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1.
Front Public Health ; 12: 1393188, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38903566

RESUMEN

Background: Transgender and gender diverse (TGD) individuals face significant healthcare barriers, with one of the most critical being the inadequate knowledge and skills of healthcare professionals (HCPs) in TGD health. To address this issue, we undertook a project to develop a distance learning course for all healthcare professions, encompassing a comprehensive range of topics related to TGD health issues. Objectives: This study aimed to evaluate the impact of a course on gender-affirming healthcare competence, with a focus on knowledge acquisition and satisfaction levels. The hypothesis was that participating in the course would enhance the participants' knowledge on the covered topics. Methods: A distance learning course, designed for all Continuing Medical Education professions, was conducted between March and September 2023. The course was structured according to the Problem-Based Learning methodology. We implemented a pre-test vs. post-test study design to evaluate the enhancement of knowledge, based on a set of Multiple Choice Questions (MCQs), and investigated users' satisfaction through the administration of a semi-structured questionnaire. We examined the pre- and post-course proportions of correct responses to questions, along with the mean score difference, categorized by learners' sex, age, and geographical area. Eventually, a Satisfaction Training Index was created. Results: The maximum capacity was reached, with 29,998 out of 30,000 available spots filled. Of those enrolled, 18,282 HCPs successfully completed the training. Post-test results revealed an increase in correct answers across all MCQs, with overall mean score rising from 48.8 to 68.0 (p < 0.001). Stratified analysis indicated improvements across all participant categories. A higher average increase among female (19.87) compared to male enrollees (17.06) was detected (p < 0.001). Both "over 55" and "46-55" age groups showed the greatest score increases compared to "35-46" and "under 35" groups, despite no significant differences in pre-test scores. Course satisfaction was high, averaging 4.38 out of 5. Top-rated aspects included "learning new concepts" (4.49), "accessibility" (4.46), and "platform functionality" (4.46). Conclusion: Our research hypothesis was confirmed by the significant increase in knowledge going from pre-test to post-test and by the high level of user satisfaction. The obtained results serve as a foundation for planning additional professional education in TGD health.


Asunto(s)
Educación a Distancia , Personal de Salud , Personas Transgénero , Humanos , Masculino , Femenino , Italia , Personal de Salud/educación , Adulto , Encuestas y Cuestionarios , Persona de Mediana Edad , Competencia Clínica , Satisfacción Personal , Atención de Afirmación de Género
2.
J Clin Endocrinol Metab ; 109(6): 1565-1579, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38099569

RESUMEN

CONTEXT: The role of body modifications induced by gonadal suppression in transgender and gender diverse adolescents on psychological functioning has not yet been evaluated. OBJECTIVE: The main aim of the present study was to explore several hormone, physical and psychological functioning changes during gonadotropin-releasing hormone analog (GnRHa) treatment in transgender and gender diverse adolescents (TGDAs). The potential relationship between the physical and hormone effects of GnRHa and psychological well-being, along with its magnitude, was assessed for the first time. METHODS: This prospective multidisciplinary study included 36 TGDA (22 assigned female at birth, and 14 assigned male at birth) who received psychological assessment followed by triptorelin prescription after referring to the Florence Gender Clinic. This study consisted of 3 time points: first referral (T0), psychological assessment (T1); and treatment with intramuscular injections of triptorelin for 3 up to 12 months (T2). Psychometric questionnaires were administered at each time point, and clinical and biochemical evaluations were performed at T1 and T2. RESULTS: The following results were found: (1) GnRHa showed efficacy in inhibiting puberty progression in TGDAs; (2) an increase in psychopathology was observed before starting GnRHa (T1) compared with baseline levels; (3) during GnRHa treatment (T2), a significant improvement in psychological functioning, as well as decrease in suicidality, body uneasiness, depression, and anxiety levels were observed; (4) hormone and physical changes (in terms of gonadotropin and sex steroid levels, height and body mass index percentiles, waist-hip ratio, and acne severity) observed during triptorelin treatment significantly correlated with a reduction in suicidal ideation, anxiety, and body image concerns. CONCLUSION: Psychological improvement in TGDA on GnRHa seems to be related to the objective body changes induced by a GnRHa. Therefore, the rationale for treatment with a GnRHa may not only be considered an extension of the evaluation phase, but also the start of a medical (even if reversible) gender-affirming path, especially in TGDAs whose puberty has already progressed.


