The interplay between climate change and ageing: A systematic review of health indicators.

Climate change and rapid population ageing pose challenges for communities and public policies. This systematic review aims to gather data from studies that present health indicators establishing the connection between climate change and the physical and mental health of the older population (≥ 65 years), who experience a heightened vulnerability to the impacts of climate change when compared to other age cohorts. This review was conducted according to the PICO strategy and following Cochrane and PRISMA guidelines. Three databases (PubMed, Scopus and Greenfile) were searched for articles from 2015 to 2022. After applying inclusion and exclusion criteria,nineteen studies were included. The findings indicated that various climate change phenomena are associated with an elevated risk of mortality and morbidity outcomes in older adults. These included cardiovascular, respiratory, renal, and mental diseases, along with physical injuries. Notably, the impact of climate change was influenced by gender, socioeconomic status, education level, and age-vulnerability factors. Climate change directly affected the health of older adults through ambient temperature variability, extreme and abnormal temperatures, strong winds, sea temperature variability, extreme El Niño-southern Oscillation (ENSO) conditions and droughts, and indirectly by air pollution resulting from wildfires. This review presents further evidence confirming that climate change significantly impacts the health and well-being of older adults. It highlights the urgency for implementing effective strategies to facilitate adaptation and mitigation, enhancing the overall quality of life for all individuals.

Translation and cross-cultural adaptation of the ABC taxonomy for medication adherence into Portuguese - Updating patients into people.

BACKGROUND: The Ascertaining Barriers to Compliance (ABC) taxonomy for describing medication adherence was created in 2012, aiming to standardize terms and definitions in research and practice. The taxonomy comprises seven terms and definitions. Originally developed in English, subsequently translated into French and German, is currently being translated to Portuguese, Spanish, Czech, Romanian and Italian, aiming to promote its global use and overcome cultural barriers. OBJECTIVES: To cross-culturally translate the ABC taxonomy into Portuguese for Portugal and Brazil. METHODS: A systematic literature search was conducted to identify published taxonomy terms and definitions in Portuguese, and to identify panelists in medication adherence. Initial mapping of terms and definitions retrieved was scrutinized by the research team to build an e-survey. The e-survey was piloted and then sent to panelists in both countries seeking consensus using a three-round Delphi method. Consensus was defined as ≥ 85% for round 1 and ≥ 75% for round 2. Terms with agreement <10% were dropped between rounds. In round 3, terms and definitions reaching agreement between 50 and 75% were classified as moderate consensus,>75-95% as consensus and >95% as strong consensus. RESULTS: A total of 778 studies were identified and 84 included, enabling the extraction of 154 terms and 32 definitions. In round 1, 164 panelists participated, 115 in round 2 and 99 in the round 3. Consensus was achieved in both countries for all seven terms and definitions, although with varying intensity of agreement. The term "Management of adherence" and the definition of "Discontinuation" obtained moderate consensus in both countries. CONCLUSIONS: A unified and unique ABC taxonomy in Portuguese was possible to develop for use in Portugal and in Brazil. Its use will harmonize and standardize the terms and definitions used in clinical practice and research.

Bisphenols A, F, S and AF trigger apoptosis and/or endoplasmic reticulum stress in human endometrial stromal cells.

Disruption of non-differentiated endometrial stromal cells could have noxious consequences in female reproduction, impairing endometrial remodelling and implantation. Following the classification of bisphenol A (BPA) as an endocrine disrupting chemical, it started to be gradually withdrawn from the market, being substituted by structural analogues, whose effects in human health are not fully understood. This work used a telomerase-immortalized human endometrial stromal cell line (St-T1b) to study the effects of BPA and its three most commercialized structural analogues (ranked: bisphenols S, F and AF) on endometrial stromal cells to understand their effects on female reproductive function. Bisphenols showed dissimilar effects. All four compounds generated endoplasmic reticulum (ER) stress. In addition, bisphenols A, F and AF induced apoptosis through different mechanisms, with bisphenol AF causing cell cycle arrest at G2/M phase. Bisphenol AF decreased mitochondrial transmembrane potential and bisphenols A, F and AF produced oxidative stress.

