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- Arginine and arginases modulate metabolism, tumor microenvironment and prostate cancer progressionPublication . Matos, Andreia; Carvalho, Marcos; Bicho, Manuel; Ribeiro, RicardoArginine availability and activation of arginine-related pathways at cancer sites have profound effects on the tumor microenvironment, far beyond their well-known role in the hepatic urea cycle. Arginine metabolism impacts not only malignant cells but also the surrounding immune cells behavior, modulating growth, survival, and immunosurveillance mechanisms, either through an arginase-mediated effect on polyamines and proline synthesis, or by the arginine/nitric oxide pathway in tumor cells, antitumor T-cells, myeloid-derived suppressor cells, and macrophages. This review presents evidence concerning the impact of arginine metabolism and arginase activity in the prostate cancer microenvironment, highlighting the recent advances in immunotherapy, which might be relevant for prostate cancer. Even though further research is required, arginine deprivation may represent a novel antimetabolite strategy for the treatment of arginine-dependent prostate cancer.
- Impact of combined training with different exercise intensities on inflammatory and lipid markers in type 2 diabetes : a secondary analysis from a 1-year randomized controlled trialPublication . Magalhães, João P.; Santos, Diana A.; Correia, Inês; Hetherington-Rauth, Megan; Ribeiro, Rogério; Raposo, João F.; Matos, Andreia; Bicho, Manuel; Sardinha, Luís B.Background: Exercise is a well-accepted strategy to improve lipid and infammatory profle in individuals with type 2 diabetes (T2DM). However, the exercise intensity having the most benefts on lipids and infammatory markers in patients with T2DM remains unclear. We aimed to analyse the impact of a 1-year combined high-intensity interval training (HIIT) with resistance training (RT), and a moderate continuous training (MCT) with RT on infammatory and lipid profle in individuals with T2DM. Methods: Individuals with T2DM (n=80, aged 59 years) performed a 1-year randomized controlled trial and were randomized into three groups (control, n=27; HIIT with RT, n=25; MCT with RT, n=28). Exercise sessions were super‑ vised with a frequency of 3 days per week. Infammatory and lipid profles were measured at baseline and at 1-year follow-up. Changes in infammatory and lipid markers were assessed using generalized estimating equations. Results: After adjusting for sex, age and baseline moderate-to-vigorous physical activity (MVPA), we observed a time-by-group interaction for Interleukin-6 (IL-6) in both the MCT with RT (β=−0.70, p=0.034) and HIIT with RT (β=−0.62, p=0.049) groups, whereas, only the HIIT with RT group improved total cholesterol (β=−0.03, p=0.045) and LDL-C (β=−0.03, p=0.034), when compared to control. No efect was observed for C-reactive protein (CRP), cortisol, tumour necrosis factor-α (TNF-α), soluble form of the haptoglobin-hemoglobin receptor CD163 (sCD163), triglycerides and HDL-C in both groups (p>0.05). Conclusions: Favorable adaptations on IL-6 were observed in both the HIIT and MCT combined with RT groups fol‑ lowing a long-term 1-year exercise intervention in individuals with T2DM. However, only the HIIT with RT prevented further derangement of total cholesterol and LDL-C, when compared to the control group. Therefore, in order to encourage exercise participation and improve infammatory profle, either exercise protocols may be prescribed, however, HIIT with RT may have further benefts on the lipid profle.
- Association of Aquaporin-3, Aquaporin-7, NOS3 and CYBA polymorphisms with hypertensive disorders in womenPublication . da Silva, Inês Vieira; Santos, Ana Carolina; Matos, Andreia; Silva, Alda Pereira da; Soveral, Graça; Rebelo, Irene; Bicho, ManuelPreeclampsia (PE), a pregnancy disorder influenced by oxidative stress and hypoxia, affects the health of the mother and baby and is associated with an increased risk of future hypertension (HT). Aquaporins are a family of water channels, comprising members that also transport glycerol (aquaglyceroporins) and hydrogen peroxide (peroxiporins), key molecules for metabolic homeostasis and redox signaling. Here, we investigated the association of Aquaporin-3 (AQP3; rs2231231), Aquaporin-7 (AQP7; rs2989924), NOS3 (4B/A intron) and CYBA (rs4673) genetic polymorphisms with the development of hypertensive disorders by qPCR/PCR in a cohort of 150 normotensive (NT) women (N = 90) or with previous PE (N = 60) during pregnancy. Prospectively, women were reclassified 2-16 years after pregnancy as NT (N = 98) or hypertensive (N = 48) and the genetic associations were reevaluated. In addition, genetic associations were reevaluated and compared between normotensive and hypertensive (HT) subjects. We found that AQP3 rs2231231, an aquaglyceroporin/peroxiporin, is associated with the development of HT, whereas AQP7, NOS3 and CYBA polymorphism did not correlate with PE or future HT. Because AQP3 was associated with hypertension only after pregnancy, its role might be related to later risk factors of hypertension such as metabolic syndrome or oxidative stress.
