Early detection and prevention of psychiatric disorders, particularly depression, remain as major global health challenges, yet reliable tools for identifying individuals before symptom onset are lacking. Here, we combine functional neuroimaging with computational modeling to identify a mechanistic biomarker of depression risk. In a population-based adolescent cohort (IMAGEN, N = 1332), we found that weakened neural representations of emotional signals were linked to depressive symptoms. Perturbation experiments in a brain-aligned deep learning model showed that this deficit reflects overregularized emotion perception, producing a negative perceptual bias. A neurocomputational signature of this mechanism predicted depression symptom onset up to 4 years later at the IMAGEN follow-up (N = 725), was associated with both a genetic-risk variant and polygenic risk for depression, and improved depression classification in a patient cohort (STRATIFY, N = 411). These findings suggest a possible mechanism linking genetic vulnerability to altered emotion perception and future depression, and propose a predictive computational marker with potential for early detection and prevention.

Urinary tract infections (UTIs) are becoming increasingly challenging to treat owing to the emergence of multidrug-resistant (MDR) strains, including uropathogenic Escherichia coli (UPEC). Clove (Syzygium aromaticum L.) has antimicrobial activity that can alter UPEC morphology and exhibit inhibitory effects. However, the mechanisms underlying the inhibition of specific small molecules remain largely unknown. This study aimed to explore the potential of small molecules in clove flower extract as anti-MDR UPEC agents using in vitro and in silico approaches. Extraction was performed using ethanol and n-hexane, yielding 27.44% and 9.9%, respectively. The ethanol extract exhibited inhibitory activity against MDR-UPEC, forming clear zones ranging from 11.07±0.32 (250 mg/mL) to 16.77±1.36 (1,000 mg/mL) in a disk diffusion assay. However, the combination of ethanol extract and ciprofloxacin resulted in antagonistic effects. GC-MS analysis of the ethanol extract identified 29 small molecules, which were subsequently analyzed using PASS Online, Lipinski's Rule of Five, and molecular docking against target proteins PBP2 and AcrB. Three small molecules showed the potential to inhibit PBP2, and ten small molecules targeted AcrB. Spesifically, 8,14-Seco-3,19-epoxyandrostane-8,14-dione, 17-acetoxy-3β-methoxy-4,4-dimethyl-, Ethyl iso-allocholate and Estra-1,3,5(10)-trien-17β-ol show binding affinities of -7.9; -7.6; dan -8.0 kcal/mol to PBP2, and -9.3; -8.5; dan -8.6 kcal/mol to AcrB, respectively. These three small molecules are promising candidates for developing plant-based antibacterial agents against MDR UPEC.

Estradiol valerate has not been studied during breastfeeding. Injectable estradiol valerate has been used to suppress lactation, usually in combination with testosterone. Generally, it should be avoided in mothers wishing to breastfeed. Oral estradiol valerate is only available in the United States in a combination oral contraceptive product that also contains dienogest. Based on the available evidence, expert opinion holds that nonhormonal methods are preferred during breastfeeding and progestin-only contraceptives are preferred over combined oral contraceptives in breastfeeding women, especially during the first 4 weeks postpartum. For further information, consult the record entitled, "Contraceptives, Oral, Combined."

