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For developing novel photosensitizers with therapeutic potential in non-malignant and malignant cutaneous disorders, the unsymmetrical porphyrin, 5-(2-hydroxy-3-methoxyphenyl)-10, 15, 20-tris-(4-carboxymethylphenyl) porphyrin, was evaluated in silico and in vitro. The cellular uptake of the investigated porphyrin and its ability to perform photodynamic therapy were investigated in terms of the viability, proliferation, and necrosis of human HaCaT keratinocytes and human Hs27 skin fibroblasts, in correlation with the predictions regarding diffusion through cell membranes, ADMET profile (absorption, distribution, metabolism, elimination, toxicity), and potential pharmacological mechanism. Molecular docking and 250 ns molecular dynamics simulations revealed that P5.2 has the potential to form a relatively stable complex with the carbonic anhydrase IX catalytic site, the lowest predicted free energy of binding (MM/PBSA) being -39.097 kcal/mol. The results of the in vitro study showed that P5.2 is incorporated within 24 h in the investigated cells, especially in HaCaT keratinocytes, indicating its photosensitizing ability. Nevertheless, P5.2 does not exert significant cytotoxicity in "dark" conditions. In turn, PDT induced a decrease in the number of metabolically active HaCaT keratinocytes within 24 h, accompanied by a 4-fold increase in lactate dehydrogenase release, indicating its ability to perform PDT in human skin cells. The experimental results suggest that the asymmetrical porphyrin is a promising candidate theranostics agent for skin disorders.
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Due to combined therapeutical emissions, a high linear energy transfer Auger-electrons with the longer ranged ß- particles, 64Cu-based radiopharmaceuticals raise particular theragnostic interest in cancer, by joined therapeutic and real-time PET imaging properties. The in vitro study aimed to investigate the biological and molecular background of 64CuCl2 therapy by analyzing the damages and stress responses inflicted in various human normal and tumor cell lines. Colon (HT29 and HCT116) and prostate carcinoma (DU145) cell lines, as well as human normal BJ fibroblasts, were treated up to 72 h with 2-40 MBq/mL 64CuCl2. Radioisotope uptake and retention were assessed, and cell viability/death, DNA damage, oxidative stress, and the expression of 84 stress genes were investigated at various time points after [64Cu]CuCl2 addition. All the investigated cells incorporated 64Cu ions similarly, independent of their tumoral or normal status, but their fate after exposure to [64Cu]CuCl2 was cell-dependent. The most striking cytotoxic effects of the radioisotope were registered in colon carcinoma HCT116 cells, for which a substantial decrease in the number of metabolically active cells, and an increased DNA damage and oxidative stress were registered. The stress gene expression study highlighted the activation of both death and repair mechanisms in these cells, related to extrinsic apoptosis, necrosis/necroptosis or autophagy, and cell cycle arrest, nucleotide excision repair, antioxidant, and hypoxic responses, respectively. The in vitro study indicated that 40 MBq/mL [64Cu]CuCl2 delivers a therapeutic effect in human colon carcinoma, but its use is limited by harmful, yet lower effects on normal fibroblasts. The exposure of tumor cells to 20 MBq/mL [64Cu]CuCl2, might be used for a softer approach aiming for a lower radiotoxicity in normal fibroblasts as compared to tumor cells. This radioactive concentration was able to induce a persistent decrease in the number of metabolically active cells, accompanied by DNA damage and oxidative stress, associated with significant changes in stress gene expression in HCT116 colon cancer cells.
