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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.
- Influence of the TAS2R38 gene single nucleotide polymorphisms in metabolism and anthropometry in thyroid dysfunctionPublication . Mendes Costa, Marta; Silva, Alda Pereira da; Santos, Ana Carolina; Ferreira, Joana; Mascarenhas, Mário Rui; Bicho, Manuel; Barbosa, AnaThe gene TAS2R38 single nucleotide polymorphisms (SNPs-P49A, A262V and V296I) can condition bitter tasting by PAV (proline–alanine–valine) and non-bitter-tasting by AVI (alanine–valine–isoleucine) homozygosity. We evaluated this polymorphisms association with thyroid function, metabolism and anthropometry parameters determined by: Endpoint analysis (SNPs); DXA (fat mass-%, total fat mass—kg, lean mass—kg); Standard methods (lipid metabolism parameters, HbA1c-%, glycemia—mg/dL, insulinemia—µIU/mL, HOMA-IR, uricemia—mg/dL, calcemia—mg/dL and BMI—kg/m2); ELISA (leptinemia—ng/mL); Spectrophotometry (Angiotensin Converting Enzyme activity—UI/L). Statistics: SPSS program; OR [IC95%]; p < 0.05. Sample: 114 hypothyroid, 49 hyperthyroid, and 179 controls. An association between A262V-valine–valine and hypothyroidism/hyperthyroidism was verified (OR = 2.841; IC95% [1.726–4.676]), p < 0.001/OR = 8.915; IC95% [4.286–18.543]), p < 0.001). Protector effect from thyroid dysfunction: A262V-alanine–valine (OR = 0.467; IC95% [0.289–0.757], p = 0.002/OR = 0.132; IC95% [0.056–0.309], p < 0.001) and PAV (OR = 0.456; IC95% [0.282–0.737], p = 0.001/OR = 0.101; IC95% [0.041–0.250], p < 0.001). Higher parameter values associated with genotypes were: fat-mass-% (V296I-valine–isoleucine), lean-mass (P49A-proline–proline; PVI), leptin (AVI), HbA1c (A262V-alanine–valine) and lower values in lean-Mass (AVI; PVV), leptin (A262V-alanine–alanine), HbA1c (PVV), uricemia (V296I-valine–isoleucine), glycemia (A262V-alanine–alanine; AAV) and plasma triglycerides (PVV). In conclusion, TAS2R38 influences thyroid function, body composition and metabolism. Bitter taste perception (PAV) and the genotype A262V-alanine–valine can protect from thyroid dysfunction. AVV, PVV and genotype A262V-valine–valine may confer higher predisposition for thyroid dysfunction, particularly PVV for hyperthyroidism.
- The contribution of precision nutrition intervention in subfertile couplesPublication . Monteiro, Jéssica; Bicho, Manuel; Valente, AnaBackground/aim: Subfertility is characterized by a decrease in reproductive efficiency, which can result in delayed pregnancy, and affects one in six individuals during their lifetime. The present narrative review aims to evaluate the contribution of precision nutrition to changes in fertility in subfertile couples. Methods: The literature review was carried out through bibliographic research in the PubMed, Scopus, SciELO and Google Scholar databases. The following search criteria were applied: (1) original articles and narrative, systematic or meta-analytic reviews, and (2) the individual or combined use of the following keywords: "genetic variation", "nutrigenetics", "precision nutrition", "couple's subfertility", and "couple's infertility". A preliminary reading of all the articles was carried out, and only those that best fit the themes and subthemes of the narrative review were selected. Results: Scientific evidence suggests that adherence to a healthy diet that follows the Mediterranean pattern is associated with increased fertility in women and improved semen quality in men, better metabolic health and reduced levels of inflammation and oxidative stress, as well as maintaining a healthy body weight. The integration of different tools, such as nutrigenetics, predictive biochemical analyses, intestinal microbiota tests and clinical nutrition software, used in precision nutrition interventions can contribute to providing information on how diet and genetics interact and how they can influence fertility. Conclusions: The adoption of a multidisciplinary and precision approach allows the design of dietary and lifestyle recommendations adapted to the specific characteristics and needs of couples with subfertility, thus optimizing reproductive health outcomes and achieving successful conception.