Environmental factors such as altitude, precipitation, and temperature shape the lipidomic profiles of the argan tree (Argania spinosa L.), supporting its adaptation to stress. This study investigated lipidomic profiling and pathways in argan tree leaves from four altitudinal zones (A: low, B: moderate, C: high, D: very high) across three Moroccan regions (Chtouka Aït Baha, Essaouira, and Tiznit) using Gas Chromatography-Mass Spectrometry (GC-MS). The GC-MS workflow included a transmethylation step that cleaves ester bonds and acetylations, yielding analytes derived from diverse precursor lipids such as glycerolipids, sterol esters, and wax esters. We identified 139 lipid analytes, categorized into fatty acyls (53 %), prenol lipids (41 %), and steroids (6 %). Shared lipids across all zones highlight core metabolic pathways essential for resilience, while unique lipids reflect zone-specific adaptations. Fourteen known analytes were identified as critical markers for regional adaptations through multivariate analyses, including Principal Component Analysis (PCA), Partial Least Squares Discriminant Analysis (PLS-DA), and Variable Importance in Projection (VIP) scores. Among these, three analytes (methyl 18-methyleicosanoate, Z,Z-11,13-Hexadecadien-1-ol, and 11-Octadecenoic acid) showed the highest accumulation in Zone A, whereas eleven analytes (Henicosyl formate, Dodecyl 2-methylbutanoate, Methyl 21-methyl-hexacosanoate, Methyl 13-methyltetradecanoate, Cetoleic acid, (Urs-12-en-3-ol, acetate, (3.beta.)-), Medicagenic acid, 2-(4a,8-Dimethyl-6-oxo-1,2,3,4,4a,5,6,8a-octahydro-naphthalen-2-yl)-propionaldehyde, A'-Neogammacer-22(29)-en-3-one, Pregna-5,17(20)-dien-3-ol, (3.beta.,17E)-, and estra-1,3,5(10)-trien-17-one, 3,4-bis(acetyloxy)- exhibited significant increases in Zone D. Multiple Linear Regression analysis showed that precipitation positively influenced analyte concentration (p = 0.00033), while altitude had a significant negative effect (p = 0.039). Pathways analysis highlighted the roles of cutin, suberin, and wax biosynthesis, as well as linoleic acid metabolism, in altitude-driven adaptations. This study demonstrates the metabolic plasticity of Argania spinosa L., offering insights for its conservation amidst climate change.

A series of 16-(α-alkoxyalkane)-17-hydrazino-estra-1(10),2,4-trien[17,16-c]-3-ol (3a-l) and estra-1(10),2,4-trien-[17,16-c]pyrazoline-3-ol derivatives (4a-d) were synthesized from corresponding arylidines 2a,b which was prepared from estrone 1 as starting material. Condensation of 1 with aldehydes gave the corresponding arylidine derivatives 2a,b which were treated with hydrazine derivatives in alcohols to give the corresponding derivatives 3a-l, respectively. Additionally, treatment of 2a,b with methyl- or phenylhydrazine in ethanolic potassium hydroxide afforded the corresponding N-substituted pyrazoline derivatives 4a-d, respectively. All these derivatives showed potent anti-ovarian cancer both in vitro and in vivo. The mechanism of anti-ovarian cancer was suggested to process via topoisomerase II and [V600E]BRAF inhibition.

The aim of this work was to study the ability of some estrogen 8α-analogues, that have CH3-group in the C-3 position, exhibit osteoprotective and cholesterolemic effects. The properties of these analogues was comparisoned with effects of native estradiol and 17α-ethynylestradiol (EE). We showed that compounds 3 ((d,l)-17β-acethoxy-3-methoxy-8α-estra-1,3,5(10)-triene) and 4 ((d,l)-3-methoxy-8α-estra-1,3,5(10)-triene-17-one) had the same osteoprotective and cholesterolemic effects as EE. The utherotropic effects of compound 3 and EE were the same, while the utherotropic activity of 17-keto derivative (compound 4) was higher than effect of EE. The osteoprotective and cholesterolemic effects of compounds 5 and 6 (d- or l-17β-acethoxy-3-methoxy-13-ethyl-8α-gone-1,3,5(10)-triene) were approximately the same, however the utherotropic action of these compounds was different: the compound 5 had significantly lower activity, but the compound 6 had the same effect in comparison with EE. Thus, all studied estrogen 8α-analogues may be used as basic constructions for structural modifications which is necessary as medications with while spectrum of biological properties.

Differential Display (DD) is a technique widely used in studies of differential expression. Most of these analyses, especially those involving fish species, are restricted to species from North America and Europe or to commercial species, as salmonids. Studies related to South American fish species are underexplored. Thus, the present work aimed to describe DD technique modifications in order to improve outcomes related to the isolation of DETs (Differentially Expressed Transcripts), using Leporinus macrocephalus, a large commercially exploited South American species, as a fish design. Different DDRT-PCR approaches were applied to brain samples and the products of the reactions were analyzed on 6% polyacrylamide gels stained with 0.17% Silver Nitrate (AgNO3). The use of PCR reactions under high stringency conditions and longer oligonucleotides based on VNTR (Variable Number of Tandem Repeats) core sequences led to better results when compared to low stringency PCR conditions and the use of decamer oligonucleotides. The improved approach led to the isolation of differentially expressed transcripts on adult males and females of L. macrocephalus. This study indicates that some modifications on the DDRT-PCR method can ensure isolation of DETs from different fish tissues and the development of robust data related to this approach.

