Pedro Rodrigues

University of Porto, Oporto, Porto, Portugal

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Publications (43)147.48 Total impact

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    ABSTRACT: Mycobacterium avium causes respiratory disease in susceptible individuals, as well as disseminated infections in immunocompromised hosts, being an important cause of morbidity and mortality among these populations. Current therapies consist of a combination of antibiotics taken for at least six months, with no more than 60% overall clinical success. Furthermore, mycobacterial antibiotic resistance is increasing worldwide, urging the need to develop novel classes of antimicrobial drugs. One potential and interesting alternative strategy is the use of antimicrobial peptides (AMP). These are present in almost all living organisms as part of their immune system, acting as a first barrier against invading pathogens. In this context, we investigated the effect of several lactoferrin-derived AMP against M. avium. Short peptide sequences from both human and bovine lactoferricins, namely hLFcin1-11 and LFcin17-30, as well as variants obtained by specific amino acid substitutions, were evaluated. All tested peptides significantly inhibited the axenic growth of M. avium, the bovine peptides being more active than the human. Arginine residues were found to be crucial for the display of antimycobacterial activity, whereas the all-D amino acid analogue of the bovine sequence displayed the highest mycobactericidal activity. These findings reveal the promising potential of lactoferricins against mycobacteria, thus opening the way for further research on their development and use as a new weapon against mycobacterial infections.
    Antimicrobial Agents and Chemotherapy 04/2014; 58(6). DOI:10.1128/AAC.02728-13 · 4.45 Impact Factor
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    ABSTRACT: Important for both host and pathogen survivals, iron is a key factor in determining the outcome of an infectious process. Iron with-holding, including sequestration inside tissue macrophages, is considered an important strategy to fight infection. However, for intra-macrophagic pathogens, such as Mycobacterium avium, host defence may depend on intracellular iron sequestration mechanisms. Ferritin, the major intracellular iron storage protein, plays a critical role in this process. In the current study, we studied ferritin expression in mouse bone marrow-derived macrophages upon infection with M. avium. We found that H-ferritin is selectively increased in infected macrophages, through an up-regulation of gene transcription. This increase was mediated by the engagement of Toll like receptor-2, and was independent of TNF-alpha or nitric oxide production. The formation of H-rich ferritin proteins and the consequent iron sequestration may be an important part of the panoply of antimicrobial mechanisms of macrophages.
    PLoS ONE 12/2013; 8(12):e82874. DOI:10.1371/journal.pone.0082874 · 3.53 Impact Factor
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    ABSTRACT: The liver, being the major site of iron storage, is particularly exposed to the toxic effects of iron. Transcription factor NRF2 is critical for protecting the liver against disease by activating the transcription of genes encoding detoxification/antioxidant enzymes. We aimed to determine if the NRF2 pathway plays a significant role in the protection against hepatic iron overload. Wild-type and Nrf2(-/-) mouse primary hepatocytes were incubated with ferric ammonium citrate. Wild-type and Nrf2(-/-) mice were fed standard rodent chow or iron-rich diet for 2 weeks, with or without daily injection of the antioxidant mito-TEMPOL. In mouse hepatocytes, iron induced the nuclear translocation of NRF2 and the expression of cytoprotective genes in an NRF2-dependent manner. Moreover, Nrf2(-/-) hepatocytes were highly susceptible to iron-induced cell death. Wild-type and Nrf2(-/-) mice fed iron-rich diet accumulated similar amounts of iron in the liver and were equally able to increase the expression of hepatic hepcidin and ferritin. Nevertheless, in Nrf2-null mice the iron loading resulted in progressive liver injury, ranging from mild confluent necrosis to severe necroinflammatory lesions. Hepatocytic cell death was associated with gross ultrastructural damage to the mitochondria. Notably, liver injury was prevented in iron-fed animals that received mito-TEMPOL. NRF2 protects the mouse liver against the toxicity of dietary iron overload by preventing hepatocytic cell death. We identify NRF2 as a potential modifier of liver disease in iron overload pathology and show the beneficial effect of the antioxidant mito-TEMPOL in a mouse model of dietary iron-induced liver injury.
