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1.
Photochem Photobiol Sci ; 23(6): 1129-1142, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38734995

RESUMO

Bacterial infections are a global health concern, particularly due to the increasing resistance of bacteria to antibiotics. Multi-drug resistance (MDR) is a considerable challenge, and novel approaches are needed to treat bacterial infections. Photodynamic inactivation (PDI) of microorganisms is increasingly recognized as an effective method to inactivate a broad spectrum of bacteria and overcome resistance mechanisms. This study presents the synthesis of a new cationic 5,15-di-imidazolyl porphyrin derivative and the impact of n-octanol/water partition coefficient (logP) values of this class of photosensitizers on PDI efficacy of Escherichia coli. The derivative with logP = -0.5, IP-H-OH2+, achieved a remarkable 3 log CFU reduction of E. coli at 100 nM with only 1.36 J/cm2 light dose at 415 nm, twice as effective as the second-best porphyrin IP-H-Me2+, of logP = -1.35. We relate the rapid uptake of IP-H-OH2+ by E. coli to improved PDI and the very low uptake of a fluorinated derivative, IP-H-CF32+, logP ≈ 1, to its poor performance. Combination of PDI with cinnamaldehyde, a major component of the cinnamon plant known to alter bacteria cell membranes, offered synergic inactivation of E. coli (7 log CFU reduction), using 50 nM of IP-H-OH2+ and just 1.36 J/cm2 light dose. The success of combining PDI with this natural compound broadens the scope of therapies for MDR infections that do not add drug resistance. In vivo studies on a mouse model of wound infection showed the potential of cationic 5,15-di-imidazolyl porphyrins to treat clinically relevant infected wounds.


Assuntos
Acroleína , Antibacterianos , Escherichia coli , Imidazóis , Fármacos Fotossensibilizantes , Porfirinas , Escherichia coli/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/síntese química , Porfirinas/farmacologia , Porfirinas/química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Acroleína/análogos & derivados , Acroleína/farmacologia , Acroleína/química , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/síntese química , Cátions/química , Cátions/farmacologia , Testes de Sensibilidade Microbiana , Animais , Camundongos , Sinergismo Farmacológico , Fotoquimioterapia
2.
Photochem Photobiol Sci ; 23(3): 539-560, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38457119

RESUMO

Antibiotic resistance represents a pressing global health challenge, now acknowledged as a critical concern within the framework of One Health. Photodynamic inactivation of microorganisms (PDI) offers an attractive, non-invasive approach known for its flexibility, independence from microbial resistance patterns, broad-spectrum efficacy, and minimal risk of inducing resistance. Various photosensitizers, including porphyrin derivatives have been explored for pathogen eradication. In this context, we present the synthesis, spectroscopic and photophysical characteristics as well as antimicrobial properties of a palladium(II)-porphyrin derivative (PdF2POH), along with its zinc(II)- and free-base counterparts (ZnF2POH and F2POH, respectively). Our findings reveal that the palladium(II)-porphyrin complex can be classified as an excellent generator of reactive oxygen species (ROS), encompassing both singlet oxygen (Φ△ = 0.93) and oxygen-centered radicals. The ability of photosensitizers to generate ROS was assessed using a variety of direct (luminescence measurements) and indirect techniques, including specific fluorescent probes both in solution and in microorganisms during the PDI procedure. We investigated the PDI efficacy of F2POH, ZnF2POH, and PdF2POH against both Gram-negative and Gram-positive bacteria. All tested compounds proved high activity against Gram-positive species, with PdF2POH exhibiting superior efficacy, leading to up to a 6-log reduction in S. aureus viability. Notably, PdF2POH-mediated PDI displayed remarkable effectiveness against S. aureus biofilm, a challenging target due to its complex structure and increased resistance to conventional treatments. Furthermore, our results show that PDI with PdF2POH is more selective for bacterial than for mammalian cells, particularly at lower light doses (up to 5 J/cm2 of blue light illumination). This enhanced efficacy of PdF2POH-mediated PDI as compared to ZnF2POH and F2POH can be attributed to more pronounced ROS generation by palladium derivative via both types of photochemical mechanisms (high yields of singlet oxygen generation as well as oxygen-centered radicals). Additionally, PDI proved effective in eliminating bacteria within S. aureus-infected human keratinocytes, inhibiting infection progression while preserving the viability and integrity of infected HaCaT cells. These findings underscore the potential of metalloporphyrins, particularly the Pd(II)-porphyrin complex, as promising photosensitizers for PDI in various bacterial infections, warranting further investigation in advanced infection models.