Asunto(s)
Hormona Liberadora de Gonadotropina , Personas Transgénero , Adolescente , Femenino , Humanos , Masculino , Hormona Liberadora de Gonadotropina/análogos & derivados , Estudios Prospectivos , Pubertad/efectos de los fármacos , Pubertad/psicología , Pubertad/fisiología , Procedimientos de Reasignación de Sexo/métodos , Personas Transgénero/psicología , Transexualidad/tratamiento farmacológico , Transexualidad/psicología , Pamoato de Triptorelina/uso terapéutico , Pamoato de Triptorelina/administración & dosificación
4.
Int J Mol Sci ; 23(18)2022 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-36142329

RESUMEN

Silibinin, a natural polyphenolic flavonoid, is known to possess anti-inflammatory, anticancer, antioxidant, and immunomodulatory properties. However, the effects of Silibinin on the maturation and immunostimulatory functions of human dendritic cells (DC) remain to be elucidated. In this study, we have attempted to ascertain whether Silibinin influences the maturation, cytokine production, and antigen-presenting capacity of human monocyte-derived DC. We show that Silibinin significantly suppresses the upregulation of costimulatory and MHC molecules in LPS-stimulated mature DC and inhibits lipopolysaccharide (LPS)-induced interleukin (IL)-12, IL-23, and TNF-α production. Furthermore, Silibinin impairs the proliferation response of the allogenic memory CD4 T lymphocytes elicited by LPS-matured DC and their Th1/Th17 profile. These findings demonstrate that Silibinin displays immunosuppressive activity by inhibiting the maturation and activation of human DC and support its potential application of adjuvant therapy in the treatment of autoimmune diseases.


Asunto(s)
Lipopolisacáridos , Monocitos , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Diferenciación Celular , Células Cultivadas , Citocinas/farmacología , Células Dendríticas , Flavonoides/farmacología , Humanos , Inmunosupresores/farmacología , Interleucina-12 , Interleucina-23 , Lipopolisacáridos/farmacología , Silibina/farmacología , Factor de Necrosis Tumoral alfa/farmacología
5.
Int J Mol Sci ; 23(16)2022 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-36012424

RESUMEN

Hypovitaminosis D is involved in various inflammatory, infectious and autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. Moreover, the active form of vitamin D, calcitriol, has been shown to modulate the immune response, playing an anti-inflammatory effect. However little is known about the mechanisms underlying this anti-inflammatory effect and the potential sex differences of calcitriol immune regulation. Hence, the aim of this study was to investigate whether calcitriol could act differently in modulating T cell immunity of age-matched male and female healthy donors. We analyzed the effects of calcitriol in T lymphocytes from healthy women and men on the expression levels of the vitamin D receptor (VDR) and pro- and anti-inflammatory cytokine production. We showed that a treatment with calcitriol induced a significant increase in the VDR expression levels of activated T lymphocytes from male and female healthy subjects. Moreover, we found that calcitriol significantly reduced the expression level of pro-inflammatory cytokines IL-17, INF-γ and TNF-α in the T lymphocytes of both sexes. Notably, we observed that calcitriol induced a significant increase in the expression level of anti-inflammatory cytokine IL-10 only in the T lymphocytes from female healthy donors. In conclusion, our study provides new insights regarding the sex-specific anti-inflammatory role of calcitriol in T cell immunity.