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The aim of the present study was to assess the effects exerted in vitro by three asymmetrical porphyrins (5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin, 5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrinatozinc(II), and 5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrinatocopper(II)) on the transmembrane potential and the membrane anisotropy of U937 cell lines, using bis-(1,3-dibutylbarbituric acid)trimethine oxonol (DiBAC4(3)) and 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p-toluenesulfonate (TMA-DPH), respectively, as fluorescent probes for fluorescence spectrophotometry. The results indicate the hyperpolarizing effect of porphyrins in the concentration range of 0.5, 5, and 50 µM on the membrane of human U937 monocytic cells. Moreover, the tested porphyrins were shown to increase membrane anisotropy. Altogether, the results evidence the interaction of asymmetrical porphyrins with the membrane of U937 cells, with potential consequences on cellular homeostasis. Molecular docking simulations, and Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) free energy of binding calculations, supported the hypothesis that the investigated porphyrinic compounds could potentially bind to membrane proteins, with a critical role in regulating the transmembrane potential. Thus, both the free base porphyrins and the metalloporphyrins could bind to the SERCA2b (sarco/endoplasmic reticulum ATPase isoform 2b) calcium pump, while the metal complexes may specifically interact and modulate calcium-dependent (large conductance calcium-activated potassium channel, Slo1/KCa1.1), and ATP-sensitive (KATP), potassium channels. Further studies are required to investigate these interactions and their impact on cellular homeostasis and functionality.
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Porfirinas , Humanos , Porfirinas/química , Células U937 , Cálcio/metabolismo , Simulação de Acoplamento Molecular , Membrana Celular/metabolismo , Trifosfato de Adenosina/metabolismoRESUMO
Despite specialists' efforts to find the best solutions for cancer diagnosis and therapy, this pathology remains the biggest health threat in the world. Global statistics concerning deaths associated with cancer are alarming; therefore, it is necessary to intensify interdisciplinary research in order to identify efficient strategies for cancer diagnosis and therapy, by using new molecules with optimal therapeutic potential and minimal adverse effects. This review focuses on studies of porphyrin macrocycles with regard to their structural and spectral profiles relevant to their applicability in efficient cancer diagnosis and therapy. Furthermore, we present a critical overview of the main commercial formulations, followed by short descriptions of some strategies approached in the development of third-generation photosensitizers.
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Neoplasias , Fotoquimioterapia , Porfirinas , Humanos , Medicina de Precisão , Porfirinas/química , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológicoRESUMO
In order to select for further development novel photosensitizers for photodynamic therapy in cutaneous disorders, three unsymmetrical porphyrins, namely 5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl) porphyrin (P2.2), 5-(2-hydroxy-5-methoxyphenyl)-10,15,20-tris-(4-carboxymethylphenyl) porphyrin (P3.2), and 5-(2,4-dihydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl) porphyrin (P4.2), along with their fully symmetrical counterparts 5,10,15,20-tetrakis-(4-acetoxy-3-methoxyphenyl) porphyrin (P2.1) and 5,10,15,20-tetrakis-(4-carboxymethylphenyl) porphyrin (P3.1) were comparatively evaluated. The absorption and fluorescence properties, as well as atomic force microscopy measurements were performed to evaluate the photophysical characteristics as well as morphological and textural properties of the mentioned porphyrins. The cellular uptake of compounds and the effect of photodynamic therapy on the viability, proliferation, and necrosis of human HaCaT keratinocytes, human Hs27 skin fibroblasts, human skin SCL II squamous cell carcinoma, and B16F10 melanoma cells were assessed in vitro, in correlation with the structural and photophysical properties of the investigated porphyrins, and with the predictions regarding diffusion through cell membranes and ADMET properties. All samples were found to be isotropic and self-similar, with slightly different degrees of aggregability, had a relatively low predicted toxicity (class V), and a predicted long half-life after systemic administration. The in vitro study performed on non-malignant and malignant skin-relevant cells highlighted that the asymmetric P2.2 porphyrin qualified among the five investigated porphyrins to be a promising photosensitizer candidate for PDT in skin disorders. P2.2 was shown to accumulate well within cells, and induced by PDT a massive decrease in the number of metabolically active skin cells, partly due to cell death by necrosis. P2.2 had in this respect a better behavior than the symmetric P.2.1 compound and the related asymmetric compound P4.2. The strong action of P2.2-mediated PDT on normal skin cells might be an important drawback for further development of this compound. Meanwhile, the P3.1 and P3.2 compounds were not able to accumulate well in skin cells, and did not elicit significant PDT in vitro. Taken together, our experiments suggest that P2.2 can be a promising candidate for the development of novel photosensitizers for PDT in skin disorders.
