Qualitative Experience of Self-Exclusion Programs: A Scoping Review.

Gambling disorder is a major public health issue in many countries. It has been defined as a persistent, recurrent pattern of gambling and is associated with substantial distress or impairment, lower quality of life, and living with a plurality of psychiatric problems. Many people suffering from gambling disorder seek help in ways other than formal treatment seeking, including self-management strategies. One example of responsible gambling tools that has gained popularity in recent years is self-exclusion programs. Self-exclusion entails individuals barring themselves from a gambling venue or a virtual platform. The aim of this scoping review is to summarize the literature on this topic and to explore participants' perceptions and experiences with self-exclusion. An electronic literature search was conducted on 16th May 2022 in the following databases: Academic Search Complete, CINAHL Plus with Full Text, Education Source, ERIC, MEDLINE with Full Text, APA PsycArticles, Psychology and Behavioral Sciences Collection, APA PsychInfo, Social Work Abstracts, and SocINDEX. The search yielded a total of 236 articles, of which 109 remained after duplicates were removed. After full-text reading, six articles were included in this review. The available literature shows that although there are many barriers and limitations to the current self-exclusion programs, self-exclusion is generally viewed as an effective responsible gambling strategy. There is a clear need to improve the current programs by increasing awareness, publicity, availability, staff training, off-site venue exclusion, and technology-assisted monitoring, as well as by adopting more holistic management approaches to gambling disorders in general.

Efficacy of a randomized controlled trial of integrative couple treatment for pathological gambling (ICT-PG): 10-month follow-up.

OBJECTIVE: Assess the efficacy of integrative couple treatment for pathological gambling (ICT-PG) in comparison to treatment provided in an individual approach. METHOD: Eighty couples were assigned randomly to ICT-PG (n = 44, Mage = 42.2, SD [13.4], n male gamblers = 29) or individual treatment (n = 36, Mage = 39.9 SD [13.0], n male gamblers = 31) with follow-ups at 4- and 10-months postadmission regarding the severity of gambling, the individual and couple's well-being. Linear mixed and generalized estimating equation models for repeated measures were applied to take into account the dependency of observations. Protocol was preregistered at www. CLINICALTRIALS: gov (ID: NCT02240485). RESULTS: Participants in both treatments generally improved over time with reductions on gambling expanses from an initial $4,000-$600 in a 90-day period following treatment, without difference across treatment conditions in money spent on gambling or frequency of gambling. However, on different indices of gambling severity, the participants in ICT-PG showed more improvement at follow-ups, with better control capacity (OR = 2.57, p < .0129) and greater reduction in gambling craving (OR = 5.83, p < .0001) and erroneous cognitions (OR = 2.63, p < .0063). The couple treatment was associated with a better individual well-being (e.g., less depression for partners, OR = 5.53; p < .0351, and gamblers, OR = 2.37; p < .0334) and couple well-being (e.g., better dyadic satisfaction for partners, OR = 2.02; p < .0057, and gamblers, OR = 3.07; p < .0212). CONCLUSIONS: The results underline the necessity to provide a greater diversity of treatment for gamblers and their partner. Further research should focus on identifying active components of ICT-PG and widen its provision to gamblers with concurrent addiction disorders. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Autophagic response to exercise in peripheral blood mononuclear cells from young men is intensity-dependent and is altered by exposure to environmental heat.

Autophagy is essential to maintaining cellular homeostasis in all eukaryotic cells and to tolerance of acute stressors such as starvation, heat, and recovery after exercise. Limited information exists regarding the exercise intensity-dependent autophagic response in humans, and it is unknown how environmental heat stress may modulate this response. Therefore, we evaluated autophagy and accompanying pathways of cellular stress [the heat-shock response (HSR), apoptosis, and acute inflammation] in peripheral blood mononuclear cells (PBMCs) from 10 young men (mean [SD]; 22 [2] years) before, immediately after and up to 6-h postexercise recovery from 30 min of low-, moderate-, and high-intensity semirecumbent cycling [40%, 55%, and 70% of maximal oxygen consumption (V̇o2max), respectively] in a temperate environment (25°C) and at 70% of V̇o2max in a hot environment (40°C). Changes in protein content were analyzed via Western blot. Each increase in exercise intensity was associated with elevations in mean body temperature. LC3-II increased after moderate-intensity exercise, with further increases after high-intensity exercise (P < 0.05). However, an increase in beclin-2 and ULK1, with a decrease in p62 was only observed after high-intensity exercise, which was paralleled by elevated TNF-α and cleaved-caspase-3, with the HSR peaking at 6 h after exercise (P < 0.05). When exercise was performed in the heat, greater LC3-II and cleaved-caspase-3 accumulation were observed; however, beclin-2 declined in recovery (P < 0.05). Therefore, our findings indicate that autophagy in PBMCs during exercise may be associated with greater heat strain exhibited during increasing exercise intensities, which is modulated by exposure to heat.

