Uncertainty deconstructed: conceptual analysis and state-of-the-art review of the ERP correlates of risk and ambiguity in decision-making.

Risk and uncertainty are central concepts of decision neuroscience. However, a comprehensive review of the literature shows that most studies define risk and uncertainty in an unclear fashion or use both terms interchangeably, which hinders the integration of the existing findings. We suggest uncertainty as an umbrella term that comprises scenarios characterized by outcome variance where relevant information about the type and likelihood of outcomes may be somewhat unavailable (ambiguity) and scenarios where the likelihood of outcomes is known (risk).These conceptual issues are problematic for studies on the temporal neurodynamics of decision-making under risk and ambiguity, because they lead to heterogeneity in task design and the interpretation of the results. To assess this problem, we conducted a state-of-the-art review of ERP studies on risk and ambiguity in decision-making. By employing the above definitions to 16 reviewed studies, our results suggest that: (a) research has focused more on risk than ambiguity processing; (b) studies assessing decision-making under risk often implemented descriptive-based paradigms, whereas studies assessing ambiguity processing equally implemented descriptive- and experience-based tasks; (c) descriptive-based studies link risk processing to increased frontal negativities (e.g., N2, N400) and both risk and ambiguity to reduced parietal positivities (e.g., P2, P3); (d) experience-based studies link risk to increased P3 amplitudes and ambiguity to increased frontal negativities and the LPC component; (e) both risk and ambiguity processing seem to be related with cognitive control, conflict monitoring, and increased cognitive demand; (f) further research and improved tasks are needed to dissociate risk and ambiguity processing.

Noscapine Acts as a Protease Inhibitor of In Vitro Elastase-Induced Collagen Deposition in Equine Endometrium.

Endometrosis is a reproductive pathology that is responsible for mare infertility. Our recent studies have focused on the involvement of neutrophil extracellular traps enzymes, such as elastase (ELA), in the development of equine endometrosis. Noscapine (NOSC) is an alkaloid derived from poppy opium with anticough, antistroke, anticancer, and antifibrotic properties. The present work investigates the putative inhibitory in vitro effect of NOSC on collagen type I alpha 2 chain (COL1A2) mRNA and COL1 protein relative abundance induced by ELA in endometrial explants of mares in the follicular or mid-luteal phases at 24 or 48 h of treatment. The COL1A2 mRNA was evaluated by qPCR and COL1 protein relative abundance by Western blot. In equine endometrial explants, ELA increased COL 1 expression, while NOSC inhibited it at both estrous cycle phases and treatment times. These findings contribute to the future development of new endometrosis treatment approaches. Noscapine could be a drug capable of preventing collagen synthesis in mare's endometrium and facilitate the therapeutic approach.

Age-related decline in emotional perspective-taking: Its effect on the late positive potential.

Aging is associated with changes in cognitive and affective functioning, which likely shape older adults' social cognition. As the neural and psychological mechanisms underlying age differences in social abilities remain poorly understood, the present study aims to extend the research in this field. To this purpose, younger (n = 30; Mage = 26.6), middle-aged (n = 30; Mage = 48.4), and older adults (n = 29; Mage = 64.5) performed a task designed to assess affective perspective-taking, during an EEG recording. In this task, participants decided whether a target facial expression of emotion (FEE) was congruent or incongruent with that of a masked intervener of a previous scenario, which portrayed a neutral or an emotional scene. Older adults showed worse performance in comparison to the other groups. Regarding electrophysiological results, while younger and middle-aged adults showed higher late positive potentials (LPPs) after FEEs congruent with previous scenarios than after incongruent FEEs, older adults had similar amplitudes after both. This insensitivity of older adults' LPPs in differentiating congruent from incongruent emotional context-target FEE may be related to their difficulty in generating information about others' inner states and using that information in social interactions.

Collagens and DNA methyltransferases in mare endometrosis.

