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Cellular and Molecular Gastroenterology... 2019Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria... (Review)
Review
Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria include photosensitivity, liver damage and increased risk of hepatocellular carcinoma, and neurovisceral involvement, including seizures. Fluorescent porphyrins that include protoporphyrin-IX, uroporphyrin and coproporphyrin, are photo-reactive; they absorb light energy and are excited to high-energy singlet and triplet states. Decay of the porphyrin excited to ground state releases energy and generates singlet oxygen. Porphyrin-induced oxidative stress is thought to be the major mechanism of porphyrin-mediated tissue damage. Although this explains the acute photosensitivity in most porphyrias, light-induced porphyrin-mediated oxidative stress does not account for the effect of porphyrins on internal organs. Recent findings demonstrate the unique role of fluorescent porphyrins in causing subcellular compartment-selective protein aggregation. Porphyrin-mediated protein aggregation associates with nuclear deformation, cytoplasmic vacuole formation and endoplasmic reticulum dilation. Porphyrin-triggered proteotoxicity is compounded by inhibition of the proteasome due to aggregation of some of its subunits. The ensuing disruption in proteostasis also manifests in cell cycle arrest coupled with aggregation of cell proliferation-related proteins, including PCNA, cdk4 and cyclin B1. Porphyrins bind to native proteins and, in presence of light and oxygen, oxidize several amino acids, particularly methionine. Noncovalent interaction of oxidized proteins with porphyrins leads to formation of protein aggregates. In internal organs, particularly the liver, light-independent porphyrin-mediated protein aggregation occurs after secondary triggers of oxidative stress. Thus, porphyrin-induced protein aggregation provides a novel mechanism for external and internal tissue damage in porphyrias that involve fluorescent porphyrin accumulation.
Topics: Animals; Carcinoma, Hepatocellular; Dermatitis, Phototoxic; Heme; Humans; Liver; Liver Neoplasms; Mice; Oxidation-Reduction; Oxidative Stress; Photosensitivity Disorders; Porphyrias; Porphyrins; Protein Aggregates; Protoporphyrins; Uroporphyrins; Zebrafish
PubMed: 31233899
DOI: 10.1016/j.jcmgh.2019.06.006 -
Life Science Alliance Jul 2024All cancer cells reprogram metabolism to support aberrant growth. Here, we report that cancer cells employ and depend on imbalanced and dynamic heme metabolic pathways,...
All cancer cells reprogram metabolism to support aberrant growth. Here, we report that cancer cells employ and depend on imbalanced and dynamic heme metabolic pathways, to accumulate heme intermediates, that is, porphyrins. We coined this essential metabolic rewiring "porphyrin overdrive" and determined that it is cancer-essential and cancer-specific. Among the major drivers are genes encoding mid-step enzymes governing the production of heme intermediates. CRISPR/Cas9 editing to engineer leukemia cell lines with impaired heme biosynthetic steps confirmed our whole-genome data analyses that porphyrin overdrive is linked to oncogenic states and cellular differentiation. Although porphyrin overdrive is absent in differentiated cells or somatic stem cells, it is present in patient-derived tumor progenitor cells, demonstrated by single-cell RNAseq, and in early embryogenesis. In conclusion, we identified a dependence of cancer cells on non-homeostatic heme metabolism, and we targeted this cancer metabolic vulnerability with a novel "bait-and-kill" strategy to eradicate malignant cells.