Peripheral Neuroprotective and Immunomodulatory Effects of 5α-Reductase Inhibitors in Parkinson's Disease Models.

Gastrointestinal disorders in Parkinson's disease (PD) have been associated with neuronal alteration in the plexus of the gut. We previously demonstrated the immunomodulatory effect of female hormones to treat enteric neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. This study made the hypothesis of obtaining similar neuroprotection as with hormone treatments by affecting steroidogenesis with two 5α-reductase inhibitors, finasteride and dutasteride. These drugs are approved to treat benign prostatic hyperplasia and alopecia and display mitochondrial effects. In MPTP-treated mice, the dopaminergic and vasoactive intestinal peptide (VIP) neurons alteration was prevented by finasteride and dutasteride, while the increase in proinflammatory macrophages density was inhibited by dutasteride treatment but not finasteride. NF-κB response, oxidative stress, and nitric oxide and proinflammatory cytokines production in vitro were only prevented by dutasteride. In addition, mitochondrial production of free radicals, membrane depolarization, decreased basal respiration, and ATP production were inhibited by dutasteride, while finasteride had no effect. In conclusion, the present results indicate that dutasteride treatment prevents enteric neuronal damages in the MPTP mouse model, at least in part through anti-inflammatory and mitochondrial effects. This suggests that drug repurposing of dutasteride might be a promising avenue to treat enteric neuroinflammation in early PD.

Differential contribution of estrogen receptors to the intestinal therapeutic effects of 17ß-estradiol in a murine model of Parkinson's disease.

Beneficial effects of estrogens have been reported in Parkinson's disease (PD) for many years. We previously reported their neuroprotective and anti-inflammatory potentials in the enteric nervous system of the intestine, a region possibly affected during the early stages of the disease according to Braak's hypothesis. Three different estrogen receptors have been characterized to date: the estrogen receptor alpha (ERα), the estrogen receptor beta (ERß) and the G protein coupled estrogen receptor 1 (GPER1). The aim of the present study was to decipher the individual contribution of each estrogen receptor to the therapeutic properties of 17ß-estradiol (E2) in the myenteric plexus of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Different agonists, 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT; ERα), 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; ERß), G1 (GPER1), and antagonists, ICI 182,780 (ERα and ERß), G15 (GPER1), were used to analyze the involvement of each receptor. We confirmed that G1 protects dopamine (DA) neurons to a similar extent as E2. An anti-inflammatory effect on proinflammatory macrophages and cultured human monocytes was also demonstrated with E2 and G1. The effects of PPT and DPN were less potent than G1 with only a partial neuroprotection of DA neurons by PPT and a partial reduction of interleukin (IL)- 1ß production in monocytes by PPT and DPN. Overall, the present results indicate that the positive outcomes of estrogens are mainly through activation of GPER1. Therefore, this suggests that targeting GPER1 could be a promising approach for future estrogen-based hormone therapies during early PD.

Do the Consequences Experienced by the People in the Life of a Problem Gambler Differ Based on the Nature of Their Relationship with the Gambler?

Consequences experienced by the partners of individuals with a gambling disorder are well documented. However, little is known about the deleterious effects experienced by other people than partners of gamblers. A better understanding of these consequences could help improve clinical practices. The goal of this paper is to compare the consequences experienced by partners of gamblers with those experienced by their close family members (parents, adult children, siblings) by using the categorization method proposed by Langham et al. (BMC Public Health, 2016). To achieve this goal, 46 semi-structured interviews were conducted. Results indicate that the extent and intensity of the consequences experienced vary widely based on their level of emotional and financial involvement with the gambler. Considering the specific elements involved for each type of person in a gambler's life, future research should distinguish participants based on the nature of their relationship with the gambler.