Inflammation and fibroproliferative diseases may be modulated by epigenetic changes. Therefore, we suggest that epigenetic mechanisms could be involved in equine endometrosis pathogenesis. DNA methylation is one of the methods to evaluate epigenetics, through the transcription of methyltransferases (DNMT1, DNMT3A, DNMT3B). The correlation between DNMTs and collagen (COL) transcripts was assessed for the different Kenney and Doig's (Current Therapy in Theriogenology. Philadelphia: WB Saunders; 1986) endometrium categories. Endometrial biopsies were randomly collected from cyclic mares. Histological classification (category I, n = 13; II A, n = 17; II B, n = 12; and III, n = 7) and evaluation of COL1A2, COL3A1 and DNMTs transcripts by qPCR, were performed. Data were analysed by one-way analysis of variance (ANOVA), Kruskal-Wallis test and Pearson correlation. As mares aged, there was an increase in endometrium fibrosis (p < .01), and in DNMT1 mRNA (p < .001). Considering DNMT3B transcripts for each category, there was an increase with fibrosis (p < .05). No changes were observed for DNMT1 and DNMT3A transcripts. However, DNMT3A mRNA levels were the highest in all categories (p < .01). In category I endometrium, a positive correlation was observed for transcripts of all DNMTs in both COLs (p < .01). In category IIA, this correlation was also maintained for all DNMTs transcripts in COL1A2 (p < .05), but only for DNMT3B in COL3A1 (p < .05). In category IIB, there was a positive correlation between DNMT3B and COL3A1 (p < .05). In category III, a positive correlation was only observed between DNMT3B and COL3A1 (p < .05). Our results suggest that there is a disturbance in COLs and DNMTs correlation during fibrosis.

Elastase inhibition affects collagen transcription and prostaglandin secretion in mare endometrium during the estrous cycle.

We have shown that bacteria induce neutrophil extracellular traps (NETs) in mare endometrium. Besides killing pathogens, NETs may contribute for endometrosis (chronic endometrium fibrosis). Since elastase (ELA) is a NETs component that regulates fibrosis and prostaglandin (PG) output, the aim was to evaluate if inhibition of ELA would affect collagen 1 (COL1) transcription and PGs secretion by endometrium explants, in different estrous cycle phases. Follicular-FP (n = 8) and mid luteal-MLP (n = 7) phases explants were cultured for 24-48 hr with medium alone (Control), ELA (0.5 µg/ml,1 µg/ml), sivelestat - ELA inhibitor (INH,10 µg/ml), or ELA (0.5 µg/ml,1 µg/ml) + INH (10 µg/ml). COL1 gene transcription was done by qRT-PCR and PGE2 and PGF2 α determination in culture medium by EIA. In FP, at 24 hr, ELA0.5 increased COL1 transcription (p < 0.001) but its inhibition (ELA0.5 + INH10) decreased COL1 transcription (p < 0.01) and PGF2 α production (p < 0.05). Also, ELA0.5 + INH10 or ELA1 + INH10 raised PGE2 production (p < 0.01). At 48 hr, ELA1 increased COL1 transcription (p < 0.01) and PGF2 α production (p < 0.001), but its inhibition (ELA1 + INH10) decreased these actions (p < 0.01; p < 0.05, respectively). Besides, ELA1 + INH10 incubation increased PGE2 (p < 0.05). PGF2 α also augmented with ELA0.5 (p < 0.001), but lowered with ELA0.5 + INH10 (p < 0.01). In MLP, ELA0.5 up-regulated COL1 transcription (24 hr, p < 0.01; 48 hr, p < 0.001), but ELA0.5 + INH10 decreased it (24 hr, p < 0.05; 48 hr, p < 0.001). At 48 hr, incubation with ELA1 also increased COL1 transcription and PGF2 α production (p < 0.05), but PGF2 α production decreased with ELA1 + INH10 incubation (p < 0.05). PGE2 production was higher in ELA1 + INH10 incubation (p < 0.05). Therefore, ELA inhibition may reduce the establishment of mare endometrial fibrosis by stimulating the production of anti-fibrotic PGE2 and inhibiting pro-fibrotic PGF2 α.

