Photodynamic therapy (PDT) is a special form of phototherapy in which oxygen is needed, in addition to light and a drug called a photosensitiser (PS), to create cytotoxic species that can destroy ...cancer cells and various pathogens. PDT is often used in combination with other antitumor and antimicrobial therapies to sensitise cells to other agents, minimise the risk of resistance and improve overall outcomes. Furthermore, the aim of combining two photosensitising agents in PDT is to overcome the shortcomings of the monotherapeutic approach and the limitations of individual agents, as well as to achieve synergistic or additive effects, which allows the administration of PSs in lower concentrations, consequently reducing dark toxicity and preventing skin photosensitivity. The most common strategies in anticancer PDT use two PSs to combine the targeting of different organelles and cell-death mechanisms and, in addition to cancer cells, simultaneously target tumour vasculature and induce immune responses. The use of PDT with upconversion nanoparticles is a promising approach to the treatment of deep tissues and the goal of using two PSs is to improve drug loading and singlet oxygen production. In antimicrobial PDT, two PSs are often combined to generate various reactive oxygen species through both Type I and Type II processes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The bacterium Legionella pneumophila is still one of the probable causes of waterborne diseases, causing serious respiratory illnesses. In the aquatic systems, L. pneumophila exists inside ...free-living amoebae or can form biofilms. Currently developed disinfection methods are not sufficient for complete eradication of L. pneumophila biofilms in water systems of interest. Photodynamic inactivation (PDI) is a method that results in an antimicrobial effect by using a combination of light and a photosensitizer (PS). In this work, the effect of PDI in waters of natural origin and of different hardness, as a treatment against L. pneumophila biofilm, was investigated. Three cationic tripyridylporphyrins, which were previously described as efficient agents against L. pneumophila alone, were used as PSs. We studied how differences in water hardness affect the PSs’ stability, the production of singlet oxygen, and the PDI activity on L. pneumophila adhesion and biofilm formation and in biofilm destruction. Amphiphilic porphyrin showed a stronger tendency for aggregation in hard and soft water, but its production of singlet oxygen was higher in comparison to tri- and tetracationic hydrophilic porphyrins that were stable in all water samples. All three studied porphyrins were shown to be effective as PDI agents against the adhesion of the L. pneumophila to polystyrene, against biofilm formation, and in the destruction of the formed biofilm, in their micromolar concentrations. However, a higher number of dissolved ions, i.e., water hardness, generally reduced somewhat the PDI activity of all the porphyrins at all tested biofilm growth stages.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
is an environmental bacterium, an opportunistic premise plumbing pathogen that causes the Legionnaires' disease.
presents a serious health hazard in building water systems, due to its high resistance ...to standard water disinfection methods. Our aim was to study the use of photodynamic inactivation (PDI) against
. We investigated and compared the photobactericidal potential of five cationic dyes. We tested toluidine blue (TBO) and methylene blue (MB), and three 3-
-methylpyridylporphyrins, one tetra-cationic and two tri-cationic, one with a short (CH
) and the other with a long (C
H
) alkyl chain, against
in tap water and after irradiation with violet light. All tested dyes demonstrated a certain dark toxicity against
; porphyrins with lower minimal effective concentration (MEC) values than TBO and MB. Nanomolar MEC values, significantly lower than with TBO and MB, were obtained with all three porphyrins in PDI experiments, with amphiphilic porphyrin demonstrating the highest PDI activity. All tested dyes showed increasing PDI with longer irradiation (0-108 J/cm
), especially the two hydrophilic porphyrins. All three porphyrins caused significant changes in cell membrane permeability after irradiation and
, co-cultivated with
after treatment with all three porphyrins and irradiation, did not recover in amoeba. We believe our results indicate the considerable potential of cationic porphyrins as effective anti-
agents.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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•Photophysical properties of two porphyrin photosensitizers studied.•Absorption and fluorescence spectra measured in different solvents.•Fluorescence decays measured by ...time-correlated single photon counting.•Optimized structures calculated at the TD-B3LYP/6-31++G(d,p) level of theory.•The triplet excited state lifetimes measured by laser flash photolysis.