Assuntos
Anti-Infecciosos , Fotoquimioterapia , Porfirinas , Animais , Humanos , Porfirinas/farmacologia , Porfirinas/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio , Staphylococcus aureus , Oxigênio Singlete/química , Plâncton , Paládio/farmacologia , Fotoquimioterapia/métodos , Anti-Infecciosos/química , Biofilmes , Oxigênio , Mamíferos
3.
Molecules ; 28(23)2023 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-38067548

RESUMO

Novel hybrid TiO2-based materials were obtained by adsorption of two different porphyrins on the surface of nanoparticles-commercially available 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrin (TPPS) and properly modified metalloporphyrin-5,10,15,20-tetrakis(2,6-difluoro-3-sulfophenyl)porphyrin palladium(II) (PdF2POH). The immobilization of porphyrins on the surface of TiO2 was possible due to the presence of sulfonyl groups. To further elevate the adsorption of porphyrin, an anchoring linker-4-hydroxybenzoic acid (PHBA)-was used. The synthesis of hybrid materials was proven by electronic absorption spectroscopy, dynamic light scattering (DLS), and photoelectrochemistry. Results prove the successful photosensitization of TiO2 to visible light by both porphyrins. However, the presence of the palladium ion in the modifier structure played a key role in strong adsorption, enhanced charge separation, and thus effective photosensitization. The incorporation of halogenated metalloporphyrins into TiO2 facilitates the enhancement of the comprehensive characteristics of the investigated materials and enables the evaluation of their performance under visible light. The effectiveness of reactive oxygen species (ROS) generation was also determined. Porphyrin-based materials with the addition of PHBA seemed to generate ROS more effectively than other composites. Interestingly, modifications influenced the generation of singlet oxygen for TPPS but not hydroxyl radical, in contrast to PdF2POH, where singlet oxygen generation was not influenced but hydroxyl radical generation was increased. Palladium (II) porphyrin-modified materials were characterized by higher photostability than TPPS-based nanostructures, as TPPS@PHBA-P25 materials showed the highest singlet oxygen generation and may be oxidized during light exposure. Photocatalytic activity tests with two model pollutants-methylene blue (MB) and the opioid drug tramadol (TRML)-confirmed the light dose-dependent degradation of those two compounds, especially PdF2POH@P25, which led to the virtually complete degradation of MB.

4.
Cell Mol Biol (Noisy-le-grand) ; 69(11): 30-35, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-38015545

RESUMO

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. The tumor suppressor gene MT-CO1, and Kristen Rat Sarcoma Virus (KRAS), an oncogene are primarily responsible for controlling cell apoptosis, cell cycle arrest, and cell proliferation, and any irregularities in these genes could lead to cancer. This study aims to examine the expression of KRAS and MT-CO1 in CRC biopsy specimens and investigate their relationship with one another in CRC patients residing in the Erbil city of Kurdistan Region, Iraq. The study involved categorizing 42 sets of colorectal cancer tissues and their corresponding controls based on their types and patients' clinical characteristics. The expression of KRAS and MT-CO1 in the samples was assessed using Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR), with statistical significance set at p<0.05. The expression of KRAS was found to be significantly higher in CRC compared to the control (n=42, p=0.0001). On the other hand, the expression of MT-CO1 did not exhibit significant differences compared to the control group with a p-value of 0.12. Furthermore, the Chi-square and correlation analysis results depicted that MT-CO1 expression negatively correlates with KRAS expression (p= 0.0001, r= -0.047) in CRC tissues. In conclusion, the variation in the expression of KRAS and MT-CO1, and their correlations could potentially serve as a good indicator in the detection and prognosis of CRC, which might lead to better translational research on the same. However, for a better understanding of the underlying mechanisms, further analysis is required.


Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Oncogenes , Biópsia , Apoptose , Neoplasias Colorretais/genética
5.
Pharmaceuticals (Basel) ; 15(6)2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35745616

RESUMO

Immune checkpoint targeting immunotherapy has revolutionized the treatment of certain cancers in the recent years. Determination of the status of immune checkpoint expression in particular cancers may assist decision making. Here, we describe the development of a single-stranded aptamer-based molecular probe specifically recognizing human PD-L1. Target engaging aptamers are selected by iterative enrichment from a random ssDNA pool and the binding is characterized biochemically. Specificity and dose dependence is demonstrated in vitro in the cell culture using human kidney tumor cells (786-0), human melanoma cells (WM115 and WM266.4) and human glioblastoma LN18 cancer cells. The utility of the probe in vivo is demonstrated using two mouse tumor models, where we show that the probe exhibits excellent potential in imaging. We postulate that further development of the probe may allow universal imaging of different types of tumors depending on their PD-L1 status, which may find utility in cancer diagnosis.

6.
ACS Appl Mater Interfaces ; 14(13): 14981-14996, 2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35344328

RESUMO

Advances in the research of nanoparticles (NPs) with controlled charge and size are driven by their potential application in the development of novel technologies and innovative therapeutics. This work reports the synthesis, characterization, and comprehensive biological evaluation of AgNPs functionalized by N,N,N-trimethyl-(11-mercaptoundecyl) ammonium chloride (TMA) and trisodium citrate (TSC). The prepared AgNPs were well characterized in terms of their morphological, spectroscopic and functional properties and biological activities. The implementation of several complementary techniques allowed not only the estimation of the average particle size (from 3 to 40 nm depending on the synthesis procedure used) but also the confirmation of the crystalline nature of the NPs and their round shape. To prove the usefulness of these materials in biological systems, cellular uptake and cytotoxicity in microbial and mammalian cells were determined. Positively charged 10 nm Ag@TMA2 revealed antimicrobial activity against Gram-negative bacteria with a minimum inhibitory concentration (MIC) value of 0.17 µg/mL and complete eradication of Escherichia coli (7 logs) for Ag@TMA2 at a concentration of 0.50 µg/mL, whereas negatively charged 10 nm Ag@TSC1 was effective against Gram-positive bacteria (MIC = 0.05 µg/mL), leading to inactivation of Staphylococcus aureus at relatively low concentrations. In addition, the largest 40 nm Ag@TSC2 was shown to exhibit pronounced anticancer activity against murine colon carcinoma (CT26) and murine mammary gland carcinoma (4T1) cells cultured as 2D and 3D tumor models and reduced toxicity against human HaCaT keratinocytes. Among the possible mechanisms of AgNPs are their ability to generate reactive oxygen species, which was further evaluated in vitro and correlates well with cellular accumulation and overall activity of AgNPs. Furthermore, we confirmed the anticancer efficacy of the most potent Ag@TSC2 in hiPSC-derived colonic organoids and demonstrated that the NPs are biocompatible and applicable in vivo. A pilot study in BALB/c mice evidenced that the treatment with Ag@TSC2 resulted in temporary (>60 days) remission of CT26 tumors.


Assuntos
Nanopartículas Metálicas , Prata , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Mamíferos , Nanopartículas Metálicas/química , Camundongos , Testes de Sensibilidade Microbiana , Projetos Piloto , Prata/química , Prata/farmacologia
7.
Adv Inorg Chem ; 79: 65-103, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35095189

RESUMO

Although the whole world is currently observing the global battle against COVID-19, it should not be underestimated that in the next 30 years, approximately 10 million people per year could be exposed to infections caused by multi-drug resistant bacteria. As new antibiotics come under pressure from unpredictable resistance patterns and relegation to last-line therapy, immediate action is needed to establish a radically different approach to countering resistant microorganisms. Among the most widely explored alternative methods for combating bacterial infections are metal complexes and nanoparticles, often in combination with light, but strategies using monoclonal antibodies and bacteriophages are increasingly gaining acceptance. Photodynamic inactivation (PDI) uses light and a dye termed a photosensitizer (PS) in the presence of oxygen to generate reactive oxygen species (ROS) in the field of illumination that eventually kill microorganisms. Over the past few years, hundreds of photomaterials have been investigated, seeking ideal strategies based either on single molecules (e.g., tetrapyrroles, metal complexes) or in combination with various delivery systems. The present work describes some of the most recent advances of PDI, focusing on the design of suitable photosensitizers, their formulations, and their potential to inactivate bacteria, viruses, and fungi. Particular attention is focused on the compounds and materials developed in our laboratories that are capable of killing in the exponential growth phase (up to seven logarithmic units) of bacteria without loss of efficacy or resistance, while being completely safe for human cells. Prospectively, PDI using these photomaterials could potentially cure infected wounds and oral infections caused by various multidrug-resistant bacteria. It is also possible to treat the surfaces of medical equipment with the materials described, in order to disinfect them with light, and reduce the risk of nosocomial infections.