Attentional deficits in fibromyalgia: an ERP study with the oddball dual task and emotional stroop task.

The present study investigated the neural correlates of attentional deficits in fibromyalgia through an Oddball Dual Task and an Emotional Stroop Task, both performed during EEG recordings. Thirty female participants were recruited, being divided into two groups: a group of patients with fibromyalgia (FM, n = 15, Mage = 51.87, SDage = 7.12) and a healthy control group (HC, n = 15, Mage = 46.13, SDage = 8.41). In the Emotional Stroop Task, the behavioural results showed that patients with FM had less hits and longer times reactions than healthy controls. These results were consistent with those obtained with our Event-related Potential (ERP) methodology, which evidenced that patients with FM had higher frontal latencies in the P200 time-window compared to healthy controls. Regarding the Oddball Dual Task, we found that patients with FM had lower P300 amplitudes than healthy participants. Moreover, we found that rare stimuli elicited higher P300 amplitudes than frequent stimuli for healthy controls, but this comparison was non-significant for patients with FM. Taken together, our results suggest that fibromyalgia may be associated to a reduced processing speed, along to reduced neural resources to process stimuli, mainly in distinguishing relevant (rare) and irrelevant (frequent) stimuli according to the goals of the task. Altogether, our results seem to support the hypothesis of generalized attentional deficits in FM.

Handwriting Changes in Alzheimer's Disease: A Systematic Review.

BACKGROUND: Handwriting is a complex process involving fine motor skills, kinesthetic components, and several cognitive domains, often impaired by Alzheimer's disease (AD). OBJECTIVE: Provide a systematic review of handwriting changes in AD, highlighting the effects on motor, visuospatial and linguistic features, and to identify new research topics. METHODS: A search was conducted on PubMed, Scopus, and Web of Science to identify studies on AD and handwriting. The review followed PRISMA norms and analyzed 91 articles after screening and final selection. RESULTS: Handwriting is impaired at all levels of the motor-cognitive hierarchy in AD, particularly in text, with higher preservation of signatures. Visuospatial and linguistic features were more affected. Established findings for motor features included higher variability in AD signatures, higher in-air/on-surface time ratio and longer duration in text, longer start time/reaction time, and lower fluency. There were conflicting findings for pressure and velocity in motor features, as well as size, legibility, and pen lifts in general features. For linguistic features, findings were contradictory for error patterns, as well as the association between agraphia and severity of cognitive deficits. CONCLUSIONS: Further re-evaluation studies are needed to clarify the divergent results on motor, general, and linguistic features. There is also a lack of research on the influence of AD on signatures and the effect of AD variants on handwriting. Such research would have an impact on clinical management (e.g., for early detection and patient follow-up using handwriting tasks), or forensic examination aimed at signatory identification.

Effects of aging on face processing: An ERP study of the own-age bias with neutral and emotional faces.

Older adults systematically show an enhanced N170 amplitude during the visualization of facial expressions of emotion. The present study aimed to replicate this finding, further investigating if this effect is specific to facial stimuli, present in other neural correlates of face processing, and modulated by own-age faces. To this purpose, younger (n = 25; Mage = 28.36), middle-aged (n = 23; Mage = 48.74), and older adults (n = 25; Mage = 67.36) performed two face/emotion identification tasks during an EEG recording. The results showed that groups did not differ regarding P100 amplitude, but older adults had increased N170 amplitude for both facial and non-facial stimuli. The event-related potentials analysed were not modulated by an own-age bias, but older faces elicited larger N170 in the Emotion Identification Task for all groups. This increased amplitude may reflect a higher ambiguity of older faces due to age-related changes in their physical features, which may elicit higher neural resources to decode. Regarding P250, older faces elicited decreased amplitudes than younger faces, which may reflect a reduced processing of the emotional content of older faces. This interpretation is consistent with the lower accuracy obtained for this category of stimuli across groups. These results have important social implications and suggest that aging may hamper the neural processing of facial expressions of emotion, especially for own-age peers.

