Percorrer por autor "Vale, Nuno"
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- Cell Model of Depression: Reduction of Cell Stress with MirtazapinePublication . Correia, Ana Salomé; Fraga, Sónia; Teixeira, João Paulo; Vale, NunoDepression is a very prevalent and complex disease. This condition is associated with a high rate of relapse, making its treatment a challenge. Thus, an intensive investigation of this disease and its treatment is necessary. In this work, through cell viability assays (MTT and neutral red assays) and alkaline comet assays, we aimed to test the induction of stress in human SH-SY5Y cells through the application of hydrocortisone and hydrogen peroxide and to test the reversal or attenuation of this stress through the application of mirtazapine to the cells. Our results demonstrated that hydrogen peroxide, and not hydrocortisone, can induce cellular stress, as evidenced by DNA damage and a global cellular viability reduction, which were alleviated by the antidepressant mirtazapine. The establishment of a cellular model of depression through stress induction is important to study new possibilities of treatment of this disease using cell cultures.
- Chlamydial and Gonococcal Genital Infections: A Narrative ReviewPublication . Rodrigues, Rafaela; Vieira-Baptista, Pedro; Catalão, Carlos; Borrego, Maria José; Sousa, Carlos; Vale, NunoSexually transmitted infections (STIs) constitute one of the leading causes of disease burden worldwide, leading to considerable morbidity, mortality, health expenditures, and stigma. Of note are the most common bacterial STIs, chlamydial and gonococcal infections, whose etiological agents are Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG), respectively. Despite being usually asymptomatic, in some cases these infections can be associated with long-term severe complications, such as pelvic inflammatory disease, chronic pelvic pain, infertility, ectopic pregnancy, and increased risk of other STIs acquisition. As the symptoms, when present, are usually similar in both infections, and in most of the cases these infections co-occur, the dual-test strategy, searching for both pathogens, should be preferred. In line with this, herein we focus on the main aspects of CT and NG infections, the clinical symptoms as well as the appropriate state-of-the-art diagnostic tests and treatment. Cost-effective strategies for controlling CT and NG infections worldwide are addressed. The treatment for both infections is based on antibiotics. However, the continuing global rise in the incidence of these infections, concomitantly with the increased risk of antibiotics resistance, leads to difficulties in their control, particularly in the case of NG infections. We also discuss the potential mechanism of tumorigenesis related to CT infections. The molecular bases of CT and NG infections are addressed, as they should provide clues for control or eradication, through the development of new drugs and/or effective vaccines against these pathogens.
- Combination anthelmintic/antioxidant activity against Schistosoma MansoniPublication . Gouveia, Maria João; Brindley, Paul J.; Rinaldi, Gabriel; Gärtner, Fátima; da Costa, José Manuel Correia; Vale, NunoSchistosomiasis is a major neglected tropical disease. Treatment for schistosomiasis with praziquantel (PZQ), which is effective against the parasite, by itself is not capable to counteract infection-associated disease lesions including hepatic fibrosis. There is a pressing need for novel therapies. Due to their biological properties, antioxidant biomolecules might be useful in treating and reverting associated pathological sequelae. Here, we investigated a novel therapy approach based on a combination of anthelmintic drugs with antioxidant biomolecules. We used a host-parasite model involving Bioamphalaria glabrata and newly transformed schistosomula (NTS) of Schistosoma mansoni. For in vitro drug screening assays, was selected several antioxidants and evaluated not only antischistosomal activity but also ability to enhance activity of the anthelmintic drugs praziquantel (PZQ) and artesunate (AS). The morphological alterations induced by compounds alone/combined were assessed on daily basis using an inverted and automated microscope to quantify NTS viability by a fluorometric-based method. The findings indicated that not only do some antioxidants improve antischistosomal activity of the two anthelmintics, but they exhibit activity per se, leading to high mortality of NTS post-exposure. The combination index (CI) of PZQ + Mel (CI = 0.80), PZQ + Resv (CI = 0.74), AS + Resv (CI = 0.34), AS + NAC (CI = 0.89), VDT + Flav (CI = 1.03) and VDT + Resv (CI = 1.06) reveal that they display moderate to strong synergism. The combination of compounds with discrete mechanisms of action might provide a valuable adjunct to contribution for treatment of schistosomiasis-associated disease.
- Drug Repurposing for Schistosomiasis: Combinations of Drugs or BiomoleculesPublication . Gouveia, Maria; Brindley, Paul; Gärtner, Fátima; Costa, José; Vale, NunoSchistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated with infection. Moreover, due to the development of the potential emergence of PZQ-resistant strains, the search for additional or alternative antischistosomal drugs have become a public health priority. The current drug discovery for schistosomiasis has been slow and uninspiring. By contrast, repurposing of existing approved drugs may offer a safe, rapid and cost-effective alternative. Combined treatment with PZQ and other drugs with different mode of action, i.e., antimalarials, shows promise results. In addition, a combination of anthelminthic drugs with antioxidant might be advantageous for modulating oxidative processes associated with schistosomiasis. Herein, we review studies dealing with combination therapies that involve PZQ and other anthelminthic drugs and/or antioxidant agents in treatment of schistosomiasis. Whereas PZQ combined with antioxidant agents might or might not interfere with anthelminthic efficacy, combinations may nonetheless ameliorate tissue damage and infection-associated complications. In fact, alone or combine with other drugs, antioxidants might be a valuable adjuvant to reduce morbidity and mortality of schistosomiasis. Therefore, attempting new combinations of anthelmintic drugs with other biomolecules such as antioxidants provides new avenues for discovery of alternatives to PZQ.