The present study was undertaken to examine the effect of acute treatment with 17β-estradiol on post-ischemic cardiac dysfunction and norepinephrine overflow and its possible mechanisms. Male rat hearts were perfused with the Langendorff method and subjected to 40 min of global ischemia followed by 30 min of reperfusion. Each drug was perfused from 15 min before ischemia to 5 min after reperfusion. During reperfusion, 17β-estradiol treatment showed significantly greater functional recovery of left ventricular developed pressure (LVDP), left ventricular end diastolic pressure (LVEDP), and dP/dt(max). Excessive norepinephrine release in coronary effluent from the post-ischemic heart was notably suppressed by treatment with 17β-estradiol. These beneficial effects of 17β-estradiol were not observed in the presence of the nitric oxide synthase inhibitor N(G)-nitro-l-arginine and estrogen receptor antagonist ICI 182,780 ((7α, 17β)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol), respectively. When NO(2)/NO(3) levels in coronary effluents after the onset of reperfusion were measured, reverse-correlation relationships between NO(2)/NO(3) production and ischemia/reperfusion-induced cardiac dysfunction, as well as norepinephrine overflow were observed. These findings suggest that 17β-estradiol exerts cardioprotective effects against ischemia/reperfusion-induced cardiac dysfunction, at least in part, by suppressing norepinephrine overflow, and that nitric oxide production via estrogen receptor activation plays a key role in this process.

Although sex differences in asthma severity are recognized, the mechanisms by which sex steroids such as estrogen influence the airway are still under investigation. Airway tone, a key aspect of asthma, represents a balance between bronchoconstriction and dilation. Nitric oxide (NO) from the bronchial epithelium is an endogenous bronchodilator. We hypothesized that estrogens facilitate bronchodilation by generating NO in bronchial epithelium. In acutely dissociated human bronchial epithelial cells from female patients exposure to 17β-estradiol (E(2); 10 pM-100 nM) resulted in rapid increase of diaminofluorescein fluorescence (NO indicator) within minutes, comparable with that induced by ATP (20 μM). Estrogen receptor (ER) isoform-specific agonists (R,R)-5,11-diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol (THC) (ERα) and diaryl-propionitrile (DPN) (ERβ) stimulated NO production to comparable levels and at comparable rates, whereas the ER antagonist 7α,17β-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol (ICI 182,780) (1 μM) was inhibitory. Estrogen effects on NO were mediated via caveolin-1 (blocked using the caveolin-1 scaffolding domain peptide) and by increased intracellular calcium concentration [prevented by 20 μM 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester but not by blocking Ca(2+) influx using LaCl(3)]. Estrogen increased endothelial NO synthase activation (inhibited by 100 μM N(G)-nitro-l-arginine methyl ester) and phosphorylated Akt. In epithelium-intact human bronchial rings contracted with acetylcholine (1 μM), E(2), THC, and DPN all produced acute bronchodilation in a dose-dependent fashion. Such bronchodilatory effects were substantially reduced by epithelial denudation. Overall, these data indicate that estrogens, acting via ERα or ERβ, can acutely produce NO in airway epithelium (akin to vascular endothelium). Estrogen-induced NO and its impairment may contribute to altered bronchodilation in women with asthma.