    Journal of Hepatology 09/2013; 60(2). DOI:10.1016/j.jhep.2013.09.004 · 10.40 Impact Factor
  • J.V. Neves, C.C. Caldas, P.N.S. Rodrigues
    Fish &amp Shellfish Immunology 06/2013; 34(6):1668. DOI:10.1016/j.fsi.2013.03.106 · 3.03 Impact Factor
  • Joao Neves, Pedro Rodrigues
    American Journal of Hematology 05/2013; 88(5):E149-E149. · 3.48 Impact Factor
  • American Journal of Hematology 05/2013; 88(5):E222-E222. · 3.48 Impact Factor
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    Fish Pathology 01/2012; 47(2):80-82. · 0.88 Impact Factor
  • J V Neves, C Caldas, J M Wilson, P N S Rodrigues
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    ABSTRACT: Hepcidin, an antimicrobial peptide described as a key regulator of iron metabolism, is known to respond in mammals to several stimuli, including iron overload, anemia, hypoxia and inflammation, through a number of molecular pathways. In order to understand the molecular pathways involved in the regulation of hepcidin expression in teleost fish, we have isolated for European sea bass (Dicentrarchus labrax) several coding sequences of known molecules involved on these pathways in mammals, namely jak3, stat3, tmprss6, bmp6, bmpr2, hjv, smad4, smad5, tfr1 and tfr2. The transcription levels of the isolated genes were evaluated by real-time PCR on fish subjected to experimental iron modulation (overload/deficiency) or infection with Photobacterium damsela. Results show that genes associated with the major pathway of the inflammatory response (IL6/JAK/STAT pathway) in mammals are also modulated in sea bass, being up-regulated during infection. Similarly, genes of the pathways classically associated with the response to variations in iron status (the HJV/BMP/SMAD and HFE/TfR pathways) are also modulated, mostly through down-regulation in iron deficiency and up-regulation during iron overload. Interestingly, many of these genes are also found to be up-regulated during infection, which may indicate a crosstalk between the known pathways of hepcidin regulation. These observations suggest the evolutionary conservation of the mechanisms of hepcidin regulation in teleost fish.
    Fish &amp Shellfish Immunology 12/2011; 31(6):1154-61. DOI:10.1016/j.fsi.2011.10.006 · 3.03 Impact Factor
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    ABSTRACT: Ammonia is a toxic by-product of amino acid catabolism and a common environmental pollutant that has been associated with increased disease susceptibility in fish although the mechanism is not well understood. We addressed the hypothesis that elevated environmental ammonia acts by impairing the acute phase response (APR). Specifically, we determined the impact of sub-lethal acute (24 h) and chronic (14 d) ammonia exposure on acute phase protein gene expression in zebrafish (Danio rerio) in response to a challenge with bacterial lipopolysaccharide (LPS: i.p. 10 μg/g after 24h). A panel of LPS-responsive genes (SAA, HAMP, LECT2, Hp and IL1β) were identified and evaluated by real-time quantitative PCR. Ammonia was found to impair induction of SAA, HAMP and LECT2 by 50-90%. Both short (15 min, 1h and 24h) and long-term (14 days) exposure to high environmental ammonia concentrations significantly elevated whole-body cortisol levels compared with control fish. Our results reveal for the first time that exposure to high environmental levels of ammonia suppresses the innate immune response in fish. We hypothesize that high environmental ammonia-mediated elevation of cortisol levels in zebrafish may be playing a key role in this immunosuppression, while the mechanisms involved remains to be elucidated.
    Developmental and comparative immunology 05/2011; 36(2):279-88. DOI:10.1016/j.dci.2011.04.008 · 3.71 Impact Factor
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    ABSTRACT: Anaemia is a frequent complication of chronic infectious diseases but the exact mechanisms by which it develops remain to be clarified. In the present work, we used a mouse model of mycobacterial infection to study molecular alterations of iron metabolism induced by infection. We show that four weeks after infection with Mycobacterium avium BALB/c mice exhibited a moderate anaemia, which was not accompanied by an increase on hepatic hepcidin mRNA expression. Instead, infected mice presented increased mRNA expression of ferroportin (Slc40a1), ceruloplasmin (Cp), hemopexin (Hpx), heme-oxygenase-1 (Hmox1) and lipocalin-2 (Lcn2). Both the anaemia and the mRNA expression changes of iron-related genes were largely absent in C.D2 mice which bear a functional allele of the Nramp1 gene. Data presented in this work suggest that anaemia due to a chronic mycobacterial infection may develop in the absence of elevated hepcidin expression, is influenced by Nramp1 and may involve lipocalin-2.
