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Journal of Molecular Recognition : JMR Aug 2023The G-quadruplex planar-ligand complex is used to detect heavy metal cations such as Ag , Cu , Pb , Hg , organic molecules, nucleic acids, and proteins. The interaction...
The G-quadruplex planar-ligand complex is used to detect heavy metal cations such as Ag , Cu , Pb , Hg , organic molecules, nucleic acids, and proteins. The interaction of the three planar porphyrins (L1), 5,10,15,20-tetrakis (1-ethyl-1-λ -pyridine-4-yl) porphyrin (L2), and 5,10,15,20-tetrakis (1-methyl-1-λ -pyridine-4-yl) porphyrin (L3), coming from the porphyrin family, with G-quadruplex obtained from human DNA telomeres in the presence of lithium, sodium, potassium, rubidium, cesium, magnesium, and calcium ions was studied by molecular dynamics simulation. When G-quadruplex containing divalent ions of magnesium and calcium interacts with L1, L2, and L3 ligands, the hydrogen bonds of the lower G-quadruplex sheet are more affected by ligands and the distance between guanines in the lower tetrad increases. In the case of G-quadruplex interactions containing monovalent ions with ligands, the hydrogen bond between the sheets does not follow a specific trend. For example, in the presence of lithium ions, the upper and middle sheets are more affected by ligands, while they are less affected by ligands in the presence of sodium. The binding pocket and the binding energy of the three ligands to the G-quadruplex were also obtained in the various systems. The results show that ligands make the G-quadruplex more stable through the penetration between the sheets and the interaction with the loops. Among the ligands mentioned, the interaction level of the ligand L2 is greater than the others. Our calculations are consistent with the previous experimental observations so that it can help to understand the molecular mechanism of porphyrin interaction and its derivatives with the G-quadruplex.
Topics: Humans; Porphyrins; Ligands; Lithium; Calcium; Magnesium; G-Quadruplexes; Cations; Pyridines; Sodium
PubMed: 37025015
DOI: 10.1002/jmr.3017 -
Journal of Inorganic Biochemistry Sep 2023Heme proteins perform diverse biochemical functions using a single iron porphyrin cofactor. This versatility makes them attractive platforms for the development of new... (Review)
Review
Heme proteins perform diverse biochemical functions using a single iron porphyrin cofactor. This versatility makes them attractive platforms for the development of new functional proteins. While directed evolution and metal substitution have expanded the properties, reactivity, and applications of heme proteins, the incorporation of porphyrin analogs remains an underexplored approach. This review discusses the replacement of heme with non-porphyrin cofactors, such as porphycene, corrole, tetradehydrocorrin, phthalocyanine, and salophen, and the attendant properties of these conjugates. While structurally similar, each ligand exhibits distinct optical and redox properties, as well as unique chemical reactivity. These hybrids serve as model systems to elucidate the effects of the protein environment on the electronic structure, redox potentials, optical properties, or other features of the porphyrin analog. Protein encapsulation can confer distinct chemical reactivity or selectivity of artificial metalloenzymes that cannot be achieved with the small molecule catalyst alone. Additionally, these conjugates can interfere with heme acquisition and uptake in pathogenic bacteria, providing an inroad to innovative antibiotic strategies. Together, these examples illustrate the diverse functionality that can be achieved by cofactor substitution. The further expansion of this approach will access unexplored chemical space, enabling the development of superior catalysts and the creation of heme proteins with emergent properties.
Topics: Hemeproteins; Metalloproteins; Heme; Oxidation-Reduction; Metals
PubMed: 37320889
DOI: 10.1016/j.jinorgbio.2023.112282 -
Small (Weinheim An Der Bergstrasse,... Nov 2023Nonplanar porphyrins with out-of-plane distortions play crucial roles in many biological functions and chemical applications. The artificial construction of nonplanar...
Nonplanar porphyrins with out-of-plane distortions play crucial roles in many biological functions and chemical applications. The artificial construction of nonplanar porphyrins usually involves organic synthesis and modification, which is a highly comprehensive approach. However, incorporating porphyrins into guest-stimulated flexible systems allows to manipulate the porphyrin distortion through simple ad/desorption of guest molecules. Here, a series of porphyrinic zirconium metal-organic frameworks (MOFs) is reported that exhibit guest-stimulated breathing behavior. X-Ray diffraction analysis and skeleton deviation plots confirm that the material suffers from porphyrin distortion to form a ruffled geometry under the desorption of guest molecules. Further investigation reveals that not only the degree of nonplanarity can be precisely manipulated but also the partial distortion of porphyrin in a single crystal grain can be readily achieved. As Lewis acidic catalyst, the MOF with nonplanar Co-porphyrin exhibits active properties in catalyzing CO /propylene oxide coupling reactions. This porphyrin distortion system provides a powerful tool for manipulating nonplanar porphyrins in MOFs with individual distortion profiles for various advanced applications.