- Infection with carcinogenic helminth parasites and its production of metabolites induces the formation of DNA-adductsPublication . Gouveia, Maria João; Brindley, Paul J.; Rinaldi, Gabriel; Gärtner, Fátima; da Costa, José M.C.; Vale, NunoBackground: Infections classified as group 1 biological carcinogens include the helminthiases caused by Schistosoma haematobium and Opisthorchis viverrini. The molecular mediators underlying the infection with these parasites and cancer remain unclear. Although carcinogenesis is a multistep process, we have postulated that these parasites release metabolites including oxysterols and estrogen-like metabolites that interact with host cell DNA. How and why the parasite produce/excrete these metabolites remain unclear. A gene encoding a CYP enzyme was identified in schistosomes and opisthorchiids. Therefore, it is reasonable hypothesized that CYP 450 might play a role in generation of pro-inflammatory and potentially carcinogenic compounds produced by helminth parasites such as oxysterols and catechol estrogens. Here, we performed enzymatic assays using several isoforms of CYP 450 as CYP1A1, 2E1 and 3A4 which are involved in the metabolism of chemical carcinogens that have been associated with several cancer. The main aim was the analysis of the role of these enzymes in production of helminth-associated metabolites and DNA-adducts. Method: The effect of cytochrome P450 enzymes CYP 1A1, 2E1 and 3A4 during the interaction between DNA, glycocholic acid and taurochenodeoxycholate sodium on the formation of DNA-adducts and metabolites associated with urogenital schistosomiasis (UGS) and opisthorchiasis was investigated in vitro. Liquid chromatography/mass spectrometry was used to detect and identify metabolites. Main findings: Through the enzymatic assays we provide a deeper understanding of how metabolites derived from helminths are formed and the influence of CYP 450. The assays using compounds similar to those previously observed in helminths as glycocholic acid and taurochenodeoxycholate sodium, allowed the detection of metabolites in their oxidized form and their with DNA. Remarkably, these metabolites were previously associated with schistosomiaisis and opisthorchiasis. Thus, in the future, it may be possible to synthesize this type of metabolites through this methodology and use them in cell lines to clarify the carcinogenesis process associated with these diseases. Principal conclusions: Metabolites similar to those detected in helminths are able to interact with DNA in vitro leading to the formation of DNA adducts. These evidences supported the previous postulate that imply helminth-like metabolites as initiators of helminthiases-associated carcinogenesis. Nonetheless, studies including these kinds of metabolites and cell lines in order to evaluate its potential carcinogenic are required.
- Potent cationic antimicrobial peptides against Mycobacterium tuberculosis in vitroPublication . Silva, Sara; Santos-Silva, Anabela; da Costa, José Manuel Correia; Vale, NunoBackground: Tuberculosis (TB) is known to be one of the 10 causes of global death by infectious agents. The increasing numbers of multiple antibiotic resistance (MDR-TB) and cases of extensive resistance to antibiotics (XDR-TB) have led to the development of new and effective TB therapy. Cationic antimicrobial peptides (CAMPs) have emerged in the research as a safe and effective treatment against a variable range of bacterial and fungi pathogens, including Mycobacterium tuberculosis (M. tuberculosis). Method: This study developed a new CAMP coupled with cinnamic acid derivatives, and studied the antimicrobial activity against clinical isolates of M. tuberculosis (H37Rv) and MDR-TB. Results: All modified CAMPs showed enhanced activity against both M. tuberculosis strains and were capable of disrupting heavy clumping of mycobacteria in culture. In addition, all modified CAMPs were able to substantially inhibit the intracellular growth of both strains at low concentrations. Conclusions: The characteristic proprieties of cinnamic acid+CAMP(n) successfully inhibited the growth of both clinical isolates M. tuberculosis and MDR-TB in vitro and have, for now, promising use as a drug adjuvant due to their effect on mycobacteria growth.
- Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and ResistancePublication . Vale, Nuno; Gouveia, Maria João; Rinaldi, Gabriel; Brindley, Paul J.; Gärtner, Fátima; Correia da Costa, José M.Schistosomiasis, a major neglected tropical disease, affects more than 250 million people worldwide. Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. PZQ is the drug of choice for the treatment of schistosomiasis; it is effective against all major forms of schistosomiasis, although it is less active against juvenile than mature parasites. A pyrazino-isoquinoline derivative, PZQ is not considered to be toxic and generally causes few or transient, mild side effects. Increasingly, mass drug administration targeting populations in sub-Saharan Africa where schistosomiasis is endemic has led to the appearance of reduced efficacy of PZQ, which portends the selection of drug-resistant forms of these pathogens. The synthesis of improved derivatives of PZQ is attracting attention, e.g., in the (i) synthesis of drug analogues, (ii) rational design of pharmacophores, and (iii) discovery of new compounds from large-scale screening programs. This article reviews reports from the 1970s to the present on the metabolism and mechanism of action of PZQ and its derivatives against schistosomes.