Evaluation of a prenatal screening decision aid: A mixed methods pilot study.

BACKGROUND: We developed a decision aid (DA) to help pregnant women and their partners make informed decisions about prenatal screening for trisomy. We aimed to determine its usefulness for preparing for decision-making and its acceptability among end-users. METHODS: In this mixed-methods pilot study, we recruited participants in three prenatal care settings in Quebec City. Eligible women were over 18 and more than 16 weeks pregnant or had given birth recently. We asked them about the usefulness of the DA using an interview grid based on the Technology Acceptance Model. We performed descriptive statistics and deductive analysis. RESULTS: Thirty-nine dyads or individuals participated in the study. Mean usefulness score was 86.2 ± 13. Most participants found the amount of information in the DA just right (79.5%), balanced (89.7%), and very useful (61.5%). They were less satisfied with the presentation and the values worksheet and suggested different values clarification methods. CONCLUSION: Rigorous pilot tests of DAs with patients are an important stage in their development before the more formal assessments that precede scaling up the DA in clinical practice. PRACTICE IMPLICATIONS: The next version of the DA will integrate the suggestions of end-users for better decision-making processes about prenatal screening for trisomy.

Effect of Docosahexaenoic Acid (DHA) at the Enteric Level in a Synucleinopathy Mouse Model.

The aggregation of alpha-synuclein protein (αSyn) is a hallmark of Parkinson's disease (PD). Considerable evidence suggests that PD involves an early aggregation of αSyn in the enteric nervous system (ENS), spreading to the brain. While it has previously been reported that omega-3 polyunsaturated fatty acids (ω-3 PUFA) acts as neuroprotective agents in the brain in murine models of PD, their effect in the ENS remains undefined. Here, we studied the effect of dietary supplementation with docosahexaenoic acid (DHA, an ω-3 PUFA), on the ENS, with a particular focus on enteric dopaminergic (DAergic) neurons. Thy1-αSyn mice, which overexpress human αSyn, were fed ad libitum with a control diet, a low ω-3 PUFA diet or a diet supplemented with microencapsulated DHA and then compared with wild-type littermates. Our data indicate that Thy1-αSyn mice showed a lower density of enteric dopaminergic neurons compared with non-transgenic animals. This decrease was prevented by dietary DHA. Although we found that DHA reduced microgliosis in the striatum, we did not observe any evidence of peripheral inflammation. However, we showed that dietary intake of DHA promoted a build-up of ω-3 PUFA-derived endocannabinoid (eCB)-like mediators in plasma and an increase in glucagon-like peptide-1 (GLP-1) and the redox regulator, Nrf2 in the ENS. Taken together, our results suggest that DHA exerts neuroprotection of enteric DAergic neurons in the Thy1-αSyn mice, possibly through alterations in eCB-like mediators, GLP-1 and Nrf2.

Automatic segmentation and tracking of biological prosthetic heart valves.

Purpose: Prosthetic heart valve designs must be rigorously tested using cardiovascular equipment. The valve orifice area over time constitutes a key quality metric which is typically assessed manually, thus a tedious and error-prone task. From a computer vision viewpoint, a major unsolved issue lies in the orifice being partly occluded by the leaflets' inner side or inaccurately depicted due to its transparency. Here, we address this issue, which allows us to focus on the accurate and automatic computation of valve orifice areas. Approach: We propose a segmentation approach based on the detection of the leaflets' free edges. Using video frames recorded with a high-speed digital camera during in vitro simulations, an initial estimation of the orifice area is first obtained via active contouring and thresholding and then refined to capture the leaflet free edges via a curve transformation mechanism. Results: Experiments on video data from pulsatile flow testing demonstrate the effectiveness of our approach: a root-mean-square error (RMSE) on the temporal extracted orifice areas between 0.8% and 1.2%, an average Jaccard similarity coefficient between 0.933 and 0.956, and an average Hausdorff distance between 7.2 and 11.9 pixels. Conclusions: Our approach significantly outperformed a state-of-the-art algorithm in terms of evaluation metrics related to valve design (RMSE) and computer vision (accuracy of the orifice shape). It can also cope with lower quality videos and is better at processing frames showing an almost closed valve, a crucial quality for assessing valve design malfunctions related to their improper closing.

Impaired autophagy following ex vivo heating at physiologically relevant temperatures in peripheral blood mononuclear cells from elderly adults.