The spectral and photophysical properties of two porphyrins, 5-(4-acetamidophenyl)-10,15,20-tris(N-methylpyridinium-3-yl)porphyrin trichloride (1) and its Zn(II) complex 2 were investigated in different solvents by absorption, steady-state and time-resolved fluorescence spectroscopy, and laser flash photolysis. The findings were corroborated by computations at the TD-B3LYP/6-31++G(d,p) level of theory. The absorption spectra of 1 and 2 are the typical for porphyrins and their Zn complexes with the Soret bands at ≈ 420 nm and 430 nm, respectively, and the Q-bands at 515–650 nm, and 560–605 nm. Smaller differences in the absorption spectra compared to the symmetric porphyrins were assigned to more pronounced HOMO and HOMO-1 energy levels splitting in the asymmetric molecules. The temperature dependence of the absorption spectra with hypsochromic shifts suggests the formation of H-aggregates. The emission spectra are situated at 600–700 nm, and the vibronic resolution of the spectra for 1 depends on the solvent and the excitation wavelength, which was assigned due to the tautomerism by H-transfer within the porphyrin core. Quantum yields of fluorescence for 1 and 2 in methanolic solutions are Φf = 0.072 and 0.051, respectively. Although, the steady-state fluorescence spectra do not indicate that 1 and 2 form aggregates in methanolic and aqueous solutions (at <10-4 M), singlet decays measured by time-correlated single photon counting for both compounds were fit to multiexponential functions, which was explained by formation of aggregates in more concentrated solutions. Furthermore, at very high concentrations of 1 in CH3OH (>10-4 M), the dynamic formation of aggregates was evidenced by new bathochromically shifted band in the emission spectrum and the growth kinetics in the time-resolved fluorescence measurement. Triplet excited states of 1 and 2 were probed by laser flash photolysis. The triplets are populated with quantum yields of intersystem crossing, ΦISC = 0.34 and 0.41, respectively and lifetimes of the triplet excited states are in millisecond time-scale. Both triplets are quenched by O2 with the rate constants approaching diffusion limits. Relative quantum yields for the singlet oxygen formation are 0.86 and 0.92 respectively, rendering porphyrins 1 and 2 applicable for photodynamic therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Opportunistic premise plumbing pathogens (OPPPs) form a group of microorganisms that normally live in water supply systems and have adapted especially well to the conditions in premise plumbing ...systems, and as such pose a threat to human health. Since the beginning of the 21st century, this threat has been escalating, and it is becoming increasingly evident that current water disinfection methods fall short in effectively controlling these pathogens. In researching new approaches to this emergency, phototherapy looks promising, especially one that combines photosensitizers, light, and oxygen, which is known as photodynamic inactivation (PDI). This review describes the main characteristics of the recognized (Pseudomonas aeruginosa, Legionella pneumophila, and Mycobacterium avium) and most important emerging OPPPs, and it offers a brief overview of current disinfection methods and their limitations in the fight against OPPPs. The principle and outcomes of PDI with endogenous and, in particular, exogenous photosensitizers are then explained and described through representative examples of PDI on recognized and emerging OPPPs and their biofilms. Finally, the prospects and future directions of PDI research in water disinfection and control of OPPPs are discussed.