- Schistosoma haematobium: identification of new estrogenic molecules with estradiol antagonistic activity and ability to inactivate estrogen receptor in mammalian cellsPublication . Botelho, Mónica Catarina; Soares, Raquel; Vale, Nuno; Ribeiro, Ricardo; Camilo, Vânia; Almeida, Raquel; Medeiros, Rui; Gomes, Paula; Machado, José Carlos; Costa, José Manuel Correia daWe have previously identified the expression of an estradiol (E2)-related molecule by Schistosoma haematobium total antigen (Sh). We now show that this molecule has an antagonistic effect of estradiol in vitro. Our results are consistent with the existence of an estrogenic molecule that antagonizes the activity of estradiol. We found evidence for this molecule as we identified and characterized by mass spectrometry new estrogenic molecules previously unknown, present in schistosome worm extracts and sera of Schistosoma-infected individuals. We also show that Sh is able to interact in vitro with estrogen receptor (ER), explaining how host endocrine system can favor the establishment of schistosomes. These findings highlight the exploitation of the host endocrine system by schistosomes and represent an additional regulatory component of schistosome development that defines a novel paradigm enabling host–parasite interactions. The identification of these molecules opens new ways for the development of alternative drugs to treat schistosomiasis.
- The antioxidants resveratrol and N-acetylcysteine enhance anthelmintic activity of praziquantel and artesunate against Schistosoma mansoniPublication . Gouveia, Maria João; Brindley, Paul J.; Azevedo, Carlos; Gärtner, Fátima; da Costa, José M. C.; Vale, NunoBackground: Treatment of schistosomiasis has relied on the anthelmintic drug praziquantel (PZQ) for more than a generation. Despite its celebrated performance for treatment and control of schistosomiasis and other platyhelminth infections, praziquantel has some shortcomings and the inability of this drug to counteract disease sequelae prompts the need for novel therapeutic strategies. Methods: Using a host-parasite model involving Biomphalaria glabrata and Schistosoma mansoni we established mechanical transformation of S. mansoni cercariae into newly transformed schistosomula (NTS) and characterized optimal culture conditions. Thereafter, we investigated the antischistosomal activity and ability of the antioxidants N-acetylcysteine (NAC) and resveratrol (RESV) to augment the performance of praziquantel and/or artesunate (AS) against larval stages of the parasite. Drug effects were evaluated by using an automated microscopical system to study live and fixed parasites and by transmission electron microscopy (TEM). Results: Transformation rates of cercariae to schistosomula reached ~ 70% when the manipulation process was optimized. Several culture media were tested, with M199 supplemented with HEPES found to be suitable for S. mansoni NTS. Among the antioxidants studied, RESV alone or combined with anthelminthic drugs achieved better results rather N-acetylcysteine (NAC). TEM observations demonstrated that the combination of AS + RESV induced severe, extensive alterations to the tegument and subtegument of NTS when compared to the constituent compounds alone. Two anthelmintic-antioxidant combinations, praziquantel-resveratrol [combination index (CI) = 0.74] and artesunate-resveratrol (CI = 0.34) displayed moderate and strong synergy, respectively. Conclusions: The use of viability markers including staining with propidium iodide increased the accuracy of drug screening assays against S. mansoni NTS. The synergies observed might be the consequence of increased action by RESV on targets of AS and PZQ and/or they may act through concomitantly on discrete targets to enhance overall antischistosomal action. Combinations of active agents, preferably with discrete modes of action including activity against developmental stages and/or the potential to ameliorate infection-associated pathology, might be pursued in order to identify novel therapeutic interventions.
- The role of estradiol metabolism in urogenital schistosomiasis-induced bladder cancerPublication . Vale, Nuno; Gouveia, Maria J.; Rinaldi, Gabriel; Santos, Júlio; Santos, Lúcio Lara; Brindley, Paul J.; da Costa, José M. CorreiaUrogenital schistosomiasis is a neglected tropical disease that can lead to bladder cancer. How urogenital schistosomiasis induces carcinogenesis remains unclear, although there is evidence that the human blood fluke Schistosoma haematobium, the infectious agent of urogenital schistosomiasis, releases estradiol-like metabolites. These kind of compounds have been implicated in other cancers. Aiming for enhanced understanding of the pathogenesis of the urogenital schistosomiasis-induced bladder cancer, here we review, interpret, and discuss findings of estradiol-like metabolites detected in both the parasite and in the human urine during urogenital schistosomiasis. Moreover, we predict pathways and enzymes that are involved in the production of these metabolites emphasizing their potential effects on the dysregulation of the tumor suppressor gene p53 expression during urogenital schistosomiasis. Enhanced understanding of these potential carcinogens may not only shed light on urogenital schistosomiasis-induced neoplasia of the bladder, but would also facilitate development of interventions and biomarkers for this and other infection-associated cancers at large.