Methylprednisolone (MP) is used to treat a variety of neurological disorders involving white matter injury, including multiple sclerosis, acute disseminated encephalomyelitis, and spinal cord injury (SCI). Although its mechanism of action has been attributed to anti-inflammatory or antioxidant properties, we examined the possibility that MP may have direct neuroprotective activities. Neurons and oligodendrocytes treated with AMPA or staurosporine died within 24 h after treatment. MP attenuated oligodendrocyte death in a dose-dependent manner; however, neurons were not rescued by the same doses of MP. This protective effect was reversed by the glucocorticoid receptor (GR) antagonist (11, 17)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one (RU486) and small interfering RNA directed against GR, suggesting a receptor-dependent mechanism. MP reversed AMPA-induced decreases in the expression of anti-apoptotic Bcl-x(L), caspase-3 activation, and DNA laddering, suggesting anti-apoptotic activity in oligodendrocytes. To examine whether MP demonstrated this selective protection in vivo, neuronal and oligodendrocyte survival was assessed in rats subjected to spinal cord injury (SCI); groups of rats were treated with or without MP in the presence or absence of RU486. Eight days after SCI, MP significantly increased oligodendrocytes (CC-1-immunoreactive cells) after SCI, but neuronal (neuronal-specific nuclear protein-immunoreactive cells) number remained unchanged; RU486 reversed this protective effect. MP also inhibited SCI-induced decreases in Bcl-x(L) and caspase-3 activation. Consistent with these findings, the volume of demyelination, assessed by Luxol fast blue staining, was attenuated by MP and reversed by RU486. These results suggest that MP selectively inhibits oligodendrocyte but not neuronal cell death via a receptor-mediated action and may be a mechanism for its limited protective effect after SCI.

Icariin and icaritin with prenyl group have been demonstrated for their selective estrogen receptor modulating activities. We screened their effects on cell growth in human prostate carcinoma PC-3 cell line (estrogen receptor positive) in vitro. PC-3 cell line was used for the measurement of anti-carcinoma activities of 0-100 micromol/l icaritin and 30 micromol/l icariin. 1 micromol/l 17-beta estradiol (E(2)) served as the estrogen positive control, and 1 micromol/l ICI 182,780 [7 alpha-[9 (4,4,5,5,5-pentafluoropentyl) sulfinyl] nonyl]-estra-1,3,5(10)-triene-3,17h-diol]] served as the specific estrogen receptor antagonist. Primary cultured rat prostate basal cells used as cell growth selective control. The growth-inhibitory effects were analyzed using MTT assay, and fluorochrome staining, flow cytometry, and immunoblotting were employed to illustrate the possible mechanisms. When treated with icaritin for 24 to 72 h, cell growth was strongly inhibited (at 48 h IC(50) was 10.74+/-1.59 micromol/l, P<0.001) companied with a mitochondrial transmembrane potential (_Psim) drop. Meanwhile, few changes in IC(50) could be observed when co-incubated with ICI 182,780. Icaritin-induced growth inhibition was associated with G(1) arrest (P<0.05), and G(2)-M arrest depending upon doses. Consistently with G(1) arrest, icaritin increased protein expressions of pRb, p27(Kip1) and p16(Ink4a), while showed decrease in phosphorylated pRb, Cyclin D1 and CDK4. Comparatively, icariin has much lower effects on PC-3 cells and showed only weak G(1) arrest, suggesting a possible structure-activity relationship. These findings suggested a novel anticancer efficacy of icaritin mediated selectively via induction of cell cycle arrest but not associated with estrogen receptors in PC-3 cells.

N,N'-Dialkyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamines show structural analogy with estrogens and selective estrogen receptor modulators. Because the vasodilator properties of these compounds are unknown, we investigated their potential to relax porcine coronary arteries and determined the mechanism(s) of relaxation. Isolated porcine coronary arterial rings were suspended in organ chambers, precontracted with KCl (30 mM), and the relaxant response was determined by measurement of changes in isometric force. Dependent on the chemical structure, the drugs induced concentration-dependent relaxation in rings with and without endothelium. N,N'-Dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (8) was most potent and showed a 12- to 15-fold higher vasodilatory effect than 17beta-estradiol (E2). The vasorelaxation was independent of endothelium. Calcium concentration-dependent contractions in high-potassium depolarizing medium were insurmountably inhibited by 8. The effect of the L-type Ca2+ channel activator (S)-(-)-Bay K 8644 [(S)-(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridine-carboxylic acid methyl ester], which induced a leftward shift of Ca2+ contraction, was blocked by 8. The relaxant response to 8 was unaffected by the estrogen receptor antagonist ICI 182,780 (7alpha-[9-[(4,4,5,5,5-pentafluoropentyl]-sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17beta-diol) and K+ channel blockers, i.e., TEA, glibenclamide, and 4-aminopyridine. Furthermore, the vasodilatory effect of 8 was unaffected by the adenylyl cyclase inhibitor SQ 22536 [9-(tetrahydro-2-furanyl)-9H-purin-6-amine], the guanylyl cyclase inhibitor ODQ [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one], the protein kinase A inhibitor KT 5720 [(9S,10S,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg: 3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid hexyl ester], the protein kinase G inhibitor KT 5823 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester], and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB 203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole]. Western blot analysis demonstrated that 8, unlike E2, raloxifene, and tamoxifen, failed to stimulate p38 MAPK. It is concluded that N,N'-dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine induces endothelium-independent relaxation of coronary arteries; the mechanism apparently involves inhibition of L-type Ca2+ channels. The drug may be protective against cardiovascular diseases.