Asunto(s)
Calcitriol , Factores Sexuales , Linfocitos T , Calcitriol/farmacología , Citocinas/metabolismo , Femenino , Humanos , Masculino , Receptores de Calcitriol/metabolismo , Linfocitos T/metabolismo , Vitamina D/metabolismo , Vitaminas/metabolismo
6.
J Clin Med ; 11(10)2022 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-35628902

RESUMEN

The burden of sexually transmitted infections (STIs) in the transgender population remains an underestimated issue. The aims of the present study were to evaluate the prevalence of either self-reported and serological STIs and to describe socio-demographic and clinical characteristics of transgender individuals with STIs. A consecutive series of 705 transgender individuals (assigned-male at birth, AMAB n = 377; assigned-female at birth, AFAB n = 328) referring to six Italian gender clinics were included. Sociodemographic and clinical information was collected during the first visit. In a subsample of 126 individuals prevalence of STIs (human immunodeficiency virus, HIV; hepatitis C, HCV; hepatitis B, HBV; syphilis) were evaluated through serology tests. The self-reported prevalence of HIV, HBV, HCV and syphilis infection in the total sample were 3.4%, 1.6%, 2.6% and 2.0%, respectively. In the subsample who underwent serological tests, higher rates of serological prevalence were found (9.5%, 4.0%, 5.6% and 7.9% for HIV, HBV, HCV and syphilis, respectively). When comparing transgender people with or without self-reported STIs, unemployment, previous incarceration, justice problems and sex work resulted more frequent in the first group (p< 0.03 for all). Regarding health status, we observed higher rates of lifetime substance abuse and psychiatric morbidities in trans people with at least one reported STI (p < 0.05). The prevalence of STIs exceeded that reported in general population and STIs correlates underline the importance of stigma and discrimination as determinants of transgender health.

7.
Anticancer Res ; 42(2): 767-779, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35093875

RESUMEN

BACKGROUND/AIM: About 40% of patients with diffuse large cell lymphoma (DLBCL) still have a poor prognosis. Additionally, DLBCL patients treated with doxorubicin are at risk of cardiac failure. Growing evidence suggests an antitumor and cardioprotective activity exerted by estrogen via its binding to estrogen receptor (ER) ß. The aim of this study was to evaluate the anticancer activity of the phytoestrogen silibinin, an ERß selective agonist, on DLBCL growth, and its potential cardioprotective effect. MATERIALS AND METHODS: DLBCL cell lines SUDHL-8, SUDHL-6, and RIVA were used. The anti-tumor activity of silibinin was also evaluated in vivo in NOD/SCID/IL2Rg-/- (NSG) xenografted mice. AC16 human ventricular cardiomyocytes were used to investigate the cardioprotective effects of silibinin. RESULTS: In vitro silibinin induced apoptosis and autophagy, and blocked tumor cell proliferation, also protecting AC16 cardiomyocytes from doxorubicin-induced toxicity. In vivo silibinin induced cell death and autophagy, and reduced tumor volume. CONCLUSION: Silibinin represents a promising therapeutic tool.


Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Receptor beta de Estrógeno/agonistas , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Silibina/uso terapéutico , Animales , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/toxicidad , Humanos , Linfoma de Células B Grandes Difuso/patología , Ratones , Miocitos Cardíacos/efectos de los fármacos , Silibina/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Biol Sex Differ ; 12(1): 63, 2021 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-34809704

RESUMEN

BACKGROUND: Several biomarkers have been identified to predict the outcome of COVID-19 severity, but few data are available regarding sex differences in their predictive role. Aim of this study was to identify sex-specific biomarkers of severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19. METHODS: Plasma levels of sex hormones (testosterone and 17ß-estradiol), sex-hormone dependent circulating molecules (ACE2 and Angiotensin1-7) and other known biomarkers for COVID-19 severity were measured in male and female COVID-19 patients at admission to hospital. The association of plasma biomarker levels with ARDS severity at admission and with the occurrence of respiratory deterioration during hospitalization was analysed in aggregated and sex disaggregated form. RESULTS: Our data show that some biomarkers could be predictive both for males and female patients and others only for one sex. Angiotensin1-7 plasma levels and neutrophil count predicted the outcome of ARDS only in females, whereas testosterone plasma levels and lymphocytes counts only in males. CONCLUSIONS: Sex is a biological variable affecting the choice of the correct biomarker that might predict worsening of COVID-19 to severe respiratory failure. The definition of sex specific biomarkers can be useful to alert patients to be safely discharged versus those who need respiratory monitoring.