Pharmacological Adherence Behavior Changes during COVID-19 Outbreak in a Portugal Patient Cohort.

Concerns, behaviours, and beliefs influence how people deal with COVID-19. Understanding the factors influencing adherence behaviour is of utmost importance to develop tailored interventions to increase adherence within this context. Hence, we aimed to understand how COVID-19 affected adherence behaviour in Portugal. A cross-sectional online survey was conducted between 1 March and 3 April 2021. Descriptive statistics were performed, as well as univariable and multivariable regression models. Of the 1202 participants, 476 who were taking at least one medication prescribed by the doctor were selected. Of these, 78.2% were female, and the mean age was 40.3 ± 17.9 years old. About 74.2% were classified as being highly adherent. During the pandemic, 8.2% of participants reported that their adherence improved, while 5.9% had worsened adherence results. Compared with being single, widowers were 3 times more prone to be less adherent (OR:3.390 [1.106-10.390], p = 0.033). Comorbid patients were 1.8 times (OR:1.824 [1.155-2.881], p = 0.010) more prone to be less adherent. Participants who reported that COVID-19 negatively impacted their adherence were 5.6 times more prone to be less adherent, compared with those who reported no changes (OR:5.576 [2.420-12.847], p < 0.001). None of the other variables showed to be significantly associated with pharmacological adherence.

Applying the FAIR4Health Solution to Identify Multimorbidity Patterns and Their Association with Mortality through a Frequent Pattern Growth Association Algorithm.

The current availability of electronic health records represents an excellent research opportunity on multimorbidity, one of the most relevant public health problems nowadays. However, it also poses a methodological challenge due to the current lack of tools to access, harmonize and reuse research datasets. In FAIR4Health, a European Horizon 2020 project, a workflow to implement the FAIR (findability, accessibility, interoperability and reusability) principles on health datasets was developed, as well as two tools aimed at facilitating the transformation of raw datasets into FAIR ones and the preservation of data privacy. As part of this project, we conducted a multicentric retrospective observational study to apply the aforementioned FAIR implementation workflow and tools to five European health datasets for research on multimorbidity. We applied a federated frequent pattern growth association algorithm to identify the most frequent combinations of chronic diseases and their association with mortality risk. We identified several multimorbidity patterns clinically plausible and consistent with the bibliography, some of which were strongly associated with mortality. Our results show the usefulness of the solution developed in FAIR4Health to overcome the difficulties in data management and highlight the importance of implementing a FAIR data policy to accelerate responsible health research.

FAIR4Health: Findable, Accessible, Interoperable and Reusable data to foster Health Research.

Due to the nature of health data, its sharing and reuse for research are limited by ethical, legal and technical barriers. The FAIR4Health project facilitated and promoted the application of FAIR principles in health research data, derived from the publicly funded health research initiatives to make them Findable, Accessible, Interoperable, and Reusable (FAIR). To confirm the feasibility of the FAIR4Health solution, we performed two pathfinder case studies to carry out federated machine learning algorithms on FAIRified datasets from five health research organizations. The case studies demonstrated the potential impact of the developed FAIR4Health solution on health outcomes and social care research. Finally, we promoted the FAIRified data to share and reuse in the European Union Health Research community, defining an effective EU-wide strategy for the use of FAIR principles in health research and preparing the ground for a roadmap for health research institutions. This scientific report presents a general overview of the FAIR4Health solution: from the FAIRification workflow design to translate raw data/metadata to FAIR data/metadata in the health research domain to the FAIR4Health demonstrators' performance.

Pre-Frailty and Frailty in Dialysis and Pre-Dialysis Patients: A Systematic Review of Clinical and Biochemical Markers.