- Association of myeloperoxidase polymorphism (G463A) with cervix cancerPublication . Castelão, Cindy; Silva, Alda Pereira da; Matos, Andreia; Inácio, Ângela; Bicho, Manuel; Medeiros, Rui; Bicho, Maria ClaraCervical cancer is the fourth most common cancer affecting women worldwide, according to the latest IARC release with 528 000 new cases every year. Infection by high-risk human papillomavirus (HPV) is necessary but not sufficient for progression to cancer. Epithelial tissues, the target of HPV infection, are heavily exposed to reactive oxygen species (ROS). Hypochlorous acid (HOCl) is a very potent ROS, and it is produced by myeloperoxidase (MPO). MPO, a lysosomal enzyme expressed in polymorphonuclear neutrophils (PMN), has the potential to kill HPV transformed cells, as a component of an intercellular induced-apoptosis pathway. This enzyme catalyzes the production of HOCl in the presence of hydrogen peroxide (H2O2). The H2O2 produced by the Doderlein's bacillus will interact with MPO, contributing to the intercellular induced-apoptosis pathway. We studied a functional polymorphism in the promoter region of MPO (G463A) and how it may affect the risk of developing cervix cancer. A sample of 100 patients with invasive cervical cancer and 122 control women were genotyped for MPO polymorphism by PCR-RFLP method. The statistical method used was χ(2). We found that women with the GG genotype had lower risk for cervical cancer than the women who displayed the heterozygous genotype GA (OR = 0.546, 95 % CI = 0.315-0.939, p = 0.028, OR = 2.210, 95 % CI = 1.257-3.886, p = 0.008, respectively). The genotype that leads to a higher concentration of ROS (GG) presents itself as a protection factor in comparison to the homozygous genotype (AA). This can be explained by the interaction of HOCl and superoxide of transformed cells that will generate apoptosis-inducing hydroxyl radicals.
- Saúde ambiental : caderno de notas soltas IIIPublication . Santos, Ricardo; Santos, Osvaldo; Abreu, Ana; Caminha, Luís; Costa, Andreia; Sul, Susana; Nogueira, Paulo Jorge; Henriques, Adriana; Arriaga, Miguel; Câmara, Gisele; Alarcão, Violeta; Rodrigues, Fatima; Branquinho, Cátia Sofia dos Santos; Noronha, Catarina; Moraes, Bárbara; Gaspar, Tania; Matos, Margarida Gaspar de; Santos, David; Feteira-Santos, Rodrigo; Martins, Raquel; Capitão, Carolina; Barreto, Elias; Matos, Andreia; Bicho, Maria Clara; Bicho, Manuel; Candeias, Pedro; Virgolino, Ana; Várzea, Inês; Antunes, Francisco; Bárbara, Cristina; Mendes, Gabriel; Caneiras, Catia; Ramalho, João Francisco; Santos, Maria Leonor; Riso, Brígida; Sousa, IsabelaNa sua 3.ª edição, o Caderno de Notas Soltas pretende reunir diferentes perspetivas e metodologias, celebrando a sua razão de ser e a nobreza da sua génese intimamente ligada à realidade dos estudantes. Na verdade, passados três anos retomamos uma colaboração firmada desde a primeira hora com a Associação de Estudantes da Faculdade de Medicina de Lisboa (AEFML), num registo de proximidade da comunidade estudantil e dos interesses das gerações futuras.
- Genetic modulation of HPV infection and cervical lesions: role of oxidative stress-related genesPublication . Inácio, Angela; Aguiar, Laura; Rodrigues, Beatriz; Pires, Patrícia; Ferreira, Joana; Matos, Andreia; Mendonça, Inês; Rosa, Raquel; Bicho, Manuel; Medeiros, Rui; Bicho, Maria ClaraHuman papillomavirus (HPV) infection is a necessary but not sufficient factor for the development of invasive cervical cancer (ICC) and high-grade intraepithelial lesion (HSIL). Oxidative stress is known to play a crucial role in HPV infection and carcinogenesis. In this study, we comprehensively investigate the modulation of HPV infection, HSIL and ICC, and ICC through an exploration of oxidative stress-related genes: CβS, MTHFR, NOS3, ACE1, CYBA, HAP, ACP1, GSTT1, GSTM1, and CYP1A1. Notably, the ACE1 gene emerges as a prominent factor with the presence of the I allele offering protection against HPV infection. The association of NOS3 with HPV infection is perceived with the 4a allele showing a protective effect. The presence of the GSTT1 null mutant correlates with increased susceptibility to HPV infection, HSIL and ICC, and ICC. This study also uncovers intriguing epistatic interactions among some of the genes that further accentuate their roles in disease modulation. Indeed, the epistatic interactions between the BB genotype (ACP1) and DD genotype (ECA1) were shown to increase the risk of HPV infection, and the interaction between BB (ACP1) and 0.0 (GSTT1) was associated with HPV infection and cervical lesions. These findings underscore the pivotal role of four oxidative stress-related genes in HPV-associated cervical lesions and cancer development, enriching our clinical understanding of the genetic influences on disease manifestation. The awareness of these genetic variations holds potential clinical implications.