    Immunobiology 04/2011; 216(10):1127-34. DOI:10.1016/j.imbio.2011.04.004 · 3.18 Impact Factor
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    ABSTRACT: The SLC11A1/Nramp1 and SLC11A2/Nramp2 genes belong to the SLC11/Nramp family of transmembrane divalent metal transporters, with SLC11A1 being associated with resistance to pathogens and SLC11A2 involved in intestinal iron uptake and transferrin-bound iron transport. Both members of the SLC11 gene family have been clearly identified in tetrapods; however SLC11A1 has never been documented in teleost fish and is believed to have been lost in this lineage during early vertebrate evolution. In the present work we characterized the SLC11 genes in teleosts and evaluated if the roles attributed to mammalian SLC11 genes are assured by other fish specific SLC11 gene members. Two different SLC11 genes were isolated in the European sea bass (Dicentrarchus. labrax), and named slc11a2-α and slc11a2-β, since both were found to be evolutionary closer to tetrapods SLC11A2, through phylogenetic analysis and comparative genomics. Induction of slc11a2-α and slc11a2-β in sea bass, upon iron modulation or exposure to Photobacterium damselae spp. piscicida, was evaluated in in vivo or in vitro experimental models. Overall, slc11a2-α was found to respond only to iron deficiency in the intestine, whereas slc11a2-β was found to respond to iron overload and bacterial infection in several tissues and also in the leukocytes. Our data suggests that despite the absence of slc11a1, its functions have been undertaken by one of the slc11a2 duplicated paralogs in teleost fish in a case of synfunctionalization, being involved in both iron metabolism and response to bacterial infection. This study provides, to our knowledge, the first example of this type of sub-functionalization in iron metabolism genes, illustrating how conserving the various functions of the SLC11 gene family is of crucial evolutionary importance.
    BMC Evolutionary Biology 04/2011; 11:106. DOI:10.1186/1471-2148-11-106 · 3.41 Impact Factor
  • J.V. Neves, I.A.S. Olsson, G. Porto, P.N. Rodrigues
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    ABSTRACT: Export Date: 18 November 2011, Source: Scopus
  • João V Neves, Jonathan M Wilson, Pedro N S Rodrigues
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    ABSTRACT: Iron is essential for growth and survival, but it is also toxic when in excess. Thus, there is a tight regulation of iron that is accomplished by the interaction of several genes including the iron transporter transferrin and iron storage protein ferritin. These genes are also known to be involved in response to infection. The aim of this study was to understand the role of transferrin and ferritin in infection and iron metabolism in fish. Thus, sea bass transferrin and ferritin H cDNAs were isolated from liver, cloned and characterized. Transferrin constitutive expression was found to be highest in the liver, but also with significant expression in the brain, particularly in the highly vascularized region connecting the inferior lobe of the hypothalamus and the saccus vasculosus. Ferritin, on the other hand, was expressed in all tested organs, but also significantly higher in the liver. Fish were subjected to either experimental bacterial infection or iron modulation and transferrin and ferritin mRNA expression levels were analyzed, along with several iron regulatory parameters. Transferrin expression was found to decrease in the liver and increase in the brain in response to infection and to increase in the liver in iron deficiency. Ferritin expression was found to inversely reflect transferrin in the liver, increasing in infection and iron overload and decreasing in iron deficiency, whereas in the brain, ferritin expression was also increased in infection. These findings demonstrate the evolutionary conservation of transferrin and ferritin dual functions in vertebrates, being involved in both the immune response and iron metabolism.
