol] was a significant predictor (p<0.0001) of the degree of symptom improvement following 16 weeks on drug (i.e., decrease in HAM-D₂₁ total score). The model demonstrated that the interaction of CSF S-CIT concentrations and clinical improvement was the most powerful predictor of AUC cortisol responsiveness. Conclusion The present study shows that decreased AUC cortisol was highly associated with S-CIT concentrations in plasma and CSF. Therefore, our data suggest that the CSF or plasma S-CIT concentrations rather than the R/S-CIT dose should be considered as an indicator of the selective serotonergic reuptake inhibitors (SSRIs) effect on HPA axis responsiveness as measured by AUC cortisol response.     

Effect of penbutolol on neuroendocrine responses to buspirone and mood in SSRI‐refractory patients: a preliminary study

The β‐adrenoceptor antagonist, penbutolol, is an effective serotonin_1A (5‐HT_1A) receptor antagonist in the rat and through this action enhances the ability of selective serotonin re‐uptake inhibitors (SSRIs) to increase levels of serotonin in terminal fields. In healthy volunteers, penbutolol (40 mg orally), produced a modest attenuation of the prolactin response to the 5‐HT_1A receptor antagonist, buspirone (30 mg orally), but did not antagonise the hypothermic response. Furthermore, penbutolol addition (40 mg daily for 3 weeks) failed to improve the symptomatology of 10 depressed patients who had shown an inadequate clinical response to serotonergic antidepressants. These preliminary data suggest that at the typical dose used to treat hypertension, penbutolol does not antagonise 5‐HT_1A autoreceptors in humans and does not augment the effect of serotonergic antidepressants in treatment non‐responders. Copyright © 1999 John Wiley & Sons, Ltd.     

Effects of Corticotropin-Releasing Factor on Circadian Locomotor Rhythm in the Golden Hamster

Stress produces a reduction in the amplitude of some circadian rhythms. The neurochemical mechanisms underlying stress-induced changes in circadian rhythms are not known. To investigate a possible role of corticotropin-releasing factor (CRF) in this phenomenon, three related experiments were carried out: activity rhythms of male golden hamsters (10/14 hours light/dark entrained, lights on at 0800 h) were measured 1) following the intracerebroventricular administration of CRF (0.5, 1.0, 2.0, or 4.0 μg) at two different times of day, 2) following social stress (30-min resident–intruder confrontation), 3) and following the administration of the CRF-antagonist α-helical CRF_9–41 (2.0 μg) prior to a 15-min resident–intruder confrontation. CRF produced a significant, dose-related decrease in circadian rhythm amplitude following administration in the morning hours, but not in the afternoon. CRF also induced transient increases in activity post injection concomitant with an activation of the hypothalamic–pituitary–adrenocortical (HPA) system. Stress similarly reduced the amplitude of activity patterns and stimulated the HPA system. The stress-induced depression of circadian rhythm amplitude was significantly attenuated following α-helical CRF_9–41. These data suggest a role for CRF in the stress-related modulation of circadian locomotor rhythm amplitude.     

Detection of bioactive peptides including gonadotrophin‐releasing factors (GnRHs) in horse urine using ultra‐high performance liquid chromatography–high resolution mass spectrometry (UHPLC/HRMS)

The use of bioactive peptides as a doping agent in both human and animal sports has become increasingly popular in recent years. As such, methods to control the misuse of bioactive peptides in equine sports have received attention. This paper describes a sensitive accurate mass method for the detection of 40 bioactive peptides and two non‐peptide growth hormone secretagogues (< 2 kDa) at low pg/mL levels in horse urine using ultra‐high performance liquid chromatography‐high resolution mass spectrometry (UHPLC/HRMS). A simple mixed‐mode cation exchange solid‐phase extraction (SPE) cartridge was employed for the extraction of 42 targets and/or their in vitro metabolites from horse urine. The final extract was analyzed using UHPLC/HRMS in positive electrospray ionization (ESI) mode under both full scan and data independent acquisition (DIA, for MS²). The estimated limits of detection (LoD) for most of the targets could reach down to 10 pg/mL in horse urine. This method was validated for qualitative detection purposes. The validation data, including method specificity, method sensitivity, extraction recovery, method precision, and matrix effect were reported. A thorough in vitro study was also performed on four gonadotrophin‐releasing factors (GnRHs), namely leuprorelin, buserelin, goserelin, and nafarelin, using the S9 fraction isolated from horse liver. The identified in vitro metabolites have been incorporated into the method for controlling the misuse of GnRHs. The applicability of this method was demonstrated by the identification of leuprorelin and one of its metabolites, Leu M4, in urine obtained after intramuscular administration of leuprorelin to a thoroughbred gelding (castrated horse).     

Development and validation of a simple and sensitive liquid chromatography–tandem mass spectrometry method for quantifying trimetazidine in human plasma

1. A simple and sensitive liquid chromatography–tandem mass spectrometry (LC‐MS‐MS) method for quantifying trimetazidine in human plasma was developed and validated. Sample preparation was based on deproteinating with acetonitrile. 2. Chromatography was performed on a C18 analytical column (5 μm; 150 × 2.1 mm i.d.) and the retention times for trimetazidine and cetirizine (used as the internal standard) were 1.8 and 3.0 min, respectively. The ionization was optimized using an electrospray ionization source and enhanced selectivity was achieved using tandem mass spectrometry. The calibration curve ranged from 0.1 to 200 ng/mL. The inter‐day precision, accuracy and the relative standard deviation (RSD) were all < 15%. The analyte was shown to be stable over the time‐scale of the entire procedure. 3. The robustness of the method was demonstrated by the good reproducibility of the results obtained during the analysis of clinical samples.     

Angiotensin‐(1–7) treatment ameliorates angiotensin II‐induced apoptosis of human umbilical vein endothelial cells

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