- Hepatitis C pretreatment profile and gender differences : cognition and disease severity effectsPublication . Pires Barreira, David; Marinho, Rui; Bicho, Manuel; Flores, Isabel; Fialho, Renata; Ouakinin, SílviaBackground: The hepatitis C virus (HCV) is known to infect the brain, however, the findings based on associated neuropsychiatric syndrome are controversial and the association itself remains unclear. Gender research in HCV infection is limited, failing to integrate the role of gender differences in neurocognitive syndrome. The aim of this study was to characterize psychological and neurocognitive profiles in HCV-infected patients before treatment and to explore gender differences in those profiles, as well as the impact of disease severity. Methods: A total of 86 patients diagnosed with chronic hepatitis C were included. Depression and anxiety were assessed using Hamilton anxiety scale (HAM-A), Hamilton depression scale (HAM-D), Beck Depression Inventory (BDI). For cognition, a neuropsychological battery to measure attention, concentration and memory was used, and executive function components validated for the Portuguese population was also used before starting treatment. To identify the disease severity, platelet ratio index, and FibroScan® were used. Results: A statistically significant gender effect was found on HAM-A (B = 0.64, CI: 0.17–1.11) and HAM-D (B = 0.62, CI: 0.14–1.09), with women scoring higher compared to men. Regarding neuropsychological scores, significant differences between gender were identified in executive functions measured by Trail Making Test (TMT B) (B = 0.48, CI: 0.02–0.97), TMT B-A (B = 0.26, CI: −39.2 to −3.7) and in digit span total (B = −0.52, CI: −1.0 to −0.04), with women performing worse than men. Controlling for years of substance dependence, TMT-B and TMT B-A showed significant gender differences. Regarding the presence or absence of substance dependence, only HAM-A and HAM-D remained significant. For categorical variables, Digit Span Total was also influenced by gender, with women being more likely to be impaired: odds ratio (OR) = 7.07, CI: 2.04–24.45), and a trend was observed for Digit Span Backward (OR = 3.57, CI: 1.31–9.75). No significant differences were found between disease severity and neurocognitive performance. Conclusion: Data suggest that gender has an influence on depression, anxiety and cognitive functions with women showing greater impairment compared with men. This effect seems to be influenced by substance dependence.
- Interaction between HFE and haptoglobin polymorphisms and its relation with plasma glutathione levels in obese childrenPublication . Aguiar, Laura; Marinho, Cláudia; Martins, Rute; Alho, Irina; Ferreira, Joana; Levy, Pilar Quinhones; Faustino, Paula; Bicho, Manuel; Inácio, AngelaObesity among children has emerged as a serious public health problem. The growing prevalence of childhood obesity has led to the appearance of serious complications, including a chronic systemic inflammation associated with oxidative stress. In the present study, we analysed the interaction between two genes related with iron metabolism - HFE and haptoglobin - and the plasmatic concentration of glutathione, as a way to evaluate the antioxidant response capacity in obesity. To achieve this, 118 obese children and 89 eutrophic children were recruited for the study. Results showed that although obese children present a significantly decreased tGSH levels, once we analysed separately children based on their haptoglobin phenotype, the decreased tGSH levels is significant only for the Hp 2 allele. Additionally, Hp 2.2 obese children carrying H63D polymorphism show significantly lower tGSH/GSSG values. Our results found an association of haptoglobin and HFE with oxidative stress in childhood obesity.
- Psychosocial and neurocognitive factors associated with Hepatitis C : implications for future health and wellbeingPublication . Barreira, David Pires; Marinho, Rui; Bicho, Manuel; Fialho, Renata; Ouakinin, Silvia Raquel SoaresBackground: Hepatitis C virus (HCV) infection involves changes not only from the point of view of physical health, but also emotional, and social that have a significant impact on the quality of life of these patients. According to the literature review, it seems that there is an important association between psychosocial factors, in particular on a cognitive level and disease progression. The aim of this mini-review is to summarize recent literature looking at the associations between psychosocial and neurocognitive factors and HCV. Methods: PubMed/Medline was systematically searched for psychosocial and neurocognitive factors associated with hepatitis C, treatment adherence, and patient wellbeing. Results: Patients present with a range of extrahepatic symptoms including fatigue, anxiety, depression, and neurocognitive dysfunction. HCV's impact on quality of life and wellbeing has serious clinical and social implications. Conclusion: Hepatitis C and its management continue to have a profound impact on health and psychologic wellbeing. Considering the serious extrahepatic implications for individuals, it is imperative that healthcare professionals pay close attention to psychosocial and neurocognitive factors. The focus on combined clinical approaches could enhance understanding about the health and social impacts of hepatitis C along the life course.