8.
MethodsX ; 8: 101393, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34430289

RESUMO

Surveying people via the Internet presents both opportunities and challenges. The opportunities include quick access to respondents all over the world enabling fast realization of surveys at low costs. The challenges include a lack of control over both the sampling process and research implementation, as well as low response rates. This article describes a method of obtaining an appropriate sample of people for survey research utilising the power of the Internet, while simultaneously allowing the researcher to minimise risk thanks to enhanced control over the sampling process and the implementation of the survey. The proposed method could be used mainly in economic and social surveys; it allows researchers to reach selected groups of respondents and to conduct surveys on a global scale.•The proposed sampling method uses LinkedIn's network structure to quickly reach a dispersed population•Creating a list of units belonging to the study population resembles the snowball method, though the units are selected for the sample by the researcher and not indicated by the respondents.

9.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445786

RESUMO

Diabetes, and several diseases related to diabetes, including cancer, cardiovascular diseases and neurological disorders, represent one of the major ongoing threats to human life, becoming a true pandemic of the 21st century. Current treatment strategies for diabetes mainly involve promoting ß-cell differentiation, and one of the most widely studied targets for ß-cell regeneration is DYRK1A kinase, a member of the DYRK family. DYRK1A has been characterized as a key regulator of cell growth, differentiation, and signal transduction in various organisms, while further roles and substrates are the subjects of extensive investigation. The targets of interest in this review are implicated in the regulation of ß-cells through DYRK1A inhibition-through driving their transition from highly inefficient and death-prone populations into efficient and sufficient precursors of islet regeneration. Increasing evidence for the role of DYRK1A in diabetes progression and ß-cell proliferation expands the potential for pharmaceutical applications of DYRK1A inhibitors. The variety of new compounds and binding modes, determined by crystal structure and in vitro studies, may lead to new strategies for diabetes treatment. This review provides recent insights into the initial self-activation of DYRK1A by tyrosine autophosphorylation. Moreover, the importance of developing novel DYRK1A inhibitors and their implications for the treatment of diabetes are thoroughly discussed. The evolving understanding of DYRK kinase structure and function and emerging high-throughput screening technologies have been described. As a final point of this work, we intend to promote the term "diabetic kinome" as part of scientific terminology to emphasize the role of the synergistic action of multiple kinases in governing the molecular processes that underlie this particular group of diseases.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Diabetes Mellitus/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Quinases Dyrk
10.
Int J Mol Sci ; 21(22)2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33218103

RESUMO

Resistance of microorganisms to antibiotics has led to research on various therapeutic strategies with different mechanisms of action, including photodynamic inactivation (PDI). In this work, we evaluated a cationic, neutral, and anionic meso-tetraphenylporphyrin derivative's ability to inactivate the Gram-negative and Gram-positive bacteria in a planktonic suspension under blue light irradiation. The spectroscopic, physicochemical, redox properties, as well as reactive oxygen species (ROS) generation capacity by a set of photosensitizers varying in lipophilicity were investigated. The theoretical calculations were performed to explain the distribution of the molecular charges in the evaluated compounds. Moreover, logP partition coefficients, cellular uptake, and phototoxicity of the photosensitizers towards bacteria were determined. The role of a specific microbial efflux pump inhibitor, verapamil hydrochloride, in PDI was also studied. The results showed that E. coli exhibited higher resistance to PDI than S. aureus (3-5 logs) with low light doses (1-10 J/cm2). In turn, the prolongation of irradiation (up to 100 J/cm2) remarkably improved the inactivation of pathogens (up to 7 logs) and revealed the importance of photosensitizer photostability. The PDI potentiation occurs after the addition of KI (more than 3 logs extra killing). Verapamil increased the uptake of photosensitizers (especially in E. coli) due to efflux pump inhibition. This effect suggests that PDI is mediated by ROS, the electrostatic charge interaction, and the efflux of photosensitizers (PSs) regulated by multidrug-resistance (MDR) systems. Thus, MDR inhibition combined with PDI gives opportunities to treat more resistant bacteria.