Asunto(s)
Biomarcadores/sangre , COVID-19/complicaciones , Hospitalización , Síndrome de Dificultad Respiratoria/complicaciones , Síndrome de Dificultad Respiratoria/diagnóstico , Insuficiencia Respiratoria/complicaciones , Insuficiencia Respiratoria/diagnóstico , Caracteres Sexuales , Adulto , Enzima Convertidora de Angiotensina 2/sangre , Angiotensinas/sangre , COVID-19/sangre , Estradiol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Dificultad Respiratoria/sangre , Insuficiencia Respiratoria/sangre , SARS-CoV-2 , Testosterona/sangre
9.
Front Pharmacol ; 12: 683529, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34054557

RESUMEN

The outcome of COVID-19 appears to be influenced by vitamin D status of population. Although epidemiological data indicate that COVID-19 produces more severe symptoms and higher mortality in elderly in comparison to young patients and in men in comparison to women to date sex and age differences in vitamin D status in infected patients have not been evaluated yet. In this study we evaluated the levels of circulating 25(OH)D in patients hospitalized for COVID-19 divided accordingly to their sex and age. We also correlated 25(OH)D levels with patient's respiratory status (i.e., PaO2/FiO2 ratio) and with sex hormones plasma levels to analyze the potential relationship of these parameters. We found no significant differences in plasma levels of 25(OH)D between pre- and post-menopausal female patients and age matched male patients. Interestingly, the 25(OH)D plasma levels positively correlated to PaO2/FiO2 ratio only in young patients, regardless of their sex. We also found a significantly positive correlation between 17ß-estradiol and 25(OH)D in elderly women and between testosterone and 25(OH)D in elderly men, supporting the role of sex hormones in maintaining 25(OH)D levels. In conclusion, we suggest that a synergy between vitamin D and sex hormones could contribute to the age-related outcome of COVID-19.

10.
Biol Sex Differ ; 12(1): 12, 2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33436077

RESUMEN

Over the last decades, a central role for vitamin D in immune modulation has been well established. The active form of vitamin D, i.e., 1,25-dihydroxyvitamin D, through the interaction with vitamin D receptor, exerts different activities on the innate and adaptive immune system, among which suppression of inflammation and promotion of tolerogenic responses. Vitamin D insufficiency has been linked to autoimmune disorders that commonly display significant differences between females and males due to genetic, epigenetic, hormonal, and environmental factors. Notably, a number of studies recently showed a cross-talk between vitamin D and the sex hormone estrogen. Estrogen-mediated effects on immune response may favor a Th1 profile or a Th2 profile, depending on hormone concentration. Thus, estrogen-mediated effects appear to be variable on autoimmunity depending on its concentration but also on the pathogenic mechanisms underlying the different autoimmune diseases (i.e., Th1- or Th2-mediated diseases). Notably, estrogen has been demonstrated to enhance vitamin D function favoring its accumulation, and increasing the expression of vitamin D receptor, thus resulting in a more potent anti-inflammatory response in females than males. On the other hand, vitamin D has been shown to downregulate in immune cells the expression of aromatase, which converts testosterone to estrogen, leading to a decrease in estrogen level. Overall, available data allow us to hypothesize a higher protective effect of vitamin D-based therapeutic approaches in women, at least in fertile age, than in men. Future studies are needed to expand current knowledge on the immunomodulatory role of vitamin D in a sex and gender perspective, paving the way to a more personalized therapeutic approach in autoimmune diseases.