Topics: Humans; Heme; Porphyrins; Cell Line, Tumor; CRISPR-Cas Systems; Neoplasms; Metabolic Networks and Pathways; Cell Differentiation; Gene Editing; Animals; Mice
PubMed: 38649187
DOI: 10.26508/lsa.202302547 -
International Journal of Molecular... May 2022Oxygen evolution reaction (OER) plays a pivotal role in the development of renewable energy methods, such as water-splitting devices and the use of Zn-air batteries.... (Review)
Review
Oxygen evolution reaction (OER) plays a pivotal role in the development of renewable energy methods, such as water-splitting devices and the use of Zn-air batteries. First-row transition metal complexes are promising catalyst candidates due to their excellent electrocatalytic performance, rich abundance, and cheap price. Metalloporphyrins are a class of representative high-efficiency complex catalysts owing to their structural and functional characteristics. However, OER based on porphyrin systems previously have been paid little attention in comparison to the well-described oxygen reduction reaction (ORR), hydrogen evolution reaction, and CO reduction reaction. Recently, porphyrin-based systems, including both small molecules and porous polymers for electrochemical OER, are emerging. Accordingly, this review summarizes the recent advances of porphyrin-based systems for electrochemical OER. Firstly, the electrochemical OER for water oxidation is discussed, which shows various methodologies to achieve catalysis from homogeneous to heterogeneous processes. Subsequently, the porphyrin-based catalytic systems for bifunctional oxygen electrocatalysis including both OER and ORR are demonstrated. Finally, the future development of porphyrin-based catalytic systems for electrochemical OER is briefly prospected.
Topics: Catalysis; Oxidation-Reduction; Oxygen; Porphyrins; Water
PubMed: 35682721
DOI: 10.3390/ijms23116036 -
Molecules (Basel, Switzerland) Aug 2023Tolyporphins were discovered some 30 years ago as part of a global search for antineoplastic compounds from cyanobacteria. To date, the culture HT-58-2, comprised of a... (Review)
Review
Tolyporphins were discovered some 30 years ago as part of a global search for antineoplastic compounds from cyanobacteria. To date, the culture HT-58-2, comprised of a cyanobacterium-microbial consortium, is the sole known producer of tolyporphins. Eighteen tolyporphins are now known-each is a free base tetrapyrrole macrocycle with a dioxobacteriochlorin (14), oxochlorin (3), or porphyrin (1) chromophore. Each compound displays two, three, or four open β-pyrrole positions and two, one, or zero appended -glycoside (or -OH or -OAc) groups, respectively; the appended groups form part of a geminal disubstitution motif flanking the oxo moiety in the pyrroline ring. The distinct structures and repertoire of tolyporphins stand alone in the large pigments-of-life family. Efforts to understand the cyanobacterial origin, biosynthetic pathways, structural diversity, physiological roles, and potential pharmacological properties of tolyporphins have attracted a broad spectrum of researchers from diverse scientific areas. The identification of putative biosynthetic gene clusters in the HT-58-2 cyanobacterial genome and accompanying studies suggest a new biosynthetic paradigm in the tetrapyrrole arena. The present review provides a comprehensive treatment of the rich science concerning tolyporphins.
Topics: Tetrapyrroles; Cyanobacteria; Porphyrins; Cardiac Glycosides
PubMed: 37630384
DOI: 10.3390/molecules28166132 -
Molecules (Basel, Switzerland) May 2022Porphyrin ligands, showing a significant affinity for cancer cells, also have the ability to chelate metallic radioisotopes to form potential diagnostic... (Review)
Review
Porphyrin ligands, showing a significant affinity for cancer cells, also have the ability to chelate metallic radioisotopes to form potential diagnostic radiopharmaceuticals. They can be applied in single-photon emission computed tomography (SPECT) and positron emission tomography (PET) to evaluate metabolic changes in the human body for tumor diagnostics. The aim of this paper is to present a short overview of the main metallic radionuclides complexed by porphyrin ligands and used in these techniques. These chelation reactions are discussed in terms of the complexation conditions and kinetics and the complex stability.
Topics: Chelating Agents; Humans; Ligands; Molecular Imaging; Nuclear Medicine; Porphyrins; Radioisotopes
PubMed: 35630788
DOI: 10.3390/molecules27103311 -
ACS Applied Bio Materials Dec 2023This study presents the synthesis and characterization of monosubstituted cationic porphyrin as a photodynamic therapeutic agent. Cationic porphyrin was converted into...