The present study characterises the vasorelaxant response to raloxifene in isolated rings of porcine coronary artery. Tissues precontracted either with KCl (30 mM) or prostaglandin F(2alpha) (PGF(2alpha); 3 microM) were concentration-dependently relaxed by raloxifene (0.1-10 microM). Relaxation was not inhibited by the estrogen receptor antagonist 7alpha-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17beta-diol (ICI 182,780; 1 microM). Preincubation with raloxifene (1-3 microM) caused an inhibition of the KCl or PGF(2alpha)-induced contraction. The effects of raloxifene were independent of the endothelium. The relaxant response to raloxifene was slow in the onset and could not be reversed after repeated washings. Raloxifene did not affect Ca(2+) release from intracellular stores since it failed to inhibit a transient contraction induced by caffeine (10 mM). Raloxifene-induced relaxation was not influenced by the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM; 10-20 microM). Calcium-induced contractions in Ca(2+)-free high K(+) (60 mM) depolarising medium were concentration-dependently inhibited by raloxifene (0.3-3 microM). If arterial rings were incubated with the L-type Ca(2+) channel activator (S)-(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridine carboxylic acid methyl ester ((S)-(-)-Bay K 8644; 0.1 microM), cumulative concentration-response curves to Ca(2+) were shifted to the left. Raloxifene (0.3-3 microM) inhibited the effect of (S)-(-)-Bay K 8644 in a concentration-dependent manner. 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB 203580; 10 microM), an inhibitor of p38 mitogen-activated protein kinase (MAPK), diminished raloxifene-induced relaxation in endothelium-denuded arterial rings. Western blot analysis demonstrated that raloxifene stimulated p38 MAPK. It is concluded that raloxifene has an inhibitory effect on voltage-gated and receptor-operated L-type Ca(2+) channels in porcine coronary arteries, thus inducing vascular relaxation independent of the endothelium. p38 MAPK is, at least in part, involved in the relaxant response to raloxifene.

Estrogen is known to induce rapid vasodilatory response in isolated arteries. Because estrogen is a nonselective receptor agonist, the involvement of estrogen receptor (ER) subtypes in acute estrogenic responses has remained elusive. Acute administration of the selective ERalpha agonist 4,4',4''-(4-propyl-[(1)H]pyrazole-1,3,5-triyl) tris-phenol (PPT) to precontracted aortic rings from intact female rats dose-dependently induced an ER-dependent vascular relaxation fully overlapping to that induced by 17beta-estradiol. By contrast, the selective ERbeta agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) had no acute effect on vasomotion. This short-term vasorelaxant action of PPT was abolished by the NO synthase inhibitor N(omega)-nitro-l-arginine methyl ester and by endothelium removal. In aortic tissues from ovariectomized (OVX) rats, however, neither 17beta-estradiol nor PPT induced acute vascular relaxation. The effect of PPT was restored in preparations from estrogen-replaced OVX rats, whereas DPN remained ineffective even after estrogen replacement. PPT acted through an ER-dependent mechanism, as shown by impaired response in the presence of the anti-estrogen ICI 182,780 (7alpha,17beta-[9[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol). Accordingly, isolated rat aortic endothelial cells expressed both ERalpha and ERbeta. These data show that selective ERalpha but not ERbeta agonists reproduced the acute vasodilation of estrogen via a receptor-mediated pathway in the aorta from intact as well as 17beta-estradiol-replaced OVX rats. This beneficial effect was undetectable in tissues from OVX rats. Selective pharmacological targeting of ER subtypes may thus represent a novel and promising approach in the treatment of vascular disease.