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Photodynamic therapy (PDT), a highly targeted therapy with acceptable side effects, has emerged as a promising therapeutic option in oncologic pathology. One of the issues that needs to be addressed is related to the complex network of cellular responses developed by tumor cells in response to PDT. In this context, this study aims to characterize in vitro the stressors and the corresponding cellular responses triggered by PDT in the human colon carcinoma HT29 cell line, using a new asymmetric porphyrin derivative (P2.2) as a photosensitizer. Besides investigating the ability of P2.2-PDT to reduce the number of viable tumor cells at various P2.2 concentrations and fluences of the activating light, we assessed, using qRT-PCR, the expression levels of 84 genes critically involved in the stress response of PDT-treated cells. Results showed a fluence-dependent decrease of viable tumor cells at 24 h post-PDT, with few cells that seem to escape from PDT. We highlighted following P2.2-PDT the concomitant activation of particular cellular responses to oxidative stress, hypoxia, DNA damage and unfolded protein responses and inflammation. A web of inter-connected stressors was induced by P2.2-PDT, which underlies cell death but also elicits protective mechanisms that may delay tumor cell death or even defend these cells against the deleterious effects of PDT.
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The neurotensin is a tridecapeptide involved in the proliferation of colon cancer, the overexpression of neurotensin receptors occurring at an early stage development of many tumours. Targeting neurotensin receptors by using the same biological active molecule is an effective approach for both imaging quantification and treatment. The present work aimed to demonstrate the ability of radiolabelled neurotensin to specifically target colon cancer cells, and substantiate its usefulness in targeted imaging and radiotherapy, depending on the emission of the coupled radioisotope. Syntheses of 68Ga-DOTA-NT and 177Lu-DOTA-NT were developed to obtain a level of quality suitable for preclinical use with consistent high synthesis yields. Radiochemical purity meets the pharmaceutical requirements, and it is maintained 4 h for 68Ga-DOTA-NT and 48 h for 177Lu-DOTA-NT. Extensive in vitro studies were conducted to assess the uptake and retention of 68Ga-DOTA-NT, the amount of non-specific binding of neurotensin and the effect of 177Lu-DOTA-NT on HT-29 cells. In vivo biodistribution of 68Ga-DOTA-NT revealed significant uptake at the tumour site, along with fast clearance evidenced by decreasing activity in kidneys and blood after 60 min p.i. 177Lu-DOTA-NT exhibited similar uptake in the tumour, but also a significant uptake at 14 days p.i. in the bone marrow was reported. These results successfully demonstrated the potential of neurotensin to deliver imaging/therapeutic 68Ga/177Lu radioisotopes pair, but also the need for further evaluation of the possible radiotoxicity effects on the liver, kidneys or bone marrow.
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The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) triggers homeostatic responses against a plethora of environmental or endogenous deviations in redox metabolism, inflammation, proteostasis, etc. Therefore, pharmacological activation of NRF2 is a promising therapeutic strategy for several chronic diseases that are underlined by low-grade oxidative inflammation and dysregulation of redox metabolism, such as neurodegenerative, cardiovascular, and metabolic diseases. While NRF2 activation is useful in inhibiting carcinogenesis, its inhibition is needed in constituted tumors where NRF2 provides a survival advantage in the challenging tumor niche. This review describes the electrophilic and non-electrophilic NRF2 activators with clinical projection in various chronic diseases. We also analyze the status of NRF2 inhibitors, which are for the moment in a proof-of-concept stage. Advanced in silico screening and medicinal chemistry are expected to provide new or repurposing small molecules with increased potential for fostering the development of targeted NRF2 modulators. The nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) is rapidly degraded by proteasomes under a basal condition in a Keap1-dependent manner. ROS oxidatively modifies Keap1 to release NRF2 and allow its nuclear translocation. Here it binds to the antioxidant response element to regulate gene transcription. An alternative mechanism controlling NRF2 stability is glycogen synthase kinase 3 (GSK-3)-induced phosphorylation. Indicated in blue are NRF2-activating and NRF2-inhibiting drugs.