    Developmental and comparative immunology 08/2009; 33(7):848-57. DOI:10.1016/j.dci.2009.02.001 · 3.71 Impact Factor
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    ABSTRACT: PPAR isotypes have been previously identified in the teleost brown trout (Salmo trutta f. fario) and their organ distribution pattern established. Being that the liver is a vital metabolic organ presenting expression of all isotypes and also knowing that estrogens/estrogen receptors seem to interact with PPARs, we hypothesized that the latter may very well change seasonally. So, we studied the expression of these receptors in the liver, along the annual reproductive cycle and in both genders. According to real-time RT-PCR, PPARalpha mRNA expression in females was significantly higher in May and lower in September than in other seasons. No significant variation was observed along the year in males. A significant difference between genders occurred in May, when PPARalpha expression was higher for females. PPARbeta expression showed little variation along the reproductive cycle in females, but in males it was significantly higher in December than in the other seasons. No significant differences existed between genders. PPARgamma was more expressed in February than in September and December, for females. As to males, it was more expressed in February than in all other seasons. No significant differences were observed between genders. The study proved our hypothesis that PPARs gene expression varies along the year. Moreover, PPARalpha expression in females followed the same annual variation pattern as peroxisome volumes and enzyme activities, and an inverse pattern relatively to the salmonid type annual plasma estradiol levels. The data agrees with the idea that PPARalpha is under estradiol modulation and that cross-talk between this receptor and the estrogen receptor possibly exists.
    General and Comparative Endocrinology 03/2009; 161(1):146-52. DOI:10.1016/j.ygcen.2008.11.019 · 2.67 Impact Factor
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    ABSTRACT: Mice expressing a vav-bcl-2 transgene were tested for their resistance to an experimental infection with Mycobacterium avium. When compared with control littermates, transgenic mice exhibited an increase in the resistance to infection which was independent of B or T lymphocytes and did not require the production of gamma interferon. Macrophages from both control and transgenic mice showed equal permissiveness to M. avium growth in vitro. Finally, transgenic mice expressed diminished circulating iron levels which correlated with the increased resistance to infection.
    Clinical & Experimental Immunology 02/2009; 156(1):61-8. DOI:10.1111/j.1365-2249.2008.03867.x · 3.28 Impact Factor
  • International Journal of Antimicrobial Agents 03/2007; 29. DOI:10.1016/S0924-8579(07)71579-0 · 4.26 Impact Factor
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    ABSTRACT: Hepatic iron overload in hemochomatosis patients can be highly variable but in general it develops in older patients. The purpose of this study was to compare development of iron load in of beta2m-/- and Hfe-/- mice paying special attention to liver pathology in older age groups. Liver iron content of beta2m-/-, Hfe-/- and control B6 mice of different ages (varying from 3 weeks to 18 months) was examined. Additional parameters (haematology indices, histopathology, lipid content and ferritin expression) were also studied in 18-month-old mice. The beta2m-/- strain presents higher hepatic iron content, hepatocyte nuclear iron inclusions, mitochondria abnormalities. In addition, hepatic steatosis was a common observation in this strain. In the liver of Hfe-/- mice, large mononuclear infiltrates positive for ferritin staining were commonly observed. The steatosis commonly observed the beta2m-/- mice may be a reflection of its higher hepatic iron content. The large hepatic mononuclear cell infiltrates seen in Hfe-/- stained for ferritin, may point to the iron sequestration capacity of lymphocytes and contribute to the clarification of the differences found in the progression of hepatic iron overload and steatosis in older animals from the two strains.