With the increasing threat of climate change and the accompanying rise in the frequency and severity of extreme heat events, there are growing health concerns for heat-vulnerable elderly adults. Elderly adults are at increased risk of developing heat-related injuries, in part due to age-related declines in thermoregulatory and cellular function. Regarding the latter, the process of autophagy is activated as a cellular protective mechanism to counter heat-induced stress, but the extent that heat stress activates autophagy in elderly adults is not known. Further, the interplay between autophagy, the heat shock response (HSR), the acute inflammatory response, and apoptosis remains poorly understood in elderly adults. Therefore, the purpose of this study was to examine changes in autophagy, the HSR, inflammation, and apoptosis following increasing levels of ex vivo heat stress representative of physiologically relevant increases in body core temperatures (37-41 °C). Whole blood from 20 elderly adults (72 ± 4 years; 14 men, 6 women) was heated (via water immersion) to temperatures representative of normal resting conditions (normothermia; 37 °C), in addition to moderate and severe heat stress conditions (39, and 41 °C, respectively) for 90 min. Peripheral blood mononuclear cells (PBMC) were isolated and protein markers of autophagy, the HSR, acute inflammation, and apoptosis were examined. No significant increases in markers of autophagy or the HSR were observed following any temperature condition. However, an increase in acute inflammation was observed above baseline following moderate heat stress (39 °C), with further increases in inflammation and apoptosis observed during severe heat stress (41 °C). Our findings indicate that PBMCs from elderly adults do not exhibit increases in autophagy or the HSR following severe heat stress, potentially contributing to the elevated risk of cellular dysfunction seen in elderly adults during heat stress.

Web-Based Training for Nurses on Shared Decision Making and Prenatal Screening for Down Syndrome: Protocol for a Randomized Controlled Trial.

BACKGROUND: Pregnant women often find it difficult to choose from among the wide variety of available prenatal screening options. To help pregnant women and their partners make informed decisions based on their values, needs, and preferences, a decision aid and a web-based shared decision making (SDM) training program for health professionals have been developed. In Canada, nurses provide maternity care and thus can train as decision coaches for prenatal screening. However, there is a knowledge gap about the effectiveness of SDM interventions in maternity care in nursing practice. OBJECTIVE: This study aims to assess the impact of an SDM training program on nurses' intentions to use a decision aid for prenatal screening and on their knowledge and to assess their overall impressions of the training. METHODS: This is a 2-arm parallel randomized trial. French-speaking nurses working with pregnant women in the province of Quebec were recruited online by a private survey firm. They were randomly allocated (1:1 ratio) to either an experimental group, which completed a web-based SDM training program that included prenatal screening, or a control group, which completed a web-based training program focusing on prenatal screening alone. The experimental intervention consisted of a 3-hour web-based training hosted on the Université Laval platform with 4 modules: (1) SDM; (2) Down syndrome prenatal screening; (3) decision aids; and (4) communication between health care professionals and the patient. For the control group, the topic of SDM in Module 1 was replaced with "Context and history of prenatal screening," and the topic of decision aids in Module 3 was replaced with "Consent in prenatal screening." Participants completed a self-administered sociodemographic questionnaire with close-ended questions. We also assessed the participants' (1) intention to use a decision aid in prenatal screening clinical practice, (2) knowledge, (3) satisfaction with the training, (4) acceptability, and (5) perceived usefulness of the training. The randomization was done using a predetermined sequence and included 40 nurses. Participants and researchers were blinded. Intention to use a decision aid will be assessed by a t test. Bivariate and multivariate analysis will be performed to assess knowledge and overall impressions of the training. RESULTS: This study was funded in 2017 and approved by Genome Canada. Data were collected from September 2019 to late January 2020. This paper was initially submitted before data analysis began. Results are expected to be published in winter 2020. CONCLUSIONS: Study results will inform us on the impact of an SDM training program on nurses' intention to use and knowledge of decision aids for prenatal screening and their overall impressions of the training. Participant feedback will also inform an upgrade of the program, if needed. TRIAL REGISTRATION: ClinicalTrials.gov NCT04162288; https://clinicaltrials.gov/ct2/show/NCT04162288. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/17878.

Regulation of autophagy following ex vivo heating in peripheral blood mononuclear cells from young adults.