Asunto(s)
Enfermedades Autoinmunes , Estrógenos , Femenino , Humanos , Masculino , Receptores de Calcitriol , Caracteres Sexuales , Vitamina D
11.
J Sex Med ; 17(1): 142-151, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31735612

RESUMEN

INTRODUCTION: As far as we know, no studies to date have investigated the psychobiological correlates of sexual distress (SD) nor the impact of hormonal treatment (HT) on SD in transgender persons. AIM: To evaluate the psychobiological correlates of SD and assess the effects of HT on SD in transgender persons without gender-affirming surgery. METHODS: A consecutive series of 301 transgender persons (160 transwomen and 141 transmen) was considered for the cross-sectional study, and a subset of 72 subjects was studied in a 2-year follow-up. A physical examination was performed. Blood samples were drawn for determination of cortisol levels. Subjects completed psychometric measures. During 2 years of HT, the evaluation of SD was prospectively repeated. MAIN OUTCOME MEASURE: Psychobiological correlates of SD in transgender population. Changes in SD during gender affirming hormonal treatment. CLINICAL IMPLICATIONS: Knowing how hormonal treatment influence SD will help care providers when counseling transgender people. STRENGTHS & LIMITATIONS: To the authors' knowledge, this is the first study prospectively evaluating the impact of gender affirming hormonal treatment on sexual distress in transgender individuals. The main limitations are represented by the small size of the sample and the use of questionnaires validated only in the cisgender population. RESULTS: SD showed a positive correlation with body uneasiness (P < .0001) and with dissatisfaction toward gender-related body parts or shapes (all P < .05). In addition, SD correlated positively with general psychopathology (P < .0001), alexithymia, social anxiety, and humiliation scales (all P < .05). In transmen, SD was positively associated with autism levels (P < .005), as well as with cortisol levels (P < .02). A significant correlation between SD and perceived discrimination was observed in transwomen (P < .05). In transwomen, SD was positively associated with hair density and negatively with breast growth (both P < .05). Finally, in transmen, a negative correlation was found between SD and hair density (P < .05). When the impact of HT on SD was evaluated, a significant reduction of SD was observed across time in both transwomen and transmen (P = .001 and P = .01, respectively). CONCLUSIONS: The present results support the efficacy of HT in reducing SD in transgender persons. Ristori J, Cocchetti C, Castellini G, et al. Hormonal Treatment Effect on Sexual Distress in Transgender Persons: 2-Year Follow-Up Data. J Sex Med 2020;17:142-151.


Asunto(s)
Hormonas/administración & dosificación , Personas Transgénero/psicología , Transexualidad/psicología , Adolescente , Adulto , Estudios Transversales , Emociones , Femenino , Estudios de Seguimiento , Humanos , Masculino , Psicometría , Encuestas y Cuestionarios , Adulto Joven
12.
Cells ; 8(7)2019 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-31331091

RESUMEN

Tamoxifen resistance is a major hurdle in the treatment of estrogen receptor (ER)-positive breast cancer. The mechanisms of tamoxifen resistance are not fully understood although several underlying molecular events have been suggested. Recently, we identified autoantibodies reacting with membrane-associated ERα (anti-ERα Abs) in sera of breast cancer patients, able to promote tumor growth. Here, we investigated whether anti-ERα Abs purified from sera of ER-positive breast cancer patients could contribute to tamoxifen resistance. Anti-ERα Abs inhibited tamoxifen-mediated effects on cell cycle and proliferation in MCF-7 cells. Moreover, anti-ERα Abs hampered the tamoxifen-mediated reduction of tumor growth in SCID mice xenografted with breast tumor. Notably, simvastatin-mediated disaggregation of lipid rafts, where membrane-associated ERα is embedded, restored tamoxifen sensitivity, preventing anti-ERα Abs effects. In conclusion, detection of serum anti-ERα Abs may help predict tamoxifen resistance and concur to appropriately inform therapeutic decisions concerning hormone therapy in ER-positive breast cancer patients.