Patients under dialysis are known to be more vulnerable to frailty, a dynamic geriatric syndrome defined as a state of vulnerability to stressors, due to numerous metabolic changes. With rise of life expectancy globally, it is important to understand the complexity of the pathophysiology of frailty and identify possible markers that can help with the prognosis and diagnosis of frailty. The aim of this systematic review is to give an overview of the knowledge regarding clinical and biochemical markers associated with pre-frailty and frailty in dialysis and pre-dialysis patients. In November 2020, PubMed, Embase and Web of Science were searched. Studies regarding biomarkers associated with (pre-)frailty in (pre-)dialysis patients were included. This systematic review identified clinical and biochemical markers in pre-frail and frail patients under dialysis or pre-dialysis published in the literature. This study shows that more investigation is necessary to identify markers that can differentiate these processes to be used as a diagnostic and prognostic tool in routine care and management of geriatric needs. Interventions that can improve health outcomes in pre-frail and frail older adults under dialysis or pre-dialysis are essential to improve not only the individual's quality of life but also to reduce the burden to the health systems.

Lesson learned from an international training program on patients medication adherence for healthcare professionals.

SUMMARY: Objective. Healthcare professionals play a crucial role for promoting medication adherence in older adults. This research aimed to assess changes in professionals' opinions about medication adherence after attending a course, collecting suggestions for future educational programs. Method. A one-week course on medication adherence in older adults was held involving 32 healthcare professionals and students from Italy, Portugal and Poland as part of the Erasmus+ Skills4Adherence Project. Prior to and at the end of the course, participants provided three keyword answers through a Google Form. Responses were collectively discussed and commented on. Results. At the end of the course a general tendency to put more attention on patient's beliefs and engagement was revealed. The caregivers' role was also underlined. As to suggestions for education, three keywords were considered not enough to characterize adherence issues. Conversely, professionals considered collective discussions and roleplaying to be effective for increasing awareness on this theme. Discussion and conclusion. Several changes in healthcare professionals' opinions regarding determinants of medicationadherence were revealed after this dedicated course. Overall, multidisciplinary and practical training programs should be proposed for increasing healthcare professionals' awareness of factors impacting on medication adherence in older adults.

Persistence as a Robust Indicator of Medication Adherence-Related Quality and Performance.

Medication adherence is a priority for health systems worldwide and is widely recognised as a key component of quality of care for disease management. Adherence-related indicators were rarely explicitly included in national health policy agendas. One barrier is the lack of standardised adherence terminology and of routine measures of adherence in clinical practice. This paper discusses the possibility of developing adherence-related performance indicators highlighting the value of measuring persistence as a robust indicator of quality of care. To standardise adherence and persistence-related terminology allowing for benchmarking of adherence strategies, the European Ascertaining Barriers for Compliance (ABC) project proposed a Taxonomy of Adherence in 2012 consisting of three components: initiation, implementation, discontinuation. Persistence, which immediately precedes discontinuation, is a key element of taxonomy, which could capture adherence chronology allowing the examination of patterns of medication-taking behaviour. Advances in eHealth and Information Communication Technology (ICT) could play a major role in providing necessary structures to develop persistence indicators. We propose measuring persistence as an informative and pragmatic measure of medication-taking behaviour. Our view is to develop quality and performance indicators of persistence, which requires investing in ICT solutions enabling healthcare providers to review complete information on patients' medication-taking patterns, as well as clinical and health outcomes.

Frailty Status and Polypharmacy Predict All-Cause Mortality in Community Dwelling Older Adults in Europe.

European population ageing is associated with frailty, a complex geriatric syndrome, and polypharmacy, both resulting in adverse health outcomes. In this study we aimed to evaluate the impact of frailty and polypharmacy, on mortality rates, within 30 months, using a cohort of SHARE participants aged 65 years old or more. Frailty was assessed using a version of Fried's phenotype criteria operationalized to SHARE while polypharmacy was defined as taking five or more drugs per day. We found a prevalence of 40.4% non-frail, 47.3% pre-frail and 12.3% frail participants. Moreover, a prevalence of polypharmacy of 31.3% was observed, being 3 three times more prevalent in frail individuals and two times in pre-frail individuals, when compared with non-frail. Individuals with both conditions had shown higher mortality rates. Comparing with non-polymedicated non-frail individuals all the other conditions are more prone to die within 30 months. Polymedicated older and male participants exhibited also higher mortality rates. This work shows polypharmacy and frailty to be associated with a higher risk of all-cause of mortality and highlights the need to decrease 'unnecessary' polypharmacy to reduce drug-related issues and also the need to assess frailty early to prevent avoidable adverse outcomes.