There is an increasing need to discover effective methods for treating municipal wastewater and addressing the threat of multidrug-resistant (MDR) strains of bacteria spreading into the environment ...and drinking water. Photodynamic inactivation (PDI) that combines a photosensitiser and light in the presence of oxygen to generate singlet oxygen and other reactive species, which in turn react with a range of biomolecules, including the oxidation of bacterial genetic material, may be a way to stop the spread of antibiotic-resistant genes. The effect of 5,10,15,20-(pyridinium-3-yl)porphyrin tetrachloride (TMPyP3) without light, and after activation with violet-blue light (VBL) (394 nm; 20 mW/cm.sup.2 ), on MDR strains of Pseudomonas aeruginosa, Klebsiella pneumoniae and K. pneumoniae OXA-48 in tap water and municipal wastewater was investigated. High toxicity (~2 muM) of TMPyP3 was shown in the dark on both strains of K. pneumoniae in tap water, while on P. aeruginosa toxicity in the dark was low (50 muM) and the PDI effect was significant (1.562 muM). However, in wastewater, the toxicity of TMPyP3 without photoactivation was much lower (12.5-100 muM), and the PDI effect was significant for all three bacterial strains, already after 10 min of irradiation with VBL (1.562-6.25 muM). In the same concentrations, or even lower, an anti-adhesion effect was shown, suggesting the possibility of application in biofilm control. By studying the kinetics of photoinactivation, it was found that with 1,562 muM of TMPyP3 it is possible to achieve the complete destruction of all three bacteria after 60 min of irradiation with VBL. This study confirmed the importance of studying the impact of water constituents on the properties and PDI effect of the applied photosensitiser, as well as checking the sensitivity of targeted bacteria to light of a certain wavelength, in conditions as close as possible to those in the intended application, to adjust all parameters and perfect the method.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A series of N‐methylated and N‐oxidised tripyridyl porphyrins were synthesised, characterised, and their PDT activity was studied with six cell lines. All the tested porphyrins with a long alkyl ...chain, except one, were more efficient for PDT than an N‐methylated hydrophilic porphyrin and N‐oxidised porphyrin without the long alkyl chain. Generally, N‐methylated tripyridyl porphyrins were more active than those N‐oxidised, but IC50 values for phototoxicity of two N‐oxides, named TOPyP3‐C17H33O and TOPyP3‐C17H35, were still in the nanomolar concentration range for most of the tested cell lines. However, TOPyP3‐C17H35 did not show phototoxicity on human foreskin fibroblast cells. Two methylated amphiphilic porphyrins, named TMPyP3‐C17H33 and TMPyP4‐C17H35, showed significant dark toxicity, whereas none of the oxidopyridyl porphyrins were toxic without light activation. The selected photosensitisers were shown to be apoptosis inducers, and had inhibitory effects on the clonogenic growth of HCT116 and HeLa cells. All three N‐methylated amphiphilic porphyrins significantly reduced the migratory potential of HCT116 cells. Porphyrins TMPyP3‐C17H35 and TOPyP3‐C17H35 reduced the activity of acid ceramidase, whereas TOPyP3‐C17H33O had a significant inhibitory effect on sphingosine kinase 1 activity in HeLa cells. Compounds with this dual activity were shown to be the most promising photosensitisers, with potential to treat invasive cancers.
A red light for cancer: With the aim of targeting sphingolipid metabolism for improved photodynamic therapy, N‐methylated and N‐oxidised tripyridyl porphyrins with long alkyl chains were shown to inhibit acid ceramidase and sphingosine kinase 1, and were efficient photosensitisers for the direct killing of cancer cells and the inhibition of clonogenic growth and migration. Thus, these compounds show potential to advance current treatment strategies for cancer patients.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Porphyrins are frequently employed in photodynamic therapy (PDT), a non-invasive technique primarily utilized to treat subcutaneous cancers, as photosensitizing agents (PAs). The development of a new ...PA with improved tissue selectivity and efficacy is crucial for expanding the application of PDT for the management of diverse cancers. We investigated the systemic effects of 5,10,15,20-tetrakis(N-methylpyridinium-3-yl)-porphyrin (TMPyP3) using Drosophila melanogaster adult males. We established the oral administration schedule and demonstrated that TMPyP3 was absorbed and stored higher in neuronal than in non-neuronal extracts. Twenty-four hours after oral TMPyP3 photoactivation, the quantity of hydrogen peroxide (H2O2) increased, but exclusively in the head extracts. Regardless of photoactivation, TMPyP3 resulted in a reduced concentration of H2O2 after 7 days, and this was linked with a decreased capacity to climb, as indicated by negative geotaxis. The findings imply that systemic TMPyP3 therapy may disrupt redox regulation, impairing cellular signaling and behavioral outcomes in the process. To determine the disruptive effect of porphyrins on redox homeostasis, its duration, and the mechanistic variations in retention across various tissues, more research is required.