- Contribution of haptoglobin phenotypic variation to the presence of hyperhomocysteinemia in type 2 diabetics with and without angiopathyPublication . Ferreira, Isabel; Bicho, Manuel; Valente, AnaBackground/aim: The genetic polymorphism of haptoglobin (Hp) has been associated with several cardiovascular risk factors, but a possible relationship between Hp phenotypic variation and increased levels of homocysteine (Hcy) and cysteine (Cy) is still unknown. The objective of this study is to evaluate the relationship between the Hp polymorphism and hyperhomocysteinemia (HHcy) and hypercysteinemia (HCy) in type 2 diabetics (T2D) with and without angiopathy (AGP). Methods: A case-control study was carried out on 293 adults: Group I (GI) - 75 subjects with T2D and AGP; Group II (GII) - 75 subjects with T2D without AGP; Group III (GIII) - 143 controls. Plasma levels of Hcy, Cy and vitamin B6 were measured by high performance liquid chromatography (HPLC) and vitamins B9 and B12 determined by electrochemiluminescence (ECL). The Hp polymorphism was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and peroxidase staining. The results were analyzed in SPSS®, version 26.0 with a significance of 95%. Results: Mean Hcy concentrations were significantly lower in carriers of the Hp2-2 phenotype (6.14 µM; p = 0.046) compared to the other genotypes. The presence of Hp2-1 is associated with an approximately 3.3 times greater probability of occurrence of HHcy (p = 0.015) and 3.7 times greater probability occurrence of HCy (p = 0.021) in T2D with AGP. Conclusion: The presence of the Hp2-1 phenotype is associated with the predisposition of HHcy and HCy in individuals with T2D and AGP, possibly through a positive heterosis mechanism. Carriers of the Hp2-2 phenotype appear to have a greater activation of the transsulfuration pathway in the Hcy cycle and consequent protection for its accumulation.
- 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.
- ABCA1 polymorphism R1587K in chronic hepatitis C Is gender-specific and modulates liver disease severity through its influence on cholesterol metabolism and liver function: a preliminary studyPublication . Ferreira, Joana; Bicho, Manuel; Serejo, FátimaChronic hepatitis C (CHC) progression is highly variable and can be influenced by lipid metabolism. The ATP-binding cassette transporter A1 (ABCA1) is involved in lipid metabolism and mediates cholesterol efflux from liver cells. ABCA1 gene polymorphism rs2230808 (R1587K) modulates lipid levels as it is located in an ABCA1 protein domain, which is essential for cholesterol efflux. We aimed to analyze the role of ABCA1 polymorphism R1587K (rs2230808) in modulating the biochemical parameters of lipid metabolism and liver function and its association with liver disease severity, according to gender. A total of 161 CHC patients were clinically, histologically, and biochemically evaluated. Genotyping was performed by melting-curve analysis and statistical analysis by SPSS 24.0. There were significant differences between ABCA1_rs2230808 genotypes and total cholesterol, γGT (γ-glutamyl-transpeptidase), and HCV-RNA. Gender differences: in females, ABCA1_rs2230808 (GG or GA) was associated with higher HCV-RNA serum levels; in males, ABCA1_rs2230808 (GG or GA) was associated with higher γGT, lower total cholesterol, increased risk for γGT ≥ 38 UI/L, and total cholesterol < 4.92 mmol/L. Only in the case of males were higher γGT and lower total cholesterol associated with severe fibrosis and steatosis. Total cholesterol < 4.92 mmol/L also associates with severe necroinflammation. We conclude that ABCA1_rs2230808 is gender-specific. ABCA1_rs2230808 Allele G was associated with different clinical and biochemical parameters, which are related to more severe liver disease.
- Influence of functional variations in genes of neurotrophins and neurotransmitter systems on the development of retinopathy of prematurityPublication . Fevereiro-Martins, Mariza; Santos, Ana Carolina; Marques-Neves, Carlos; Guimarães, Hercília; Bicho, ManuelRetinal neurodevelopment, vascularization, homeostasis, and stress response are influenced by factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), and erythropoietin (EPO). As retinopathy of prematurity (ROP) is a neurovascular retinal disease, this study analyzed the contributions of NGF (rs6330), BDNF (rs7934165), TH (rs10770141), and EPO (rs507392) genetic functional polymorphisms to the modulation of hematological and biochemical parameters of the first week of life and their association with ROP development. A multicenter cohort of 396 preterm infants (gestational age < 32 weeks or birth weight < 1500 g) was genotyped using MicroChip DNA and iPlex MassARRAY® platform. Multivariate regression followed univariate assessment of ROP risk factors. NGF (GG) genotype was associated with a higher ROP risk (OR = 1.79), which increased further (OR = 2.38) when epistatic interactions with TH (allele C) and BDNF (allele G) were present. Significant circulating biomarker differences, including bilirubin, erythrocytes, monocytes, neutrophils, lymphocytes, and platelet markers, were found between ROP and non-ROP groups, with variations depending on the polymorphism. These findings suggest that NGF (rs6330) and its interactions with related genes contribute to ROP risk, providing valuable insights into the genetic and biological mechanisms underlying the disease and identifying potential predictive biomarkers.