Under conditions of extreme heat stress, the process of autophagy has previously been shown to protect human cells, but the exact body temperature at which autophagic activation occurs is largely unknown. Further, the interplay between autophagy, the heat shock response (HSR), inflammation, and apoptosis have yet to be examined together under temperature conditions representative of human internal body temperatures at rest (37 °C) or under severe heat stress conditions (41 °C). Thus, the purpose of this study was to examine threshold changes in autophagy, the HSR, inflammation, and apoptosis to increasing levels of ex vivo heat stress. Whole blood was collected from 20 young (23 ± 4 years; 10 men, 10 women) physically active participants. Peripheral blood mononuclear cells (PBMCs) were isolated immediately (baseline) and after 90-min of whole blood heating in 37, 39, and 41 °C water baths, representative of normal resting (non-heat stress) as well as moderate and severe heat stress conditions in humans, respectively. At 37 °C, increased autophagic activity was demonstrated, with no change in the HSR, and inflammation. Subsequently, responses of autophagy, the HSR, and inflammation increased with a moderate heat stress (39 °C), with further increases in only autophagy and the HSR under a severe heat stress of 41 °C. We observed no increase in apoptosis under any temperature condition. Our findings show that in human PBMCs, the autophagy and HSR systems may act cooperatively to suppress apoptotic signaling following heat stress, which may in part be mediated by an acute inflammatory response.

How Can Partners Influence the Gambling Habits of Their Gambler Spouse?

An increasing number of clinical and empirical studies document the coping strategies used by partners of pathological gamblers (PGs). A postulate for this is that they may be useful for dealing with their partner's problematic gambling behaviors. Despite a widespread endorsement of this postulate, no study has yet documented their effectiveness: does the use of these coping strategies impact the gambler's behavior? To answer this question, semi-structured interviews were conducted with 19 participants (8 couples comprising one PG and his or her partner, one partner of a PG, and 2 PGs). Qualitative analysis of the interviews lead to a first main observation: via diverse coping strategies, partners of PGs can influence their spouse's gambling behaviors. The impact of these strategies may occur as initially expected by partners, that is by a reduction of gambling behaviors. However, the use of certain strategies can also increase the PG's gambling cravings, though this is not generally their partner's intention.

The Experience of Couples in the Process of Treatment of Pathological Gambling: Couple vs. Individual Therapy.

Context: Couple treatment for pathological gambling is an innovative strategy. There are some results supporting its potential effectiveness, but little is known about the subjective experiences of the participants. Objective: The aim of this article is to document the experiences of gamblers and their partners participating in one of two treatments, namely individual or couple. Method: In a study aiming to evaluate the efficacy of the Integrative Couple Treatment for Pathological Gambling (ICT-PG), couples who were entering specialized treatment for the addiction of one member who was a pathological gambler were randomly assigned to individual or ICT-PG. Nine months after their admission to treatment, gamblers and partners (n = 21 couples; n = 13 ICT-PG; n = 8 individual treatment) were interviewed in semi-structured interviews. A sequenced thematization method was used to extract the major themes. Results: This study highlighted five major themes in the therapeutic process noted by the gamblers and their partners mainly after the couple treatment but also partly through the individual therapy. These were: (1) the gamblers' anxiety about having to reveal their gambling problems in couple therapy; (2) the wish to develop a mutually beneficial understanding of gambling and its effects on the partners in the two types of treatments; (3) the transformation of negative attributions through a more effective intra-couple communication fostered by the couple therapy; (4) the partners' contribution to changes in gambling behavior and prevention of relapses, which were both better supported in couple therapy; and (5) the interpersonal nature of gambling and its connections with the couples' relationship. However, gamblers who were in individual treatment were more likely to mention that their partners' involvement was not necessary. Participants likewise made a few recommendations about the conditions underlying the choice of one treatment method or the other. Discussion: Participants reported satisfaction with both treatment models, but their experience was more positive in couple treatment. Complementary benefits emerged from each form of treatment, which points to future treatments involving both types. Future research should explore both the couple processes associated with attempts to stop pathological gambling and the various ways of involving partners in the gamblers' treatment.

Neuroprotective and immunomodulatory effects of raloxifene in the myenteric plexus of a mouse model of Parkinson's disease.