We used the genomic breakpoint between BCR and ABL1 genes for the DNA-based monitoring of minimal residual disease (MRD) in 48 patients with childhood acute lymphoblastic leukemia (ALL). Comparing ...the results with standard MRD monitoring based on immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements and with quantification of IKZF1 deletion, we observed very good correlation for the methods in a majority of patients; however, >20% of children (25% 8/32 with minor and 12.5% 1/8 with major-BCR-ABL1 variants in the consecutive cohorts) had significantly (>1 log) higher levels of BCR-ABL1 fusion than Ig/TCR rearrangements and/or IKZF1 deletion. We performed cell sorting of the diagnostic material and assessed the frequency of BCR-ABL1-positive cells in various hematopoietic subpopulations; 12% to 83% of non–ALL B lymphocytes, T cells, and/or myeloid cells harbored the BCR-ABL1 fusion in patients with discrepant MRD results. The multilineage involvement of the BCR-ABL1-positive clone demonstrates that in some patients diagnosed with BCR-ABL1-positive ALL, a multipotent hematopoietic progenitor is affected by the BCR-ABL1 fusion. These patients have BCR-ABL1-positive clonal hematopoiesis resembling a chronic myeloid leukemia (CML)–like disease manifesting in “lymphoid blast crisis.” The biological heterogeneity of BCR-ABL1-positive ALL may impact the patient outcomes and optimal treatment (early stem cell transplantation vs long-term administration of tyrosine-kinase inhibitors) as well as on MRD testing. Therefore, we recommend further investigations on CML-like BCR-ABL1-positive ALL.
•Combination of Ig/TCR and BCR-ABL1 genomic approach for MRD monitoring in childhood ALL reveals patients with CML-like disease.•Monitoring ALL using BCR-ABL1 genomic breakpoint is feasible and enables the most specific and sensitive MRD quantification.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Demografski podaci grada Rijeke pokazuju nastavak trenda porasta starenja populacije (19,7% starijih pod 65 godina), udio samačkih domaćinstava je također sve veći (22%). Ozljede kod stanovnika ...starijih od 65 godina najčešće su vezane uz prijelome (2508), dislokacije, uganoća i nategnuća (397), čime se smanjuje kvaliteta života stanovništva i povećavaju javnozdravstveni troškovi. Ciljana populacija su sve osobe starije od 65 godina u gradu Rijeci, samostalno pokretni koji žive u privatnim kućanstvima. Kroz program se želi postići da veći broj osoba vježba u svom domu, da se uključuje u aktivnosti klubova umirovljenika, da prakticira zaštitna ponašanja (reorganizira dom i delegira poslove), povećanje fizičke spremnosti kod ciljane populacije, bolja koncentracija, sigurnije životno okruženje te manji broj padova i lomova, bolja kvaliteta života kao i manji troškovi zdravstvenog sustava. Opravdanost ovog projekta pronalazi se i u podacima dobivenim kroz provedbe fokus grupa koje su pokazale da veći broj umirovljenika ne posjećuje klubove, nemaju informacije o prevenciji padova, manji broj umirovljenika koristi organizirano vježbanje, žele biti informirani o prevenciji padova i da su aktivni članovi spremni doći do onih neaktivnih kako bi ih informirali. Aktivnosti kroz koje želimo ostvariti naše ciljeve su predavanja za ciljanu populaciju o opasnostima od padova s ozbiljnim zdravstvenim posljedicama te o važnosti vježbanja i mogućnostima vježbanja u kući, emitirati tematske emisije na televiziji i radiju, distribuirati postere u centre primarne zdravstvene zaštite, ljekarne, mjesne odbore i autobusne stanice), letke o sigurnosnim ponašanjima u domu i izvan, plakate s preporukama osoba i obrta za sitne radove u kući. Evaluacija provedenog dijela aktivnosti pilot predavanja pokazuje da je moguće promijeniti stav i povećati svjesnost o važnosti samozaštitnih ponašanja.
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