Delay discounting in aging: The influence of cognitive and psychological variables.

Delay discounting (or temporal discounting) refers to the decrease of the subjective value of a reward as the time interval for receiving that reward increases. A recent meta-analysis showed that delay discounting appears to be similar across the lifespan as younger, middle-aged, and older adults prefer sooner rewards, despite smaller, over later rewards, even if larger. However further investigation is needed to understand the potential role of individual factors in delay discounting across the lifespan. The present study aimed to contribute to this debate, by investigating the influence of sociodemographic, neurocognitive, and psychological variables on delay discounting. For this purpose, 88 participants (30 younger, 30 middle-aged, and 28 older adults) aged between 19 and 73 years old completed the Monetary Choice Questionnaire (MCQ), a comprehensive battery of neurocognitive tests, and self-report measures of psychopathology. Results revealed no group differences in the rate of discounting. A well-established effect of the amount of the delayed reward was replicated, showing that medium rewards were less discounted than smaller rewards, and larger rewards had lower discounting rates than smaller and medium rewards-the magnitude effect. Regarding the influence of neurocognitive and psychological factors on delay discounting, better working memory, as assessed by the Corsi block-tapping task, significantly predicted larger magnitude effects. The findings of the current work are consistent with the results of previous studies, suggesting that temporal discounting is a stable function across the adult life span. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Word reading skills in autism spectrum disorder: A systematic review.

A growing body of research suggests that children with autism spectrum disorder (ASD) are at risk of reading and learning difficulties. However, there is mixed evidence on their weaknesses in different reading components, and little is known about how reading skills characterize in ASD. Thereby, the current study aimed to systematically review the research investigating this function in children with ASD. To this purpose, we reviewed 24 studies that compared (1) children with ASD and children with typical development (TD) in word and nonword reading performance, (2) children with ASD and normative data of word and nonword reading tests, and (3) the results obtained by children with ASD in word and nonword reading tests. Most of the comparisons (62%) contrasting the reading performance of children with ASD and children with TD did not find significant differences between groups in both word and nonword reading. However, all the comparisons that reported standardized results showed that children with ASD had scores that fell within population norms. Regarding the third comparison of interest, about 54% of the studies presented data for both word and nonword reading, but only one study tested the difference between them and showed that children with ASD had higher levels of word than of nonword reading. Despite these results, the heterogeneous and small samples do not allow to draw sound conclusions regarding the strategies that children with ASD use to read words. As consequence, the nature of reading difficulties presented by children with ASD are still unknown, requiring future research conducted with larger and well-characterized samples of ASD and TD, using homogeneous specific tasks designed to assess word reading strategies.

Effects of Concomitant Benzodiazepines and Antidepressants Long-Term Use on Social Decision-Making: Results From the Ultimatum Game.

Benzodiazepines and antidepressants have been shown to change responses to unfairness; however, the effects of their combined use on unfairness evaluation are unknown. This study examines the effects of concomitant benzodiazepines and antidepressants long-term use on the evaluation of fair and unfair offers. To analyze behavioral changes on responses to unfairness, we compared the performance of medicated participants and healthy controls in the Ultimatum Game (UG), both in the proposer and in the respondent role. The results showed that long-term psychotropic users had the worse economic strategy by accepting less offers than control subjects. However, in the proposer role, the unfair offers made by participants were similar between groups. The present results suggest that long-term use of psychotropic medication, specifically the combination of benzodiazepines and antidepressants, may increase the sensitivity to unfairness, resulting in higher rejection rates in conditions where this strategy is the most disadvantageous.

Awareness to utilitarian responses in later life: An ERP study with moral dilemmas.