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Fator 2 Relacionado a NF-E2 , Preparações Farmacêuticas , Quinase 3 da Glicogênio Sintase , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse OxidativoRESUMO
Recent advances and large-scale use of hybrid imaging modalities like PET-CT have led to the necessity of improving nano-drug carriers that can facilitate both functional and metabolic screening in nuclear medicine applications. In this study, we focused on the evaluation of four potential imaging nanoparticle structures labelled with the 68Ga positron emitter. For this purpose, we functionalized NHS-activated PEG-gold nanoparticles with 68Ga-DOTA-Neuromedin B, 68Ga-DOTA-PEG(4)-BBN(7-14), 68Ga-DOTA-NT and 68Ga-DOTA-Neuromedin N. In vitro binding kinetics and specific binding to human HT-29 colon carcinoma cells and DU-145 prostate carcinoma cells respectively were assessed, over 75% retention being obtained in the case of 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP in prostate tumour cells and over 50% in colon carcinoma cells. Biodistribution in NU/J mice highlighted a three-fold uptake increase in tumours at 30 min post-injection of 68Ga-DOTA-NT-AuNP and 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP compared to 68Ga-DOTA-NT and 68Ga-DOTA-PEG(4)-BBN(7-14) respectively, therewith fast distribution in prostate and colon tumours and minimum accumulation in non-targeted tissues.
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Neoplasias do Colo/diagnóstico por imagem , Ouro/administração & dosagem , Neurocinina B/análogos & derivados , Neurotensina/química , Fragmentos de Peptídeos/química , Peptídeos/química , Neoplasias da Próstata/diagnóstico por imagem , Animais , Disponibilidade Biológica , Bombesina/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Radioisótopos de Gálio/administração & dosagem , Radioisótopos de Gálio/química , Radioisótopos de Gálio/farmacocinética , Ouro/química , Ouro/farmacocinética , Células HT29 , Humanos , Masculino , Nanopartículas Metálicas/química , Camundongos , Transplante de Neoplasias , Neurocinina B/química , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/metabolismo , Receptores da Bombesina/metabolismo , Receptores de Neurotensina/metabolismoRESUMO
Repurposing drugs to target M1 macrophages inflammatory response in depression constitutes a bright alternative for commonly used antidepressants. Depression is a significant type of mood disorder, where patients suffer from pathological disturbances associated with a proinflammatory M1 macrophage phenotype. Presently, the most commonly used antidepressants such as Zoloft and Citalopram can reduce inflammation, but suffer from dangerous side effects without offering specificity toward macrophages. We employed a new strategy for drug repurposing based on the integration of RNA-seq analysis and text mining using deep neural networks. Our system employs a Google semantic AI universal encoder to compute sentences embedding. Sentences similarity is calculated using a sorting function to identify drug compounds. Then sentence relevance is computed using a custom-built convolution differential network. Our system highlighted the NRF2 pathway as a critical drug target to reprogram M1 macrophage response toward an anti-inflammatory profile (M2). Using our approach, we were also able to predict that lipoxygenase inhibitor drug zileuton could modulate NRF2 pathway in vitro. Taken together, our results indicate that reorienting zileuton usage to modulate M1 macrophages could be a novel and safer therapeutic option for treating depression.
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Anti-Inflamatórios/farmacologia , Antidepressivos/farmacologia , Hidroxiureia/análogos & derivados , Macrófagos/metabolismo , Animais , Inteligência Artificial , Células Cultivadas , Mineração de Dados , Reposicionamento de Medicamentos , Hidroxiureia/farmacologia , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Redes Neurais de Computação , Células RAW 264.7 , Semântica , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacosRESUMO
Nordihydroguaiaretic acid (NDGA) is a phenolic lignan obtained from Larrea tridentata, the creosote bush found in Mexico and USA deserts, that has been used in traditional medicine for the treatment of numerous diseases such as cancer, renal, cardiovascular, immunological, and neurological disorders, and even aging. NDGA presents two catechol rings that confer a very potent antioxidant activity by scavenging oxygen free radicals and this may explain part of its therapeutic action. Additional effects include inhibition of lipoxygenases (LOXs) and activation of signaling pathways that impinge on the transcription factor Nuclear Factor Erythroid 2-related Factor (NRF2). On the other hand, the oxidation of the catechols to the corresponding quinones my elicit alterations in proteins and DNA that raise safety concerns. This review describes the current knowledge on NDGA, its targets and side effects, and its synthetic analogs as promising therapeutic agents, highlighting their mechanism of action and clinical projection towards therapy of neurodegenerative, liver, and kidney disease, as well as cancer.