Cognitive performance in older adults across Europe based on the SHARE database.

With ageing mental health issues, as age-related cognitive decline, increase. This study aims to evaluate the prevalence of cognitive impairment among older European adults and to evaluate its association with clinical and sociodemographic variables, using SHARE. Numeracy, temporal orientation, verbal fluency, and memory were the measures used to evaluate cognitive performance. From 44 963 individuals included, mean age was 70.0±9.0 years old and 56.3% were female. Overall prevalence of impairment was of 13.0% (temporal orientation), 24.8% (numeracy), 27.6% (verbal fluency) and 50.5% (memory). Men showed higher impairment prevalence in temporal orientation and memory and lower in numeracy and verbal fluency. Age, fewer years of education, difficulties performing iADLs, physical inactivity, and poor self-perceived health were independently associated with impairment in all cognitive abilities. These results showed the burden of cognitive impairment across Europe. Factors identified as associated should be taken in consideration to develop effective interventions to prevent cognitive decline.

Instrumental Activities of Daily Living (iADL) Limitations in Europe: An Assessment of SHARE Data.

This study aims to evaluate the instrumental activities of daily living (iADLs) limitations in Europe and its association with socio-demographic characteristics, economic parameters and physical and mental health status. We used data from the wave 6 of SHARE database. Individuals were classified as having either none or one or more limitations on iADLs. Participants aged 65 or more years who answered all questions for the variables included in this work were selected. A total of 54.8% of participants were female and had a mean age of 74.37 (SD = 7.08) years. A global prevalence of 1 or more iADLs in Europe was shown to be 23.8% and more prevalent in women than in men (27.1% vs. 17.6%) and in people aged 85 years or more (51.5%). Older age, female gender, lower education, physical inactivity, frailty, having two or more chronic diseases, presence of depression, polypharmacy, poor self-perception of health and lower network satisfaction were found to be factors associated with the presence of 1 or more iADLs limitation. This study highlights the burden of iADLs limitations at the European level. These are based on a multidimensional biopsychosocial model and are associated with both health conditions and environmental factors. This intersection between the physical and social world underscores its potential as a health indicator and can, to some extent, explain some of the pronounced differences seen among European countries. Different inter-tasks can also stress different dimensions of health indicators in distinct and specific groups of individuals. Minimizing the impact of iADL limitations can improve the quality and sustainability of public health systems.

The Cannabinoid Delta-9-tetrahydrocannabinol Disrupts Estrogen Signaling in Human Placenta.

Cannabis consumption is increasing worldwide either for recreational or medical purposes. Its use during gestation is associated with negative pregnancy outcomes such as, intrauterine growth restriction, preterm birth, low birth weight, and increased risk of miscarriage, though the underlying molecular mechanisms are unknown. Cannabis sativa main psychoactive compound, Δ9-tetrahydrocannabinol (THC) is highly lipophilic, and as such, readily crosses the placenta. Consequently, THC may alter normal placental development and function. Here, we hypothesize alterations of placental steroidogenesis caused by THC exposure. The impact on placental estrogenic signaling was examined by studying THC effects upon the enzyme involved in estrogens production, aromatase and on estrogen receptor α (ERα), using placental explants, and the cytotrophoblast cell model BeWo. Aromatase expression was upregulated by THC, being this effect potentiated by estradiol. THC also increased ERα expression. Actions on aromatase were ERα-mediated, as were abolished by the selective ER downregulator ICI-182780 and dependent on the cannabinoid receptor CB1 activation. Furthermore, the presence of the aromatase inhibitor Exemestane did not affect THC-induced increase in ERα expression. However, THC effects on ERα levels were reversed by the antagonists of CB1 and CB2 receptors AM281 and AM630, respectively. Thus, we demonstrate major alterations in estrogen signaling caused by THC, providing new insight on how cannabis consumption leads to negative pregnancy outcomes, likely through placental endocrine alterations. Data presented in this study, together with our recently reported evidence on THC disruption of placental endocannabinoid homeostasis, represent a step forward into a deeper comprehension of the puzzling actions of THC.