The current study aims to provide the first insights into the neural correlates of utilitarian and deontological responses to moral dilemmas across the lifespan. To this purpose, younger (n = 30), middle-aged (n = 29), and older adults (n = 29) completed moral dilemmas during an EEG recording. Behaviorally, groups did not differ in the number of utilitarian responses and reaction times. However, at the neural level, older adults had higher Error Positivity (Pe) amplitudes than younger adults after utilitarian responses. As this effect was specific to utilitarian responses, it suggests that utilitarian decisions may induce increased conflict in the older group. These findings highlight that older adults may be more aware of the harmful outcomes of utilitarian decisions during moral decision-making.

Collagen Type III as a Possible Blood Biomarker of Fibrosis in Equine Endometrium.

Collagen pathological deposition in equine endometrium (endometrosis) is responsible for infertility. Kenney and Doig's endometrial biopsy histopathological classification is the gold standard method for endometrosis evaluation, whereby blood biomarkers identification would be less invasive and could provide additional information regarding endometrosis diagnosis and fertility prognosis. This study aimed to identify blood biomarkers for endometrosis diagnosis (42 mares were used in experiment 1), and fertility assessment (50 mares were used in experiment 2). Reproductive examination, endometrial biopsy histopathological classification (Kenney and Doig) and blood collection were performed. Endometrium and serum collagen type I (COL1) and type III (COL3), and hydroxyproline concentrations were measured (ELISA). Serum COL3 cut-off value of 60.9 ng/mL allowed healthy endometria (category I) differentiation from endometria with degenerative/fibrotic lesions (categories IIA, IIB or III) with 100% specificity and 75.9% sensitivity. This cut-off value enabled category I + IIA differentiation from IIB + III (76% specificity, 81% sensitivity), and category III differentiation from others (65% specificity, 92.3% sensitivity). COL1 and hydroxyproline were not valid as blood biomarkers. Serum COL3 cut-off value of 146 ng/mL differentiated fertile from infertile mares (82.4% specificity, 55.6% sensitivity), and was not correlated with mares' age. Only COL3 may prove useful as a diagnostic aid in mares with endometrial fibrosis and as a fertility indicator.

Metallopeptidades 2 and 9 genes epigenetically modulate equine endometrial fibrosis.

Endometrium type I (COL1) and III (COL3) collagen accumulation, periglandular fibrosis and mare infertility characterize endometrosis. Metalloproteinase-2 (MMP-2), MMP-9 and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) are involved in collagen turnover. Since epigenetic changes may control fibroproliferative diseases, we hypothesized that epigenetic mechanisms could modulate equine endometrosis. Epigenetic changes can be reversed and therefore extremely promising for therapeutic use. Methylation pattern analysis of a particular gene zone is used to detect epigenetic changes. DNA methylation commonly mediates gene repression. Thus, this study aimed to evaluate if the transcription of some genes involved in equine endometrosis was altered with endometrial fibrosis, and if the observed changes were epigenetically modulated, through DNA methylation analysis. Endometrial biopsies collected from cyclic mares were histologically classified (Kenney and Doig category I, n = 6; category IIA, n = 6; category IIB, n = 6 and category III, n = 6). Transcription of COL1A1, COL1A2, COL3A1, MMP2, MMP9, TIMP1, and TIMP2 genes and DNA methylation pattern by pyrosequencing of COL1A1, MMP2, MMP9, TIMP1 genes were evaluated. Both MMP2 and MMP9 transcripts decreased with fibrosis, when compared with healthy endometrium (category I) (P < 0.05). TIMP1 transcripts were higher in category III, when compared to category I endometrium (P < 0.05). No differences were found for COL1A1, COL1A2, COL3A1 and TIMP2 transcripts between endometrial categories. There were higher methylation levels of (i) COL1A1 in category IIB (P < 0.05) and III (P < 0.01), when compared to category I; (ii) MMP2 in category III, when compared to category I (P < 0.001) and IIA (P < 0.05); and (iii) MMP9 in category III, when compared to category I and IIA (P < 0.05). No differences in TIMP1 methylation levels were observed between endometrial categories. The hypermethylation of MMP2 and MMP9, but not of COL1A1 genes, occurred simultaneously with a decrease in their mRNA levels, with endometrial fibrosis, suggesting that this hypermethylation is responsible for repressing their transcription. Our results show that endometrosis is epigenetically modulated by anti-fibrotic genes (MMP2 and MMP9) inhibition, rather than fibrotic genes activation and therefore, might be promising targets for therapeutic use.