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Breast and prostate cancer are two of the most common malignancies worldwide. Both cancers can develop into hormone -dependent or -independent subtypes and are associated to environmental exposure in the context of an inherited predisposition. As and Cd have been linked to the onset of both cancers, with the exception of As, which lacks a definitive association with breast carcinogenesis. The two elements exert an opposite effect dependent on acute versus chronic exposure. High doses of As or Cd were shown to induce cell death in acute experimental exposure, while chronic exposure triggers cell proliferation and viability, which is no longer limited by telomere shortening and apoptosis. The chronically exposed cells also increase their invasion capacity and tumorigenic potential. At molecular level, malignant transformation is evidenced mainly by up-regulation of BCL-2, MMP-2, MMP-9, VIM, Snail, Twist, MT, MLH and down-regulation of Casp-3, PTEN, E-CAD, and BAX. The signaling pathways most commonly activated are KRAS, p53, TGF-ß, TNF-α, WNT, NRF2 and AKT. This knowledge could potentially raise public awareness over the health risks faced by the human population living or working in a polluted environment and smokers. Human exposure to As and Cd should be minimize as much as possible. Healthcare policies targeting people belonging to these risk categories should include analysis of: DNA damage, oxidative stress, molecular alterations, and systemic level of heavy metals and of essential minerals. In this review, we present the literature regarding cellular and molecular alterations caused by exposure to As or Cd, focusing on the malignant transformation of normal epithelial cells after long-term intoxication with these two carcinogens.
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Arsênio/toxicidade , Neoplasias da Mama/epidemiologia , Cádmio/toxicidade , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/toxicidade , Neoplasias da Próstata/epidemiologia , Transformação Celular Neoplásica , Humanos , Masculino , Metais PesadosRESUMO
The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) triggers the first line of homeostatic responses against a plethora of environmental or endogenous deviations in redox metabolism, proteostasis, inflammation, etc. Therefore, pharmacological activation of NRF2 is a promising therapeutic approach for several chronic diseases that are underlined by oxidative stress and inflammation, such as neurodegenerative, cardiovascular, and metabolic diseases. A particular case is cancer, where NRF2 confers a survival advantage to constituted tumors, and therefore, NRF2 inhibition is desired. This review describes the electrophilic and nonelectrophilic NRF2 activators with clinical projection in various chronic diseases. We also analyze the status of NRF2 inhibitors, which at this time provide proof of concept for blocking NRF2 activity in cancer therapy.
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Fator 2 Relacionado a NF-E2/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Ensaios Clínicos como Assunto , Curcumina/química , Curcumina/uso terapêutico , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Fator 2 Relacionado a NF-E2/agonistas , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Estresse Oxidativo , Triterpenos/química , Triterpenos/uso terapêuticoRESUMO
Recently developed short-pulsed laser sources garner high dose-rate beams such as energetic ions and electrons, x rays, and gamma rays. The biological effects of laser-generated ion beams observed in recent studies are different from those triggered by radiation generated using classical accelerators or sources, and this difference can be used to develop new strategies for cancer radiotherapy. High-power lasers can now deliver particles in doses of up to several Gy within nanoseconds. The fast interaction of laser-generated particles with cells alters cell viability via distinct molecular pathways compared to traditional, prolonged radiation exposure. The emerging consensus of recent literature is that the differences are due to the timescales on which reactive molecules are generated and persist, in various forms. Suitable molecular markers have to be adopted to monitor radiation effects, addressing relevant endogenous molecules that are accessible for investigation by noninvasive procedures and enable translation to clinical imaging. High sensitivity has to be attained for imaging molecular biomarkers in cells and in vivo to follow radiation-induced functional changes. Signal-enhanced MRI biomarkers enriched with stable magnetic nuclear isotopes can be used to monitor radiation effects, as demonstrated recently by the use of dynamic nuclear polarization (DNP) for biomolecular observations in vivo. In this context, nanoparticles can also be used as radiation enhancers or biomarker carriers. The radiobiology-relevant features of high dose-rate secondary radiation generated using high-power lasers and the importance of noninvasive biomarkers for real-time monitoring the biological effects of radiation early on during radiation pulse sequences are discussed.