Motor symptoms in Parkinson's disease (PD) are often preceded by nonmotor symptoms related to dysfunctions of the autonomic nervous system such as constipation, defecatory problems, and delayed gastric emptying. These gastrointestinal impairments are associated with the alteration of dopaminergic (DAergic) neurons in the myenteric plexus of the gut. Recently, we demonstrated the anti-inflammatory properties of estrogens to treat intestinal neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The present study aimed to investigate the neuroprotective and anti-inflammatory roles of raloxifene, a selective estrogen receptor modulator (SERM) already commercialized for osteoporosis treatment. In MPTP-treated mice, we found that raloxifene decreased the loss of DAergic neurons and prevented the increase in proinflammatory macrophage density in the myenteric plexus. Interestingly, raloxifene activity was prevented by the G protein-coupled estrogen receptor 1 (GPER1) antagonist G15, suggesting that raloxifene effects were mainly mediated by GPER1. Moreover, monocytic cell proinflammatory polarization, nuclear factor-kappa B (NF-κB) response, nitric oxide (NO), and proinflammatory cytokines production following 1-methyl-4-phenylpyridinium (MPP+) treatment were also prevented by raloxifene in vitro. Overall, the present results suggest that raloxifene may help preventing the loss of DAergic neurons in the myenteric plexus in an MPTP mouse model of PD, at least in part through its anti-inflammatory effects. This suggests that drug repurposing of raloxifene might represent a promising therapeutic avenue to prevent systemic inflammation and peripheral neuronal dysfunction at early PD stages.

Gastrointestinal Dysfunctions in Parkinson's Disease: Symptoms and Treatments.

A diagnosis of Parkinson's disease is classically established after the manifestation of motor symptoms such as rigidity, bradykinesia, and tremor. However, a growing body of evidence supports the hypothesis that nonmotor symptoms, especially gastrointestinal dysfunctions, could be considered as early biomarkers since they are ubiquitously found among confirmed patients and occur much earlier than their motor manifestations. According to Braak's hypothesis, the disease is postulated to originate in the intestine and then spread to the brain via the vagus nerve, a phenomenon that would involve other neuronal types than the well-established dopaminergic population. It has therefore been proposed that peripheral nondopaminergic impairments might precede the alteration of dopaminergic neurons in the central nervous system and, ultimately, the emergence of motor symptoms. Considering the growing interest in the gut-brain axis in Parkinson's disease, this review aims at providing a comprehensive picture of the multiple gastrointestinal features of the disease, along with the therapeutic approaches used to reduce their burden. Moreover, we highlight the importance of gastrointestinal symptoms with respect to the patients' responses towards medical treatments and discuss the various possible adverse interactions that can potentially occur, which are still poorly understood.

GPER1-mediated immunomodulation and neuroprotection in the myenteric plexus of a mouse model of Parkinson's disease.

Lewy pathology affects the gastrointestinal tract in Parkinson's disease (PD) and recent reports suggest a link between the disorder and gut inflammation. In this study, we investigated enteric neuroprotection and macrophage immunomodulation by 17ß-estradiol (E2) and the G protein-coupled estrogen receptor 1 (GPER1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model. We found that both E2 and the GPER1 agonist G1 are protective against the loss of dopamine myenteric neurons and inhibited enteric macrophage infiltration in MPTP-treated mice. Coadministration of GPER1 antagonist G15, while completely blocking the neuroprotective and anti-inflammatory effects of G1 also partially prevented those of E2. Interestingly, we found that E2 and G1 treatments could directly alter MPTP-mediated immune responses independently from neurodegenerative processes. Analyses of monocyte/macrophage NF-κB and iNOS activation and FACs immunophenotype indicated that 1-methyl-4-phenylpyridinium (MPP(+)) treatment induces a strong immune response in monocytes, comparable to that of canonical challenge by lipopolysaccharide. In these cells, G1 and E2 treatment are equally potent in promoting a shift toward an anti-inflammatory "M2" immunophenotype reducing MPP(+)-induced NF-κB and iNOS activation. Moreover, G15 also antagonized the immunomodulatory effects of G1 in MPP(+)-treated macrophages. Together these data provide the first evidence for the role of GPER1 in enteric immunomodulation and neuroprotection. Considering increasing recognition for myenteric pathology as an early biomarker for PD, these findings provide a valuable contribution for better understanding and targeting of future therapeutic strategies.

Implication of GPER1 in neuroprotection in a mouse model of Parkinson's disease.