Emotional and Attentional Bias in Fibromyalgia: A Pilot ERP Study of the Dot-Probe Task.

INTRODUCTION: The present research investigates the neural correlates of attentional bias in fibromyalgia (FM) with a dot-probe task performed during an electroencephalogram (EEG) recording. METHODS: For this purpose, 30 female participants were recruited, divided into two groups: a group of patients with FM (FM, n = 15, Mage = 51.87) and a healthy control group (HC) (HC, n = 15, Mage = 46.13). RESULTS: The results did not show behavioral differences between groups, but the EEG results showed that healthy controls had larger P300 amplitudes than patients with FM. Regarding late positive potentials (LPP), we found that patients with FM had larger amplitudes than healthy controls in a later time window. CONCLUSION: In summary, while the P300 results suggest that patients allocate less attentional resources to the task, the increased amplitudes of their LPP suggest augmented emotional processing of the target stimuli. Altogether, our results seem to support the thesis of generalized attentional deficits in FM.

Fibromyalgia (FM) is a chronic musculoskeletal pain condition. There has been discussion in the scientific literature as to whether patients with FM suffer from a generalized attentional deficit or an attentional bias­preferentially selecting pain-related information. Attentional bias in FM patients has been studied as hypervigilance, which refers to early detection of pain-related information or innocuous information. Thus, the aim of this study was to test whether there is a generalized attentional deficit or attentional bias in relation to pain in patients with FM, by studying the neural activity underlying cognitive processes, specifically with evoked potentials (P300 and late positive potential­LPP). The P300 has been related to the use of attentional resources and the LPP to affective modulation. For this purpose, we studied two groups: a group of patients with FM and a healthy control group. Our hypotheses considered that FM patients, compared to healthy controls, would show an attentional bias for pain-related words (1) reflected in higher hits and shorter reaction time when detecting the target of a cognitive task (dot-probe), and (2) manifested by increased amplitudes of P300 and LPP evoked potentials while performing the task. The electrophysiological results suggest that FM patients may have a generalized attentional deficit and, despite this being the case, FM patients are more emotionally involved in the task.

Economic decision-making in the continuum between healthy aging and Alzheimer's Disease: A systematic review of 20 years of research.

The effect of pathological aging on economic decision-making is a topic of major relevance as impairments in this domain place older adults at increased risk for financial abuse. This review aims to characterize decision-making across the continuum that goes from healthy aging to Alzheimer's Dementia. We included 42 studies comparing patients with Mild Cognitive Impairment (MCI) and healthy older adults, patients with Alzheimer's Disease (AD) and healthy older adults, and patients with MCI and patients with AD. Substantial evidence emerged suggesting that both MCI as AD affect economic decision-making. However, a non-negligible number of behavioural tasks failed to find significant differences between patients and controls, and no differences were reported between patients with MCI and AD. On the contrary, measures of financial capacity reached more robust findings, showing that healthy older adults had better performance than patients, while MCI patients showed better performance than AD patients. This review presents the main conclusions that may be drawn from significant findings, as well as the hypotheses and recommendations for future research.

The Impact of Different Types of Shift Work on Blood Pressure and Hypertension: A Systematic Review and Meta-Analysis.