Assuntos
Bactérias/efeitos dos fármacos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Bactérias/metabolismo , Bactérias/efeitos da radiação , Farmacorresistência Bacteriana/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Escherichia coli/efeitos da radiação , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/metabolismo , Bactérias Gram-Negativas/efeitos da radiação , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/metabolismo , Bactérias Gram-Positivas/efeitos da radiação , Interações Hidrofóbicas e Hidrofílicas , Luz , Microscopia Eletrônica de Varredura , Estrutura Molecular , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Porfirinas/química , Especificidade da Espécie , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismo , Staphylococcus aureus/efeitos da radiação
11.
Cancer Lett ; 492: 116-135, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32693200

RESUMO

The selectivity of photodynamic therapy (PDT) derived from the tailored accumulation of photosensitizing drug (photosensitizer; PS) in the tumor microenvironment (TME), and from local irradiation, turns it into a "magic bullet" for the treatment of resistant tumors without sparing the healthy tissue and possible adverse effects. However, locally-induced hypoxia is one of the undesirable consequences of PDT, which may contribute to the emergence of resistance and significantly reduce therapeutic outcomes. Therefore, the development of strategies using new approaches in nanotechnology and molecular biology can offer an increased opportunity to eliminate the disadvantages of hypoxia. Emerging evidence indicates that wisely designed phototherapeutic procedures, including: (i) ROS-tunable photosensitizers, (ii) organelle targeting, (iii) nano-based photoactive drugs and/or PS delivery nanosystems, as well as (iv) combining them with other strategies (i.e. PTT, chemotherapy, theranostics or the design of dual anticancer drug and photosensitizers) can significantly improve the PDT efficacy and overcome the resistance. This mini-review addresses the role of hypoxia and hypoxia-related molecular mechanisms of the HIF-1α pathway in the regulation of PDT efficacy. It also discusses the most recent achievements as well as future perspectives and potential challenges of PDT application against hypoxic tumors.


Assuntos
Hipóxia Celular/fisiologia , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Trifosfato de Adenosina/metabolismo , Catalase/metabolismo , DNA/metabolismo , Glutationa/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Neoplasias/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral
12.
Int J Mol Sci ; 21(8)2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-32316355

RESUMO

A class of amphiphilic photosensitizers for photodynamic therapy (PDT) was developed. Sulfonate esters of modified porphyrins bearing-F substituents in the ortho positions of the phenyl rings have adequate properties for PDT, including absorption in the red, increased cellular uptake, favorable intracellular localization, low cytotoxicity, and high phototoxicity against A549 (human lung adenocarcinoma) and CT26 (murine colon carcinoma) cells. Moreover, the role of type I and type II photochemical processes was assessed by fluorescent probes specific for various reactive oxygen species (ROS). The photodynamic effect is improved not only by enhanced cellular uptake but also by the high generation of both singlet oxygen and oxygen-centered radicals. All of the presented results support the idea that the rational design of photosensitizers for PDT can be further improved by better understanding the determinants affecting its therapeutic efficiency and explain how smart structural modifications can make them suitable photosensitizers for application in PDT.


Assuntos
Fármacos Fotossensibilizantes/química , Porfirinas/química , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Corantes Fluorescentes/química , Halogenação , Humanos , Luz , Camundongos , Microscopia Confocal , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/metabolismo , Porfirinas/farmacologia , Porfirinas/uso terapêutico , Espécies Reativas de Oxigênio/química , Oxigênio Singlete/química , Oxigênio Singlete/metabolismo
13.
Data Brief ; 30: 105444, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32258290