- Mountain cycling ultramarathon effects on inflammatory and hemoglobin responsesPublication . Alonso, Isanete; Matos, Andreia; Ribeiro, Ricardo; Gil, Ângela; Cardoso, Carlos; Sardinho, Luís B.; Bicho, ManuelPurpose: This study aimed to analyze the cumulative physiological burden of repetitive, strenuous exercise held during mountain cycling ultramarathon on regulatory mechanisms of hemoglobin degradation. Methods: Fifty-five nonprofessional athletes (mean age, 44.8 T 7.1 yr) participating in a 9-consecutive-day mountain cycling ultramarathon (TransPortugal) underwent anthropometric, hematological, and biochemical assessments before and immediately after the race. Participants were further stratified as completers (nine courses) or noncompleters and were divided according to the time they took to complete the race. The heme oxygenase-1 (HMOX1) functional genetic polymorphism and haptoglobin (HP) phenotypic variants were also analyzed. Results: Total leukocytes, neutrophil count, and monocyte count increased, whereas decreases in erythrocyte counts and hemoglobin were found between pre- and postultramarathon. Circulating haptoglobin (Hp) was increased, whereas its soluble receptor (sCD163) decreased. Athletes who completed all nine courses presented with increased leukocyte, neutrophil, and erythrocyte counts, as well as hemoglobin, red cell distribution width, total bilirubin, and total cholesterol levels. High-sensitivity C-reactive protein and Hp decreased in comparison with noncompleters. HMOX1 and HP genetic polymorphisms were associated with biochemical profile, notably with Hp levels. Analysis of covariance showed a significant effect of HP phenotype in Hp circulating levels at the end of race and on the magnitude of variation from pre- to postrace. Conclusions: Present findings support a comodulatory influence of genetic- and exercise-associated factors on resulting inflammatory and hemoglobin catabolic marker Hp after highly demanding endurance exercise.
- The interplay between HPV, other sexually transmissible infections and genital microbiome on cervical microenvironment (MicroCervixHPV study)Publication . Gonçalves Nobre, José Guilherme; Matos, Andreia; Carreira, Mariana; Santos, Ana Carolina; Veiga, Luisa Carvalho; Ginete, Catarina; Brito, Miguel; Pires, Marina; Pereira, Hermínia; Cardoso, Carlos; Bicho, Manuel; Bicho, Maria ClaraBackground: The importance of Cervicovaginal Microbiota in protecting against infections (such as HPV) is already well established, namely through Lactobacillus spp., as well as the mechanism through which HPV leads to Cervical Neoplasia. However, it is not possible to classify HPV as a complete carcinogen. Thus, the importance of exploring Cervicovaginal dysbiosis with the intention of deciphering this interaction with HPV, takes on greater relevance. The main objectives of this study were: 1) Comparison of the MCV composition of women with or without HPV and women with ASCUS or LSIL; 2) Characterization of cytokines present in the vaginal microenvironment; 3) Evaluation of the blood count ratios as prognostic systemic inflammatory biomarkers; 4) Correlation between MCV, HPV serotypes and cytokines. Methods: This was a retrospective, observational, multicenter, cross-sectional study. CVM analysis was performed by isolation RNA and sequencing on a NGS platform. Cytokine concentrations of CVM were obtained through Multiplex platform. Statistical analysis was performed in SPSS v 26.0. An α of 0.05 was considered statistically significant. Results: Highlighting the core of the study, CVM types of CST I and CST IV were found to influence the emergence of cervical lesions. Neutrophil-to-Lymphocyte ratio was found to impact the prognosis of ASCUS. Within CVM, Lactobacillus prevent the growth of other CST IV species, while the latter express symbiotic relationships with each other and show affinity for specific HPV serotypes. At last, RANTES chemokine is significantly elevated in cervicovaginal infections. Conclusion: The importance of using vaginal cytokine profiles and CVM is highlighted in the hypothesis of prevention of Cervical Neoplasia development, as well as in its use as a prognostic biomarker. Taken together, these insights are one step closer to personalized medicine.