This study presents the synthesis and characterization of monosubstituted cationic porphyrin as a photodynamic therapeutic agent. Cationic porphyrin was converted into ionic materials by using a single-step ion exchange reaction. The small iodide counteranion was replaced with bulky BETI and IR783 anions to reduce aggregation and enhance the photodynamic effect of porphyrin. Carrier-free ionic nanomedicines were then prepared by using the reprecipitation method. The photophysical characterization of parent porphyrin, ionic materials, and ionic nanomaterials, including absorbance, fluorescence and phosphorescence emission, quantum yield, radiative and nonradiative rate, and lifetimes, was performed. The results revealed that the counteranion significantly affects the photophysical properties of porphyrin. The ionic nanomaterials exhibited an increase in the reactive oxygen yield and enhanced cytotoxicity toward the MCF-7 cancer cell line. Examination of results revealed that the ionic materials exhibited an enhanced photodynamic therapeutic activity with a low IC value (nanomolar) in cancerous cells. These nanomedicines were mainly localized in the mitochondria. The improved light cytotoxicity is attributed to the enhanced photophysical properties and positive surface charge of the ionic nanomedicines that facilitate efficient cellular uptake. These results demonstrate that ionic material-based nanodrugs are promising photosensitizers for photodynamic therapy.
Topics: Humans; Porphyrins; Nanomedicine; Photochemotherapy; Photosensitizing Agents; Cations
PubMed: 38063308
DOI: 10.1021/acsabm.3c00809 -
Antimicrobial Agents and Chemotherapy 2015Acanthamoeba is a protist pathogen that can cause serious human infections, including blinding keratitis and a granulomatous amoebic encephalitis that almost always...
Acanthamoeba is a protist pathogen that can cause serious human infections, including blinding keratitis and a granulomatous amoebic encephalitis that almost always results in death. The current treatment for these infections includes a mixture of drugs, and even then, a recurrence can occur. Photochemotherapy has shown promise in the treatment of Acanthamoeba infections; however, the selective targeting of pathogenic Acanthamoeba has remained a major concern. The mannose-binding protein is an important adhesin expressed on the surface membranes of pathogenic Acanthamoeba organisms. To specifically target Acanthamoeba, the overall aim of this study was to synthesize a photosensitizing compound (porphyrin) conjugated with mannose and test its efficacy in vitro. The synthesis of mannose-conjugated porphyrin was achieved by mixing benzaldehyde and pyrrole, yielding tetraphenylporphyrin. Tetraphenylporphyrin was then converted into mono-nitrophenylporphyrin by selectively nitrating the para position of the phenyl rings, as confirmed by nuclear magnetic resonance (NMR) spectroscopy. The mono-nitrophenylporphyrin was reduced to mono-aminophenylporphyrin in the presence of tin dichloride and confirmed by a peak at m/z 629. Finally, mono-aminoporphyrin was conjugated with mannose, resulting in the formation of an imine bond. Mannose-conjugated porphyrin was confirmed through spectroscopic analysis and showed that it absorbed light of wavelengths ranging from 425 to 475 nm. To determine the antiacanthamoebic effects of the derived product, amoebae were incubated with mannose-conjugated porphyrin for 1 h and washed 3 times to remove extracellular compound. Next, the amoebae were exposed to light of the appropriate wavelength for 1 h. The results revealed that mannose-conjugated porphyrin produced potent trophicidal effects and blocked excystation. In contrast, Acanthamoeba castellanii incubated with mannose alone and porphyrin alone did not exhibit an antiamoebic effect. Consistently, pretreatment with mannose-conjugated porphyrin reduced the A. castellanii-mediated host cell cytotoxicity from 97% to 4.9%. In contrast, treatment with porphyrin, mannose, or solvent alone had no protective effects on the host cells. These data suggest that mannose-conjugated porphyrin has application for the targeted photodynamic therapy of Acanthamoeba infections and may serve as a model in the development of therapeutic interventions against other eukaryotic infections.