RESUMO

Competitiveness of seaports is a matter of interest not only to the economists, but also businesses, governments and international organizations. This data article provides quantitative data from the survey research on factors of competitiveness of container ports as perceived by shipping lines. The data was collected from around the world using an online questionnaire distributed through LinkedIn. The spatial dispersion of respondents corresponds approximately to the structure of global maritime container trade. The data provides full responses from 120 respondents. Each respondent assessed the importance of 20 predefined competitiveness factors on a scale of 1 (least important) to 10 (most important). For each respondent two additional characteristics are known, the location (continent) and the size of the company for which he/she works, measured by the number of employees. The data were used for a research article to determine the ranking of competitiveness factors for container ports entitled "Key factors of container port competitiveness: A global shipping lines perspective" [1]. The data can be used for another research to uncover relationships between factors of competitiveness (through e.g. factor analysis, cluster analysis), both for the whole world and for groups by continents or the size of the company.

14.
J Clin Med ; 9(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861531

RESUMO

: Photodynamic therapy (PDT) augments the host antitumor immune response, but the role of the PDT effect on the tumor microenvironment in dependence on the type of photosensitizer and/or therapeutic protocols has not been clearly elucidated. We employed three bacteriochlorins (F2BOH, F2BMet and Cl2BHep) of different polarity that absorb near-infrared light (NIR) and generated a large amount of reactive oxygen species (ROS) to compare the PDT efficacy after various drug-to-light intervals: 15 min. (V-PDT), 3h (E-PDT) and 72h (C-PDT). We also performed the analysis of the molecular mechanisms of PDT crucial for the generation of the long-lasting antitumor immune response. PDT-induced damage affected the integrity of the host tissue and developed acute (protocol-dependent) local inflammation, which in turn led to the infiltration of neutrophils and macrophages. In order to further confirm this hypothesis, a number of proteins in the plasma of PDT-treated mice were identified. Among a wide range of cytokines (IL-6, IL-10, IL-13, IL-15, TNF-α, GM-CSF), chemokines (KC, MCP-1, MIP1α, MIP1ß, MIP2) and growth factors (VEGF) released after PDT, an important role was assigned to IL-6. PDT protocols optimized for studied bacteriochlorins led to a significant increase in the survival rate of BALB/c mice bearing CT26 tumors, but each photosensitizer (PS) was more or less potent, depending on the applied DLI (15 min, 3 h or 72 h). Hydrophilic (F2BOH) and amphiphilic (F2BMet) PSs were equally effective in V-PDT (>80 cure rate). F2BMet was the most efficient in E-PDT (DLI = 3h), leading to a cure of 65 % of the animals. Finally, the most powerful PS in the C-PDT (DLI = 72 h) regimen turned out to be the most hydrophobic compound (Cl2BHep), allowing 100 % of treated animals to be cured at a light dose of only 45 J/cm2.

15.
Eur J Med Chem ; 184: 111740, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31605864

RESUMO

The increasingly limited therapeutic options for the treatment of infections caused by multi-resistant Gram-negative bacteria due to the alarming increase in bacteria resistance, renewed interest in photodynamic inactivation (PDI) of bacteria. We address PDI of multi-resistant bacteria with a new family of cationic tetra-imidazolyl phthalocyanines bearing a diversity of cationizing alkylic chain sizes, degrees of cationization and coordinating metals. The antimicrobial activities of the phthalocyanines under white light against Gram-positive and Gram-negative bacteria have remarkable differences in efficacy. We relate their spectroscopic and photophysical properties with the generation of reactive oxygen species (ROS), biological performance and structural features. We show that sub-micromolar concentrations of a Zn(II) tetra-ethyl cationic phthalocyanine reduce colonies of Gram-negative bacteria (E. coli, P. aeruginosa) and C. albicans by 7 log units while leaving mammalian cells unharmed. This is a new lead to address hard-to-treat localized infections.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Indóis/farmacologia , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Indóis/química , Isoindóis , Testes de Sensibilidade Microbiana , Microscopia Confocal , Estrutura Molecular , Imagem Óptica , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Processos Fotoquímicos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Sais/síntese química , Sais/química , Sais/farmacologia , Relação Estrutura-Atividade
16.
Sci Rep ; 9(1): 12655, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477749