The Need to Develop Standard Measures of Patient Adherence for Big Data: Viewpoint.

Despite half a century of dedicated studies, medication adherence remains far from perfect, with many patients not taking their medications as prescribed. The magnitude of this problem is rising, jeopardizing the effectiveness of evidence-based therapies. An important reason for this is the unprecedented demographic change at the beginning of the 21st century. Aging leads to multimorbidity and complex therapeutic regimens that create a fertile ground for nonadherence. As this scenario is a global problem, it needs a worldwide answer. Could this answer be provided, given the new opportunities created by the digitization of health care? Daily, health-related information is being collected in electronic health records, pharmacy dispensing databases, health insurance systems, and national health system records. These big data repositories offer a unique chance to study adherence both retrospectively and prospectively at the population level, as well as its related factors. In order to make full use of this opportunity, there is a need to develop standardized measures of adherence, which can be applied globally to big data and will inform scientific research, clinical practice, and public health. These standardized measures may also enable a better understanding of the relationship between adherence and clinical outcomes, and allow for fair benchmarking of the effectiveness and cost-effectiveness of adherence-targeting interventions. Unfortunately, despite this obvious need, such standards are still lacking. Therefore, the aim of this paper is to call for a consensus on global standards for measuring adherence with big data. More specifically, sound standards of formatting and analyzing big data are needed in order to assess, uniformly present, and compare patterns of medication adherence across studies. Wide use of these standards may improve adherence and make health care systems more effective and sustainable.

The endocannabinoid 2-arachidonoylglycerol promotes endoplasmic reticulum stress in placental cells.

Proliferation, differentiation and apoptosis of trophoblast cells are required for normal placental development. Impairment of those processes may lead to pregnancy-related diseases. Disruption of endoplasmic reticulum (ER) homeostasis has been associated with several reproductive pathologies including recurrent pregnancy loss and preeclampsia. In the unfolded protein response (UPR), specific ER-stress signalling pathways are activated to restore ER homeostasis, but if the adaptive response fails, apoptosis is triggered. Protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and Activating transcription factor 6 (ATF6) are central players in UPR and in ER-stress-induced apoptosis, as well as downstream transcription factors, as C/EBP homologous protein (CHOP). Our previous studies have shown that the endocannabinoid 2-arachidonoylglycerol (2-AG) modulates trophoblast cell turnover. Nevertheless, the role of ER-stress on 2-AG induced apoptosis and cannabinoid signalling in trophoblast has never been addressed. In this work, we used BeWo cells and human primary cytotrophoblasts isolated from term-placenta. The expression of ER-stress markers was analysed by qRT-PCR and Western blotting. ROS generation was assessed by fluorometric methods, while apoptosis was detected by the evaluation of caspase -3/-7 activities and Poly (ADP-ribose) polymerase (PARP) cleavage. Our findings indicate that 2-AG is able to induce ER-stress and apoptosis. Moreover, the eukaryotic initiation factor 2 (eIF2α)/CHOP pathway involved in ER-stress-induced apoptosis is triggered through a mechanism dependent on cannabinoid receptor CB2 activation. The results bring novel insights on the importance of ER-stress and cannabinoid signalling on 2-AG mechanisms of action in placenta.

Cannabidiol (CBD) but not tetrahydrocannabinol (THC) dysregulate in vitro decidualization of human endometrial stromal cells by disruption of estrogen signaling.