Asunto(s)
Antineoplásicos Hormonales/inmunología , Autoanticuerpos/sangre , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos/inmunología , Receptor alfa de Estrógeno/inmunología , Tamoxifeno/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos Hormonales/uso terapéutico , Femenino , Humanos , Células MCF-7 , Ratones , Ratones SCID , Persona de Mediana Edad , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Front Pharmacol ; 10: 47, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30745872

RESUMEN

Spondyloarthritis (SpA) and inflammatory bowel diseases (IBD) are chronic inflammatory diseases characterized by an aberrant immune response and inflammation with a key role for TNF in their pathogenesis. Accordingly, TNF-inhibiting therapy (TNFi) has dramatically improved the management of these diseases. However, about 30% of patients discontinue TNFi for lack of response, loss of response, and side effects and/or adverse events. Thus, the possibility to identify in advance those patients who will have a good response to TNFi would be extremely beneficial. The aim of this study was to investigate differences between males and females with either SpA or IBD in response to TNFi molecules, i.e., infliximab (IFX) and adalimumab (ADA), considering the reasons for TNFi withdraw. Data of 594 patients, 349 with IBD (M/F: 194/155) and 245 with SpA (M/F: 123/122), previously unexposed to TNFi, were collected. In the IBD group, the rate of female patients discontinuing ADA was significantly higher than that of male patients (p = 0.03). No difference emerged according to the distribution of reason for discontinuation. Otherwise, a similar discontinuation rate between female and male patients receiving IFX therapy was observed. In the SpA group, the overall discontinuation rate was not different between males and females both for ADA and IFX. However, in patients treated with ADA, males interrupted therapy more frequently than females due to lack of response (p = 0.03). In conclusion, the assessment of sex differences in TNFi response could help physicians personalize the therapeutic approach in a sex-oriented perspective.

15.
Front Immunol ; 9: 1903, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30174672

RESUMEN

Estrogens, in particular 17ß-estradiol (E2), have a strong influence on the immune system and also affect pathological conditions such as autoimmune diseases. The biological effects of E2 are mediated by two intracellular receptors, i.e., estrogen receptor (ER)α and ERß, which function as ligand-activated nuclear transcription factors producing genomic effects. Immune cells express both ERα and ERß that play a complex role in modulating inflammation. Phytoestrogens display estrogen-like effects. Among them, silibinin, the major active constituent of silymarin extracted by the milk thistle (Silybum marianum), has been suggested to have an ERß selective binding. Silibinin is known to have anti-inflammatory, hepatoprotective, and anticarcinogenic effects; however, the role of silibinin in modulating human immune responses and its impact on autoimmunity remains unclear. Aim of this study was to dissect the ability of the ERß natural ligand silibinin to modulate T cell immunity, taking into account possible differences between females and males, and to define its possible role as therapeutic tool in immune-mediated diseases. To this purpose, female and age-matched male healthy subjects and patients with active rheumatoid arthritis (RA) were recruited. We evaluated the ability of silibinin to modulate ERß expression in T lymphocytes and its effects on T cell functions (i.e., apoptosis, proliferation, and cytokine production). We also analyzed whether silibinin was able to modulate the expression of microRNA-155 (miR-155), which strongly contributes to the pathogenesis of RA driving aberrant activation of the immune system. We demonstrated that silibinin upregulated ERß expression, induced apoptosis, inhibited proliferation, and reduced expression of the pro-inflammatory cytokines IL-17 and TNF-α, through ERß binding, in T lymphocytes from female and male healthy donors. We obtained similar results in T lymphocytes from patients with active RA in term of apoptosis, proliferation, and cytokine production. In addition, we found that silibinin acted as an epigenetic modifier, down-modulating the expression of miR-155. In conclusion, our data demonstrated an immunosuppressive role of silibinin, supporting its application in the treatment of autoimmune diseases as drug, but also as dietary nutritional supplement, opening new perspective in the field of autoimmune disease management.