Shift work (SW) encompasses 20% of the European workforce. Moreover, high blood pressure (BP) remains a leading cause of death globally. This review aimed to synthesize the magnitude of the potential impact of SW on systolic blood pressure (SBP), diastolic blood pressure (DBP) and hypertension (HTN). MEDLINE, EMBASE and CENTRAL databases were searched for epidemiological studies evaluating BP and/or HTN diagnosis among shift workers, compared with day workers. Random-effects meta-analyses were performed and the results were expressed as pooled mean differences or odds ratios and 95% confidence intervals (95% CI). The Newcastle-Ottawa Scale was used to assess the risk of bias. Forty-five studies were included, involving 117,252 workers. We found a significant increase in both SBD and DBP among permanent night workers (2.52 mmHg, 95% CI 0.75-4.29 and 1.76 mmHg, 95% CI 0.41-3.12, respectively). For rotational shift workers, both with and without night work, we found a significant increase but only for SBP (0.65 mmHg, 95% CI 0.07-1.22 and 1.28 mmHg, 95% CI 0.18-2.39, respectively). No differences were found for HTN. Our findings suggest that SW is associated with an increase of BP, mainly for permanent night workers and for SBP. This is of special interest given the large number of susceptible workers exposed over time.

The Inhibitory Effect of Noscapine on the In Vitro Cathepsin G-Induced Collagen Expression in Equine Endometrium.

Cathepsin G (CAT) is a protease released by neutrophils when forming neutrophil extracellular traps that was already associated with inducing type I collagen (COL1) in equine endometrium in vitro. Endometrosis is a fibrotic condition mainly characterized by COL1 deposition in the equine endometrium. The objective was to evaluate if noscapine (an alkaloid for cough treatment with anti-neoplastic and anti-fibrotic properties) would reduce COL1A2 transcription (evaluated by qPCR) and COL1 protein relative abundance (evaluated by western blot) induced by CAT in equine endometrial explants from follicular and mid-luteal phases treated for 24 or 48 h. The explants treated with CAT increased COL1 expression. Noscapine decreased COL1A2 transcription at both estrous cycle phases, but COL1 relative protein only at the follicular phase, both induced by CAT. Additionally, the noscapine anti-fibrotic action was found to be more effective in the follicular phase. The CAT treatment caused more fibrosis at the longest period of treatment, while noscapine acted better at the shortest time of treatment. Our results showed that noscapine could act as an anti-fibrotic drug in equine endometrosis by inhibiting CAT in vitro. Noscapine offers a new promising therapeutic tool for treating fibrosis as a single non-selective agent to be considered in the future.

Enzymes Present in Neutrophil Extracellular Traps May Stimulate the Fibrogenic PGF2α Pathway in the Mare Endometrium.

Endometrosis, a fibrotic disease of mare endometrium, impairs uterine function. Prostaglandins (PG), despite modulating reproductive physiological functions, may also cause local pathological collagen deposition (fibrogenesis). We have previously shown that neutrophil extracellular traps (NETs) may also favor mare endometrosis. The aim of this study was to investigate the effect of enzymes present in NETs on PGF2α-pathway activation. Kenney and Doig's type I/IIA and IIB/III mare endometria, from follicular phase (FLP) and mid-luteal (MLP) phase, were cultured in vitro in the presence of NETs enzymes (elastase, cathepsin-G or myeloperoxidase). Production of PGF2α (EIA) and transcription (qPCR) of its synthases (PTGS2, AKR1C3) and receptor (PTGFR) genes were evaluated. PGF2α and PTGFR were influenced by endometrial category and estrous cycle phase. In FLP endometrium, NETs enzymes induced both high PGF2α production and/or PTGFR transcription. In MLP type I/IIA tissues, down-regulation of PTGFR transcripts occurred. However, in MLP type IIB/III endometrium, high levels of PTGFR transcripts were induced by NETs enzymes. As PGF2α-pathway activation facilitates fibrogenesis in other tissues, PGF2α may be involved in endometrosis pathogenesis. In the mare, the endocrine microenvironment of healthy and pathological endometrium might modulate the PGF2α pathway, as well as fibrosis outcome on endometrium challenged by NETs enzymes.