RESUMO

Three photodynamic therapy (PDT) protocols with 15 min, 3 h and 72 h drug-to-light time intervals (DLIs) were performed using a bacteriochlorin named redaporfin, as a photosensitizer. Blood flow and pO2 changes after applying these protocols were investigated in a Lewis lung carcinoma (LLC) mouse model and correlated with long-term tumor responses. In addition, cellular uptake, cytotoxicity and photocytotoxicity of redaporfin in LLC cells were evaluated. Our in vitro tests revealed negligible cytotoxicity, significant cellular uptake, generation of singlet oxygen, superoxide ion and hydroxyl radicals in the cells and changes in the mechanism of cell death as a function of the light dose. Results of in vivo studies showed that treatment focused on vascular destruction (V-PDT) leads to a highly effective long-term antineoplastic response mediated by a strong deprivation of blood supply. Tumors in 67% of the LLC bearing mice treated with V-PDT regressed completely and did not reappear for over 1 year. This significant efficacy can be attributed to photosensitizer (PS) properties as well as distribution and accurate control of oxygen level and density of vessels before and after PDT. V-PDT has a greater potential for success than treatment based on longer DLIs as usually applied in clinical practice.


Assuntos
Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/tratamento farmacológico , Oxigênio/metabolismo , Fotoquimioterapia , Porfirinas/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Estimativa de Kaplan-Meier , Camundongos Endogâmicos C57BL , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Perfusão , Porfirinas/química , Porfirinas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Distribuição Tecidual/efeitos dos fármacos , Hipóxia Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Neurol Neurochir Pol ; 53(4): 311-314, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31441498

RESUMO

AIM: Drug-induced parkinsonism (DIP) is the most common form of parkinsonism after Parkinson's disease (PD) itself. It has been widely believed that DIP is characterised by symmetry of symptoms. Studies of patients with DIP in whom PD had been ruled out by SPECT-DaTSCAN have shown that symptom asymmetry is a common element of DIP clinical presentation. The aim of our study was to determine whether the asymmetry of symptoms in DIP is related to any abnormality within the presynaptic part of the nigrostriatal dopaminergic system. MATERIALS AND METHODS: Eleven patients with the diagnosis of DIP and asymmetric symptoms were studied. Their individual SPECT-DaTSCANs were normal. Indices calculated for the whole group of radiotracer uptake in the whole striatum, putamen and caudate contralateral to more severe DIP symptoms were compared to values obtained in the opposite hemisphere. RESULTS: We did not find significant differences in radiotracer uptake in structures contralateral to more severe clinical symptoms when compared to the homolateral hemisphere. CONCLUSIONS: Our results have not confirmed the presence of a presynaptic nigrostriatal deficit which could be related to asymmetry of DIP. The factors responsible for the asymmetry of DIP symptoms should be sought in the postsynaptic part of the nigrostriatal dopaminergic system.


Assuntos
Transtornos Parkinsonianos , Proteínas da Membrana Plasmática de Transporte de Dopamina , Humanos , Transtornos Parkinsonianos/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos
18.
Neurol Neurochir Pol ; 53(2): 138-143, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30855703

RESUMO

BACKGROUND: SPECT with radioligand DaTSCAN (SPECT-DaTSCAN) is a sensitive tool used for assessing the functional integrity of the presynaptic part of the nigrostriatal dopaminergic system. The procedure is useful whenever there is a need to distinguish between neurodegenerative parkinsonism and other parkinsonian syndromes in subjects with equivocal signs and symptoms. It can be assumed that the neurologist's decision to perform SPECT-DaTSCAN depends on his or her experience and skill in the diagnosis of parkinsonian and tremor syndromes. AIMS: To assess the accuracy of referrals to SPECT-DATSCAN made by non-movement disorders specialists. MATERIAL AND METHODS: Sixty seven patients referred for SPECT-DaTSCAN by a general neurologist were studied. In all subjects, a movement disorder specialist performed the neurological examination, collected medical history, and analysed previous treatments and the results of diagnostic tests. RESULTS: Evaluation carried out by a movement disorder specialist did not confirm an indication for SPECT-DaTSCAN in 31 patients (46.3%). General neurologists needed support for clinical diagnosis with SPECT-DaTSCAN most frequently in subjects with parkinsonism even though they were presenting a full-blown disease manifestation and even though the patients met the diagnostic criteria for Parkinson's disease or one of the atypical parkinsonian syndromes. CONCLUSIONS: Our presented results probably reflect the limited experience of general neurologists in the evaluation of parkinsonian syndromes and tremor. The use of SPECT-DaTSCAN by non-movement disorders specialists is associated with a significant risk of overuse of this tool. To minimise this risk, the skills of general neurologists in diagnosing parkinsonian and tremor syndromes should be improved. Moreover, patients should be provided with access to movement disorders specialists.