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Biomarcadores/metabolismo , Lasers , Imagem Molecular/métodos , Doses de Radiação , Humanos , Fenômenos Magnéticos , FótonsRESUMO
Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein-protein or DNA-protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases.
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Doença Crônica/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Fator 2 Relacionado a NF-E2/metabolismo , Análise de Sistemas , Animais , Anti-Inflamatórios/uso terapêutico , Descoberta de Drogas , Reposicionamento de Medicamentos , Humanos , Fator 2 Relacionado a NF-E2/genéticaRESUMO
BACKGROUND: Reactive oxygen species sustain tumorigenesis and cancer progression through deregulated redox signalling which also sensitizes cancer cells to therapy. Photodynamic therapy (PDT) is a promising anti-cancer therapy based on a provoked singlet oxygen burst, exhibiting a better toxicological profile than chemo- and radiotherapy. Important gaps in the knowledge on underlining molecular mechanisms impede on its translation towards clinical applications. AIMS AND METHODS: The main objective of this review is to critically analyse the knowledge lately gained on therapeutic targets related to redox and inflammatory networks underlining PDT and its outcome in terms of cell death and resistance to therapy. Emerging therapeutic targets and pharmaceutical tools will be documented based on the identified molecular background of PDT. RESULTS: Cellular responses and molecular networks in cancer cells exposed to the PDT-triggered singlet oxygen burst and the associated stresses are analysed using a systems medicine approach, addressing both cell death and repair mechanisms. In the context of immunogenic cell death, therapeutic tools for boosting anti-tumor immunity will be outlined. Finally, the transcription factor NRF2, which is a major coordinator of cytoprotective responses, is presented as a promising pharmacologic target for developing co-therapies designed to increase PDT efficacy. CONCLUSION: There is an urgent need to perform in-depth molecular investigations in the field of PDT and to correlate them with clinical data through a systems medicine approach for highlighting the complex biological signature of PDT. This will definitely guide translation of PDT to clinic and the development of new therapeutic strategies aimed at improving PDT.
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Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Antineoplásicos/química , Humanos , Neoplasias/metabolismo , Fármacos Fotossensibilizantes/químicaRESUMO
Focus on the Warburg effect, initially descriptive of increased glycolysis in cancer cells, has served to illuminate mitochondrial function in many other pathologies. This review explores our current understanding of the Warburg effect's role in cancer, diabetes and ageing. We highlight how it can be regulated through a chain of oncogenic events, as a chosen response to impaired glucose metabolism or by chance acquisition of genetic changes associated with ageing. Such chain, choice or chance perspectives can be extended to help understand neurodegeneration, such as Alzheimer's disease, providing clues with scope for therapeutic intervention. It is anticipated that exploration of Warburg effect pathways in extreme conditions, such as deep space, will provide further insights crucial for comprehending complex metabolic diseases, a frontier for medicine that remains equally significant for humanity in space and on earth.
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Diabetes Mellitus/metabolismo , Glicólise , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , HumanosRESUMO
Abstract: We designed three unsymmetrical meso-tetrasubstituted phenyl porphyrins for further development as theranostic agents for cancer photodynamic therapy (PDT): 5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin (P2.2), Zn(II)-5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin (Zn(II)2.2) and Cu(II)-5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin (Cu(II)2.2). The porphyrinic compounds were synthesized and their structures were confirmed by elemental analysis, FT-IR, UV-Vis, EPR and NMR. The compounds had a good solubility in polar/nonpolar media. P2.2 and, to a lesser extent, Zn(II)2.2 were fluorescent, albeit with low fluoresence quantum yields. P2.2 and Zn(II)2.2 exhibited PDT-acceptable values of singlet oxygen generation. A "dark" cytotoxicity study was performed using cells that are relevant for the tumor niche (HT-29 colon carcinoma cells and L929 fibroblasts) and for blood (peripheral mononuclear cells). Cellular uptake of fluorescent compounds, cell viability/proliferation and death were evaluated. P2.2 was highlighted as a promising theranostic agent for PDT in solid tumors considering that P2.2 generated PDT-acceptable singlet oxygen yields, accumulated into tumor cells and less in blood cells, exhibited good fluorescence within cells for imagistic detection, and had no significant cytotoxicity in vitro against tumor and normal cells. Complexing of P2.2 with Zn(II) or Cu(II) altered several of its PDT-relevant properties. These are consistent arguments for further developing P2.2 in animal models of solid tumors for in vivo PDT.