Asunto(s)
Artritis Reumatoide/etiología , Artritis Reumatoide/metabolismo , Receptor beta de Estrógeno/agonistas , Inmunomodulación/efectos de los fármacos , Inmunosupresores/farmacología , Silibina/farmacología , Anciano , Apoptosis/efectos de los fármacos , Artritis Reumatoide/patología , Proliferación Celular/efectos de los fármacos , Citocinas/metabolismo , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunidad , Inmunosupresores/uso terapéutico , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Masculino , MicroARNs/genética , Persona de Mediana Edad , Silibina/uso terapéutico , Linfocitos T/inmunología , Linfocitos T/metabolismo
16.
Arthritis Res Ther ; 19(1): 178, 2017 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-28743286

RESUMEN

BACKGROUND: Primary Sjögren's syndrome (pSS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands and peripheral lymphocyte perturbation. In the current study, we aimed to investigate the possible pathogenic implication of autophagy in T lymphocytes in patients with pSS. METHODS: Thirty consecutive pSS patients were recruited together with 20 patients affected by sicca syndrome and/or chronic sialoadenitis and 30 healthy controls. Disease activity and damage were evaluated according to SS disease activity index, EULAR SS disease activity index, and SS disease damage index. T lymphocytes were analyzed for the expression of autophagy-specific markers by biochemical, molecular, and histological assays in peripheral blood and labial gland biopsies. Serum interleukin (IL)-23 and IL-21 levels were quantified by enzyme-linked immunosorbent assay. RESULTS: Our study provides evidence for the first time that autophagy is upregulated in CD4+ T lymphocyte salivary glands from pSS patients. Furthermore, a statistically significant correlation was detected between lymphocyte autophagy levels, disease activity, and damage indexes. We also found a positive correlation between autophagy enhancement and the increased salivary gland expression of IL-21 and IL-23, providing a further link between innate and adaptive immune responses in pSS. CONCLUSIONS: These findings suggest that CD4+ T lymphocyte autophagy could play a key role in pSS pathogenesis. Additionally, our data highlight the potential exploitation of T cell autophagy as a biomarker of disease activity and provide new ground to verify the therapeutic implications of autophagy as an innovative drug target in pSS.


Asunto(s)
Linfocitos T CD4-Positivos/patología , Glándulas Salivales/inmunología , Glándulas Salivales/patología , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/patología , Adulto , Anciano , Autofagia/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Regulación hacia Arriba
17.
Front Immunol ; 8: 643, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28649243

RESUMEN

Visceral adipose tissue (VAT) is a main site where metabolic and immunologic processes interplay to regulate, at local and systemic level, the inflammatory status and immune response. Obesity-associated inflammation and immune dysfunctions are inextricably linked to tumor but, in spite of intense efforts, the mechanisms underpinning this association remain elusive. In this report, we characterized the profile of VAT-associated and circulating innate lymphocyte and regulatory T (Treg) cell subsets underlying inflammatory conditions, such as obesity and colorectal cancer (CRC). Analysis of NK, NKT-like, γδ T, and Treg cell populations in VAT and blood of healthy lean subjects revealed that CD56hi NK and OX40+ Treg cells are more abundant in VAT with respect to blood. Conversely, CD56dim NK and total Treg cells are most present in the circulation, while γδ T lymphocytes are uniformly distributed in the two compartments. Interestingly, a reduced frequency of circulating activated Treg cells, and a concomitant preferential enrichment of OX40-expressing Treg cells in VAT, were selectively observed in obese (Ob) subjects, and directly correlated with body mass index. Likewise, CRC patients were characterized by a specific enrichment of VAT-associated NKT-like cells. In addition, Ob and CRC-affected individuals shared a significant reduction of the Vγ9Vδ2/γδ T cell ratio at systemic level. The alterations in the relative proportions of Treg and NKT-like cells in VAT were found to correlate with the content of pro- and anti-inflammatory polyunsaturated fatty acids (PUFA), respectively. Overall, these results provide evidence for distinct alterations of the immune cell repertoire in the periphery with respect to the VAT microenvironment that uniquely characterize or are shared by different inflammatory conditions, such as obesity and CRC, and suggest that VAT PUFA composition may represent one of the factors that contribute to shape the immune phenotypes.