This study investigated the contribution of the new G protein-coupled estrogen receptor 1 (GPER1) in neuroprotection by 17ß-estradiol in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. In intact mice, administration of GPER1 agonist G1 reproduced the effect of 17ß-estradiol in increasing striatal dopamine metabolite concentrations as well as the turnover of dopamine. GPER1 antagonist G15 blocked the effect of G1 on homovanillic acid/dopamine ratio and partially for 17ß-estradiol. MPTP mice treated with G15 were more susceptible to MPTP toxicity with a greater decrease in striatal dopamine concentration and dopamine transporter specific binding. In MPTP mice, dopamine concentrations as well as dopamine and vesicular monoamine transporter 2 specific binding showed that G1 treatment was as potent as 17ß-estradiol in protecting striatum and substantia nigra. G15 antagonized completely the neuroprotective effects of G1 in the striatum and substantia nigra as well as protection by 17ß-estradiol in the striatum but partially in the substantia nigra. This study showed an important role of GPER1 in neuroprotection and that G1 is as potent as 17ß-estradiol in mediating beneficial effects.

Nck2 promotes human melanoma cell proliferation, migration and invasion in vitro and primary melanoma-derived tumor growth in vivo.

BACKGROUND: Nck1 and Nck2 adaptor proteins are involved in signaling pathways mediating proliferation, cytoskeleton organization and integrated stress response. Overexpression of Nck1 in fibroblasts has been shown to be oncogenic. Through the years this concept has been challenged and the consensus is now that overexpression of either Nck cooperates with strong oncogenes to transform cells. Therefore, variations in Nck expression levels in transformed cells could endorse cancer progression. METHODS: Expression of Nck1 and Nck2 proteins in various cancer cell lines at different stages of progression were analyzed by western blots. We created human primary melanoma cell lines overexpressing GFP-Nck2 and investigated their ability to proliferate along with metastatic characteristics such as migration and invasion. By western blot analysis, we compared levels of proteins phosphorylated on tyrosine as well as cadherins and integrins in human melanoma cells overexpressing or not Nck2. Finally, in mice we assessed tumor growth rate of human melanoma cells expressing increasing levels of Nck2. RESULTS: We found that expression of Nck2 is consistently increased in various metastatic cancer cell lines compared with primary counterparts. Particularly, we observed significant higher levels of Nck2 protein and mRNA, as opposed to no change in Nck1, in human metastatic melanoma cell lines compared with non-metastatic melanoma and normal melanocytes. We demonstrated the involvement of Nck2 in proliferation, migration and invasion in human melanoma cells. Moreover, we discovered that Nck2 overexpression in human primary melanoma cells correlates with higher levels of proteins phosphorylated on tyrosine residues, assembly of Nck2-dependent pY-proteins-containing molecular complexes and downregulation of cadherins and integrins. Importantly, we uncovered that injection of Nck2-overexpressing human primary melanoma cells into mice increases melanoma-derived tumor growth rate. CONCLUSIONS: Collectively, our data indicate that Nck2 effectively influences human melanoma phenotype progression. At the molecular level, we propose that Nck2 in human primary melanoma promotes the formation of molecular complexes regulating proliferation and actin cytoskeleton dynamics by modulating kinases or phosphatases activities that results in increased levels of proteins phosphorylated on tyrosine residues. This study provides new insights regarding cancer progression that could impact on the therapeutic strategies targeting cancer.

[A uNick protein]. / Une protéine uNick en son genre.

Nck is an adaptor protein composed of three N-terminal Src Homology (SH) 3 domains followed by a unique C­terminal SH2 domain. Like other SH2/SH3 domains-containing adaptor proteins, Nck mediates signal transduction from activated cell surface receptors by directing the flow of information to elicit properly orchestrated cell responses. In this way, Nck appears to be unique in its contribution to a wide variety of cellular processes. Moreover, in addition to the typical signal/pY-SH2/SH3-effectors mode of signaling, Nck also transduces signals through an inverse mode of -signaling (signal-SH3/SH2-pY/effectors) and from various cell compartments. Since Nck contributes to important morphogenic and mitogenic processes, deregulated expression of Nck could be detrimental to cellular homeostasis. In agreement, Nck expression has been found upregulated in numerous types of cancer. In this paper we delineate the main molecular -signaling -complexes associated with Nck, focusing on those involved in cancer progression.