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Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/síntese química , Porfirinas/farmacologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Células HT29 , Humanos , Camundongos , Estrutura Molecular , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Porfirinas/química , Oxigênio Singlete/metabolismoRESUMO
Iron oxide nanoparticles are promising candidates for theranostics in cancer, that aims to achieve in one-step precise tumor imaging by magnetic resonance, and targeted therapy through surface attached anti-cancer drugs. The aim of this study was to investigate in preclinical setting the biocompatibility of new iron oxide-based nanoparticles that were coated with L-DOPA for improved dispersion in biological media. These nanostructures (NPs) were designed for biomedical applications as contrast agents and/or drug carriers. We investigated the effect exerted in vitro by NPs and L-DOPA on the viability and proliferation of normal mouse L929 fibroblasts. NPs exhibited good biocompatibility against these cells. Moreover, L-DOPA contained in NPs sustained fibroblasts proliferation and/or limited anti-proliferative effects of naked nanoparticles. In the animal study, C57BL/6 mice were injected intraperitoneally with a single dose of NPs (approximately 125 mg/kg body weight). We followed up hematological and histological parameters for one, three and seven days after NPs administration. Results indicated that NPs possibly induced local inflammation and consequent recruitment of peripheral lymphocytes, whilst the decrease of platelet counts may reflect tissue lesions caused by NPs. The histopathological study showed mild to moderate alterations in the hepatocytes, splenic and renal cells, while the brain parenchyma only presented nonspecific congestive changes. Taken altogether, the preclinical study indicated that the new iron oxide nanoparticles coated with L-DOPA were biocompatible against fibroblasts and had a convenient toxicological profile when administered intraperitoneally in a single dose to C57BL/6 mice. Accordingly, the proposed nanostructure is a promising candidate for imaging and treating dispersed peritoneal tumors.
Assuntos
Compostos Férricos/química , Infusões Parenterais/métodos , Levodopa/química , Nanopartículas Metálicas/química , Nanomedicina/métodos , Animais , Materiais Biocompatíveis/química , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , Materiais Revestidos Biocompatíveis , Meios de Contraste/química , Portadores de Fármacos/química , Fibroblastos/metabolismo , Hepatócitos/citologia , Linfócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanoestruturas/química , Baço/metabolismoRESUMO
In this paper, two tetrapyrrolic complexes, Zn(II)-5-(3-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin and Cu(II)-5-(3-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin were synthesized, and characterized from a spectral and biological point of view. The study provided data concerning the behavior of identical external substituents vs. two different core insertions. Some of the properties of the proposed tetrapyrrolic structures were highlighted, having photodynamic therapy of cancer as a targeted biomedical application. Elemental analysis, NMR, FTIR and UV-Vis data in various solvents were provided. A preliminary in vitro study on normal and cancer cultured cells was carried out for biocompatibility assessment in dark conditions. The preliminary in vitro study performed on human peripheral mononuclear cells exposed to tetrapyrrolic compounds (2 µM) showed that the proposed compounds had a convenient cytotoxic profile on human normal peripheral blood mononuclear cells under dark conditions. Meanwhile, the investigated compounds reduced the number of metabolically active breast tumor MCF-7 cells, with the exception of Zn(II) complex-containing a symmetrical ligand. Accordingly, preliminary in vitro data suggest that the proposed tetrapyrrolic compounds are good candidates for PDT, as they limit tumor expansion even under dark conditions, whilst sparing normal cells.