18.
Oncotarget ; 8(5): 8522-8535, 2017 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-28052027

RESUMEN

Although Hodgkin lymphoma (HL) is curable with current therapy, at least 20% of patients relapse or fail to make complete remission. In addition, patients who achieve long-term disease-free survival frequently undergo infertility, secondary malignancies, and cardiac failure, which are related to chemotherapeutic agents and radiation therapies. Hence, new therapeutic strategies able to counteract the HL disease in this important patient population are still a matter of study. Estrogens, in particular 17ß-estradiol (E2), have been suggested to play a role in lymphoma cell homeostasis by estrogen receptors (ER) ß activation. On these bases, we investigated whether the ligation of ERß by a selective agonist, the 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), could impact HL tumor growth. We found that DPN-mediated ERß activation led to a reduction of in vitro cell proliferation and cell cycle progression by inducing autophagy. In nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice engrafted with HL cells, ERß activation by DPN was able to reduce lymphoma growth up to 60% and this associated with the induction of tumor cell autophagy. Molecular characterization of ERß-induced autophagy revealed an overexpression of damage-regulated autophagy modulator 2 (DRAM2) molecule, whose role in autophagy modulation is still debated. After ERß activation, both DRAM2 and protein 1 light chain 3 (LC3), a key actor in the autophagosome formation, strictly interacted each other and localized at mitochondrial level.Altogether these results suggest that targeting ERß with selective agonists might affect HL cell proliferation and tumor growth via a mechanism that brings into play DRAM2-dependent autophagic cascade.


Asunto(s)
Autofagia/efectos de los fármacos , Receptor beta de Estrógeno/agonistas , Enfermedad de Hodgkin/tratamiento farmacológico , Nitrilos/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Regulación Neoplásica de la Expresión Génica , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/patología , Humanos , Ligandos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos NOD , Ratones SCID , Proteínas Asociadas a Microtúbulos/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Transfección , Ensayos Antitumor por Modelo de Xenoinjerto
19.
Ann Ist Super Sanita ; 52(2): 205-12, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27364395

RESUMEN

Autoimmune diseases are characterized by an exaggerated immune response leading to damage and dysfunction of specific or multiple organs and tissues. Most autoimmune diseases are more prevalent in women than in men. Symptom severity, disease course, response to therapy and overall survival may also differ between males and females with autoimmune diseases. Sex hormones have a crucial role in this sex bias, with estrogens being potent stimulators of autoimmunity and androgens playing a protective role. Accumulating evidence indicates that genetic, epigenetic and environmental factors may also contribute to sex-related differences in risk and clinical course of autoimmune diseases. In this review, we discuss possible mechanisms for sex specific differences in autoimmunity with a special focus on three paradigmatic diseases: systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.


Asunto(s)
Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/fisiopatología , Caracteres Sexuales , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/microbiología , Femenino , Hormonas Esteroides Gonadales , Humanos , Masculino , Microbiota , Factores Sexuales
20.
Oncoimmunology ; 5(2): e1074375, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27057440

RESUMEN

Estrogen receptors have recently been demonstrated at the cell surface. Unlike nuclear receptors, they are able to trigger rapid responses inside the cells. In this study, we evaluated the presence and the possible role of autoantibodies specific to estrogen receptor (anti-ER Abs) in the peripheral blood of breast cancer patients. Anti-ERα Abs were detectable in 22/48 (46%) patients' sera and their levels positively correlated with the percentage of Ki-67-positive breast cancer cells. Anti-ERα Abs purified from breast cancer patients' sera were able: (i) to recognize ERα epitopes expressed at the cell surface of ER-positive breast cancer cells, (ii) to trigger rapid extracellular signal-regulated kinase (ERK) phosphorylation, and (iii) to induce cell proliferation. Our results suggest that anti-ERα Abs can act as estrogen agonists playing a pathogenetic role as breast cancer-promoting factors. These autoantibodies could also be considered as possible peripheral blood biomarkers indicative of the breast cancer growth potential.

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