Decidualization, which comprises proliferation and differentiation of endometrial stromal cells (ESCs), is essential for the establishment of a receptive endometrium and pregnancy to occur. A deregulation of decidualization has been associated with miscarriage, infertility and other pregnancy-related disorders. The role of estradiol (E2) on decidualization has already been shown, since it regulates proliferation of ESCs and expression of progesterone receptor. In this study, we investigated the effects of phytocannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD), in proliferation and differentiation of ESCs, as well as, in E2 metabolism/signaling. We found that CBD, but not THC, inhibits ESCs differentiation. We also show that CBD prevents the increase on transcript levels of CYP19A1 gene and the elevation of E2 levels that are observed in differentiating ESCs. Moreover, we found that CBD presents anti-aromatase activity. In overall, we highlight a novel effect of CBD on human endometrial differentiation, which may lead to infertility problems.

The potential clinical benefit of targeting androgen receptor (AR) in estrogen-receptor positive breast cancer cells treated with Exemestane.

The development of acquired resistance to the aromatase inhibitors (AIs) used in clinic is being considered the major concern in estrogen-receptor positive (ER+) breast cancer therapy. Recently, androgen receptor (AR) has gained attention in the clinical setting, since it has been implicated in AIs-resistance, although, different roles for AR in cell fate have been described. In this work, our group elucidates, for the first time, the oncogenic role of AR in sensitive and resistant ER+ breast cancer cells treated with the potent third-generation steroidal AI Exemestane (Exe). We demonstrate that Exe promotes an overexpression/activation of AR, which has an oncogenic and pro-survival role in Exe-sensitive and Exe-resistant cells. Moreover, we also disclose that targeting AR with bicalutamide (CDX) in Exe-treated cells, enhances the efficacy of this AI in sensitive cells and re-sensitizes resistant cells to Exe treatment. Furthermore, by targeting AR in Exe-resistant cells, it is also possible to block the activation of the ERK1/2 and PI3K cell survival pathways, hamper ERα activation and increase ERß expression. Thus, this study, highlights a new mechanism involved in Exe-acquired resistance, implicating AR as a key molecule in this setting and suggesting that Exe-resistant cells may have an AR-dependent but ER-independent mechanism. Hence we propose AR antagonism as a potential and attractive therapeutic strategy to overcome Exe-acquired resistance or to enhance the growth inhibitory properties of Exe on ER+ breast cancer cells, improving breast cancer treatment.

[A New Paradigm in Health Research: FAIR Data (Findable, Accessible, Interoperable, Reusable)]. / Um Novo Paradigma em Investigação em Saúde: Dados FAIR (Localizáveis, Acessíveis, Interoperáveis, Reutilizáveis).

The digital era, that we are living nowadays, is transforming health, health care models and services, and the role of society in this new reality. We currently have a large amount of stored health data, including clinical, biometric, and scientific research data. Nonetheless, its potential is not being fully exploited. It is essential to foster the sharing and reuse of this data not only in research but also towards the development of health technologies in order to improve health care efficiency, as well as products, services or digital health apps, to promote preventive and individualized medicine and to empower citizens in health literacy and self-management. In this sense, the FAIR concept has emerged, which implies that health data is findable, accessible, shared and reusable, facilitating interoperability between systems, ensuring the protection of personal and sensitive data. In this paper we review the FAIR concept, 'FAIRification' process, FAIR data versus open access data, ethical issues and the general data protection regulation, and digital health and citizen science.

Vivemos uma nova era digital que está a transformar a saúde, os modelos de cuidados e serviços de saúde, e o próprio papel da sociedade nesta realidade. Atualmente dispomos de uma grande quantidade de dados de saúde armazenados, incluindo dados clínicos, biométricos e de investigação científica, cuja potencialidade não está a ser devidamente explorada. É essencial favorecer a partilha e reutilização destes dados não só na investigação, como também para o desenvolvimento de tecnologias para melhorar a eficiência dos cuidados de saúde, de produtos ou serviços de saúde digitais, promover uma medicina preventiva e individualizada, mas também o empoderamento da população em literacia em saúde e na gestão da doença. Recentemente, surgiu o conceito FAIR que implica que os dados de saúde sejam facilmente localizáveis, acessíveis, partilhados e reutilizáveis, facilitando desta forma a interoperacionalidade entre sistemas e assegurando a proteção de dados pessoais e sensíveis. Neste artigo é feita uma revisão do conceito FAIR, processo de 'FAIRificação', dados FAIR versus dados de acesso livre, questões de éticas e o regulamento geral de proteção de dados, e saúde digital e ciência cidadã.