Topics: Acanthamoeba castellanii; Antiprotozoal Agents; Benzaldehydes; Cell Line; Cells, Cultured; Humans; Magnetic Resonance Spectroscopy; Mannose; Porphyrins; Pyrroles
PubMed: 25753633
DOI: 10.1128/AAC.05126-14 -
Molecules (Basel, Switzerland) Jul 2019Antibiotics are commonly used to control, treat, or prevent bacterial infections, however bacterial resistance to all known classes of traditional antibiotics has... (Review)
Review
Antibiotics are commonly used to control, treat, or prevent bacterial infections, however bacterial resistance to all known classes of traditional antibiotics has greatly increased in the past years especially in hospitals rendering certain therapies ineffective. To limit this emerging public health problem, there is a need to develop non-incursive, non-toxic, and new antimicrobial techniques that act more effectively and quicker than the current antibiotics. One of these effective techniques is antibacterial photodynamic therapy (aPDT). This review focuses on the application of porphyrins in the photo-inactivation of bacteria. Mechanisms of bacterial resistance and some of the current 'greener' methods of synthesis of meso-phenyl porphyrins are discussed. In addition, significance and limitations of aPDT are also discussed. Furthermore, we also elaborate on the current clinical applications and the future perspectives and directions of this non-antibiotic therapeutic strategy in combating infectious diseases.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Humans; Light; Photochemotherapy; Porphyrins
PubMed: 31277423
DOI: 10.3390/molecules24132456 -
Molecules (Basel, Switzerland) Apr 2020Porphyrins and analogous macrocycles exhibit interesting photochemical, catalytic, and luminescence properties demonstrating high potential in the treatment of several... (Review)
Review
Porphyrins and analogous macrocycles exhibit interesting photochemical, catalytic, and luminescence properties demonstrating high potential in the treatment of several diseases. Among them can be highlighted the possibility of application in photodynamic therapy and antimicrobial/antiparasitic PDT, for example, of malaria parasite. However, the low efficiency generally associated with their low solubility in water and bioavailability have precluded biomedical applications. Nanotechnology can provide efficient strategies to enhance bioavailability and incorporate targeted delivery properties to conventional pharmaceuticals, enhancing the effectiveness and reducing the toxicity, thus improving the adhesion to the treatment. In this way, those limitations can be overcome by using two main strategies: (1) Incorporation of hydrophilic substituents into the macrocycle ring while controlling the interaction with biological systems and (2) by including them in nanocarriers and delivery nanosystems. This review will focus on antiparasitic drugs based on porphyrin derivatives developed according to these two strategies, considering their vast and increasing applications befitting the multiple roles of these compounds in nature.
Topics: Antiparasitic Agents; Biosensing Techniques; Drug Compounding; Humans; Indoles; Isoindoles; Molecular Structure; Porphyrins; Structure-Activity Relationship
PubMed: 32365664
DOI: 10.3390/molecules25092080 -
Molecules (Basel, Switzerland) Jun 2017This review covers the synthesis of coumarin-porphyrin, coumarin-phthalocyanine and coumarin-corrole conjugates and their potential applications. While... (Review)
Review
This review covers the synthesis of coumarin-porphyrin, coumarin-phthalocyanine and coumarin-corrole conjugates and their potential applications. While coumarin-phthalocyanine conjugates were obtained almost exclusively by tetramerization of coumarin-functionalized phthalonitriles, coumarin-porphyrin and coumarin-corrole conjugates were prepared by complementary approaches: (a) direct synthesis of the tetrapyrrolic macrocycle using formylcoumarins and pyrrole or (b) by functionalization of the tetrapyrrolic macrocycle. In the last approach a range of reaction types were used, namely 1,3-dipolar cycloadditions, hetero-Diels-Alder, Sonogashira, alkylation or acylation reactions. This is clearly a more versatile approach, leading to a larger diversity of conjugates and allowing the access to conjugates bearing one to up to 16 coumarin units.
Topics: Alkylation; Coumarins; Indoles; Isoindoles; Molecular Structure; Porphyrins; Pyrroles
PubMed: 28617340
DOI: 10.3390/molecules22060994