    International Journal of Experimental Pathology 09/2006; 87(4):317-24. DOI:10.1111/j.1365-2613.2006.00491.x · 2.05 Impact Factor
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    ABSTRACT: Background: Despite heavy alcohol consumption, only a low percentage of heavy drinkers develop liver disease. Imbalances in T-cell subsets and iron metabolism parameters are common findings in heavy drinkers, yet the possible role played by discrete T-lymphocyte subsets under heavy alcohol consumption remains unclear.Methods: To gain new insights into the possible role played by T lymphocytes during alcohol consumption, characterization of CD28 expression and TcR repertoire in peripheral blood CD4+ and CD8+ T cells by two and three-color flow cytometry was performed. A group of heavy alcohol drinkers (AHD, n= 71) and a group of age-matched controls (n= 81), both HLA-phenotyped and HFE-genotyped, constituted the groups under study.Results: Marked expansions of CD28− T cells within the CD8+ but not the CD4+ T-cell pool were observed in AHD compared with controls. These CD8+CD28− expansions were paralleled by expansions of CD8+ T cells bearing specific TcR Vα/β chains, namely Vβ5.2. Moreover, AHD, but not controls, carrying the H63D mutation in the HFE gene showed significantly higher percentages of CD28− T cells within the CD8+ T-cell pool than AHD carrying the normal HFE gene. Finally, high numbers of CD8+CD28− T cells in AHD were associated with lower levels of the liver-related enzymes ALT and GGT.Conclusions: This study showed that under active ethanol consumption, expansions of discrete CD8+ T-cell subsets occur within the CD8+ T-cell pool, that molecules of the MHC-class I locus seem to influence the extent of the expansions, and that high numbers of CD8+CD28− T cells are associated with low levels of liver enzymes in AHD.
    Alcoholism Clinical and Experimental Research 04/2006; 24(4):519 - 527. DOI:10.1111/j.1530-0277.2000.tb02020.x · 3.31 Impact Factor
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    ABSTRACT: The role of hepcidin in iron metabolism regulation and bacterial infection has been the focus of recent attention. However, in spite of the growing number of hepcidin genes known from different organisms, little is known about its putative dual function in fish. The aim of this study was to characterize the sea bass hepcidin gene and to study its role in iron metabolism and infection. The novel sea bass hepcidin gene was found to be organized into two introns and three exons with several copies present in the genome. The transcript showed a constitutive low basal expression being mainly expressed in liver and encoding a putative 85 residues long peptide. Fish were submitted either to iron status modulation or bacterial infection and the hepcidin transcript levels were analysed along with a number of other parameters. Liver hepcidin expression was found to increase in both the iron-overloaded and infected fish, while in the iron-deficient fish no alteration in expression levels was detected. These results point to the evolutionary conservation of hepcidin's dual functions.
    Developmental & Comparative Immunology 02/2006; 30(12):1156-67. DOI:10.1016/j.dci.2006.02.005 · 3.71 Impact Factor
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    ABSTRACT: Although widely studied in mammals, little information about fish peroxisome proliferator activated receptors (PPARs) is yet available. As a baseline for future studies, the three PPAR isotypes were identified in brown trout (Salmo trutta f. fario) and their organ distribution pattern was established. The cDNA fragments encoding PPARs alpha, beta and gamma were amplified by PCR, and the deduced sequences of the correspondent peptides were compared with other species sequences. Both the 183 amino acid sequence from PPARalpha and the 103 amino acid sequence from PPARbeta shared high levels of homology with the correspondent peptides of other fishes and terrestrial vertebrates, whereas PPARgamma 108 amino acid sequence showed much less similarity with non-fish PPARgamma. According to both semi-quantitative RT-PCR and real-time RT-PCR, PPARalpha mRNA predominates in white muscle, heart and liver and PPARbeta is more expressed in testis, heart, liver, white muscle and trunk kidney. PPARgamma was only detected in trunk kidney and liver by real-time RT-PCR and also in spleen by semi-quantitative RT-PCR. PPARbeta seems to be the most strongly expressed isotype, whereas PPARgamma shows a much weaker global expression.
    Biochimica et Biophysica Acta 12/2005; 1731(2):88-94. DOI:10.1016/j.bbaexp.2005.09.001 · 4.66 Impact Factor

Publication Stats

494 Citations
147.48 Total Impact Points

Institutions

  • 2005–2014
    • University of Porto
      • • Institute for Molecular and Cell Biology
      • • Instituto de Ciências Biomédicas Abel Salazar (ICBAS)
      Oporto, Porto, Portugal
  • 2000–2011
    • Institute for Molecular and Cell Biology
      Oporto, Porto, Portugal
  • 2004
    • Instituto de Ciencias
      Santa Clara de Portugal, Michoacán, Mexico