Synthetic cannabinoids JWH-018, JWH-122, UR-144 and the phytocannabinoid THC activate apoptosis in placental cells.

The increasing use of synthetic cannabinoids (SCBs) in recreational settings is becoming a new paradigm of drug abuse. Although SCBs effects mimic those of the Cannabis sativa plant, these drugs are frequently more potent and hazardous. It is known that endocannabinoid signalling plays a crucial role in diverse reproductive events such as placental development. Moreover, the negative impact of the phytocannabinoid Δ9-tetrahydrocannabinol (THC) in pregnancy outcome, leading to prematurity, intrauterine growth restriction and low birth weight is well recognized, which makes women of childbearing age a sensitive group to developmental adverse effects of cannabinoids. Placental trophoblast turnover relies on regulated processes of proliferation and apoptosis for normal placental development. Here, we explored the impact of the SCBs JWH-018, JWH-122 and UR-144 and of the phytocannabinoid THC in BeWo cell line, a human placental cytotrophoblast cell model. All the cannabinoids caused a significant decrease in cell viability without LDH release, though this effect was only detected for the highest concentrations of THC. Moreover, a cell cycle arrest at the G2/M phase was also observed. JWH-018 and JWH-122 increased reactive oxygen species (ROS) production and THC, UR-144 and JWH-122 caused loss of mitochondrial membrane potential. All the compounds were able to induce caspase-9 activation. The involvement of apoptotic pathways was further confirmed through the significant increase in caspase -3/-7 activities. For UR-144, this effect was reversed by the CB1 antagonist AM281, for JWH-018 and THC this effect was mediated by both cannabinoid receptors CB1 and CB2 while for JWH-122 it was cannabinoid receptor-independent. This work demonstrates that THC and SCBs are able to induce apoptotic cell death. Although they may act through different mechanisms and potencies, the studied cannabinoids have the potential to disrupt gestational fundamental events.

Anandamide targets aromatase: A breakthrough on human decidualization.

In each menstrual cycle endometrial stromal cells (hESC) proliferate and differentiate into specialized decidual cells, a process termed decidualization, which regulates endometrial receptivity. Decidualization is mainly controlled by sex ovarian hormones, estradiol (E2) and progesterone. E2 plays an important role in the expression of the progesterone receptor and promotes the endometrial stromal cells differentiation. Our group previously reported that anandamide (AEA) impairs decidualization through cannabinoid receptor 1 (CB1). In this study, we hypothesized whether AEA inhibitory effect on cell decidualization could be mediated through interaction with aromatase and consequent interference in estradiol production/signaling. We used an immortalized human endometrial stromal cell line (St-T1b) and human decidual fibroblasts (HdF) derived from human term placenta. In cells exposed to a differentiation stimulus, AEA-treatment prevents the increase of the expression of CYP19A1 gene encoding aromatase, E2 levels and of estradiol receptor expression, that are observed in differentiating cells. Regarding CYP19A1 mRNA levels, the effect was partially reverted by a CB1 receptor antagonist and by a COX2 inhibitor. In addition, we report that AEA presents anti-aromatase activity in placental microsomes, the nature of the inhibition being the uncommon mixed type as revealed by the kinetic studies. Structural analysis of the AEA-Aromatase complexes determined that AEA may bind to the active site pocket of the enzyme. In overall we report that AEA inhibits aromatase activity and may affect E2 signaling crucial for the decidualization process, indicating that a deregulation of the endocannabinoid system may be implicated in endometrial dysfunction and in fertility/infertility disorders.