Assuntos
Transtornos Parkinsonianos , Tomografia Computadorizada de Emissão de Fóton Único , Diagnóstico Diferencial , Humanos , Especialização
19.
Bull Environ Contam Toxicol ; 102(3): 365-370, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30656355

RESUMO

The aim of this study was to examine fertility of spiny-cheek crayfish harvested in the first half of April from the Vistula Lagoon and to compare it with that of the crayfish from freshwater habitats. The sample consisted of 47 sexually mature females shortly before they were ready to lay eggs. After determining the absolute fertility (number of eggs per ovary), the relative fertility was calculated (number of eggs per 1 g of body weight). Absolute and relative fertility of spiny-cheek crayfish females with total body length 8.1-11.6 cm was 535 and 17 eggs, respectively. Absolute and relative fertility was correlated with total body length and weight. Along with the increase in these parameters, the absolute fertility increased and the relative fertility decreased. A comparison of absolute and relative fertility of spiny-cheek crayfish from the Vistula Lagoon with the representatives of this species from freshwater habitats such as the Brda River and the Lake Dgal Wielki, showed no significant differences.


Assuntos
Astacoidea/fisiologia , Monitoramento Ambiental/métodos , Fertilidade/fisiologia , Rios/química , Água do Mar/química , Animais , Astacoidea/crescimento & desenvolvimento , Peso Corporal/fisiologia , Ecossistema , Eutrofização , Feminino , Polônia , Salinidade
20.
Nucl Med Rev Cent East Eur ; 21(2): 96-99, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30070349

RESUMO

BACKGROUND: Ultrasound is the first-line imaging in the diagnostics of the urinary system. It provides valuable morphological information, but its usefulness in assessment of the function of renal parenchyma is limited. Dynamic renal scintigraphy provides much more accurate information about parenchymal function of kidneys and urinary outflow. The aim of the study was to establish morphological ultrasound criteria for high likelihood of obstructive uropathy. MATERIAL AND METHODS: 59 patients (38 women, 21 men, between 18 and 82 years old, average age 50) with the pelvis dilatation > 10 mm in one or both kidneys newly diagnosed in ultrasound, without earlier history of kidney and urinary tract diseases or renal surgery. A total of 79 kidneys were included in the study. Ultrasound and dynamic renal scintigraphy were performed on the same day. In ultrasound, maximum anteroposterior diameter of the renal pelvis (mAPD) and anteroposterior pelvic diameter at hilum (hAPD) were obtained. The ratio of total pelvicalyceal area to the whole kidney area (%PCS) was also calculated. Uropathy was determined by the positive diuretic test in renal scintigraphy performed using 111 MBq of 99mTc-EC. RESULTS: In dynamic renal scintigraphy, features of uropathy were found in 18 out of 79 kidneys (23%). Optimal thresholds for detection of obstructive uropathy for measured ultrasound parameters were determined based on the ROC curves: mAPD ≥ 23 mm (sensitivity 94%, specificity 76%, accuracy 80%, AUROC 0.91) hAPD ≥ 20 mm (sensitivity 78%, specificity 87%, accuracy 85%, AUROC 0.82) PCA/WKA ≥ 22% (sensitivity 83%, specificity 74%, accuracy 76%, AUROC 0.85). CONCLUSIONS: Determined thresholds of parameters measuring pelvicalyceal dilatation in ultrasound, including the easiest one to obtain in routine diagnostics - mADP, provide satisfactory effectiveness in isolating kidneys with high likelihood of obstructive uropathy. Their application can optimize the selection of patients for further kidney diagnostic imaging (dynamic renal scintigrapy or urography).


Assuntos
Rim/diagnóstico por imagem , Rim/fisiopatologia , Sistema Urinário/diagnóstico por imagem , Urina , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cintilografia , Ultrassonografia , Adulto Jovem
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