PubMed: 37394703
DOI: 10.1002/smll.202304771 -
Current Treatment Options in Oncology Sep 2023Photodynamic therapy (PDT) has garnered increasing attention in cancer treatment because of its advantages such as minimal invasiveness and selective destruction. With... (Review)
Review
Photodynamic therapy (PDT) has garnered increasing attention in cancer treatment because of its advantages such as minimal invasiveness and selective destruction. With the development of PDT, impressive progress has been made in the preparation of photosensitizers, particularly porphyrin photosensitizers. However, the limited tissue penetration of the activating light wavelengths and relatively low light energy capture efficiency of porphyrin photosensitizers are two major disadvantages in conventional photosensitizers. Therefore, tissue penetration needs to be enhanced and the light energy capture efficiency of porphyrin photosensitizers improved through structural modifications. The indirect excitation of porphyrin photosensitizers using fluorescent donors (fluorescence resonance energy transfer) has been successfully used to address these issues. In this review, the enhancement of the light energy capture efficiency of porphyrins is discussed.
Topics: Humans; Photosensitizing Agents; Porphyrins; Photochemotherapy
PubMed: 37407889
DOI: 10.1007/s11864-023-01120-0 -
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue Sep 2023To investigate the effect of hyperoxia on intestinal metabolomics in mice.
OBJECTIVE
To investigate the effect of hyperoxia on intestinal metabolomics in mice.
METHODS
Sixteen 8-week-old male C57BL/6 mice were randomly divided into hyperoxia group and control group, with 8 mice in each group. The hyperoxia group was exposed to 80% oxygen for 14 days. Mice were anesthetized and euthanized, and cecal contents were collected for untargeted metabolomics analysis by liquid chromatography-mass spectrometry (LC-MS) combined detection. Orthogonal partial least square discriminant analysis (OPLS-DA), volcano plot analysis, heat map analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the effects of hyperoxia on metabolism.
RESULTS
(1) OPLS-DA analysis showed that RY was 0.967 and Q was 0.796, indicating that the model was reliable. (2) Volcano plot and heat map analysis showed significant statistical differences in the expression levels of metabolites between the two groups, with 541 up-regulated metabolites, 64 down-regulated metabolites, and 907 no differences, while the elevated 5-hydroxy-L-lysine was the most significant differential metabolite induced by high oxygen. (3) KEGG pathway enrichment analysis showed that porphyrin and chlorophyll metabolism (P = 0.005), lysine degradation (P = 0.047), and aromatic compound degradation (P = 0.024) were the targets affected by hyperoxia. (4) Differential analysis of metabolic products through KEGG enrichment pathway showed that hyperoxia had a significant impact on the metabolism of porphyrin and chlorophyll, lysine, and aromatic compounds such as benzene and o-cresol.
CONCLUSIONS
Hyperoxia significantly induces intestinal metabolic disorders. Hyperoxia enhances the metabolism of porphyrins and chlorophyll, inhibits the degradation of lysine, and delays the degradation of aromatic compounds such as benzene and o-cresol.
Topics: Mice; Male; Animals; Lysine; Hyperoxia; Benzene; Mice, Inbred C57BL; Metabolic Diseases; Oxygen; Chlorophyll; Porphyrins; Biomarkers
PubMed: 37803959
DOI: 10.3760/cma.j.cn121430-20230607-00427 -
Journal of the American Chemical Society Jul 2023We report an innovative approach to producing bacteriochlorins (bacs) via formal cycloaddition by subjecting a porphyrin to a trimolecular reaction. Bacs are...
We report an innovative approach to producing bacteriochlorins (bacs) via formal cycloaddition by subjecting a porphyrin to a trimolecular reaction. Bacs are near-infrared probes with the intrinsic ability to serve in multimodal imaging. However, despite their ability to fluoresce and chelate metal ions, existing bacs have thus offered limited ability to label biomolecules for target specificity or have lacked chemical purity, limiting their use in bio-imaging. In this work, bacs allowed a precise and controlled appending of clickable linkers, lending the porphyrinoids substantially more chemical stability, clickability, and solubility, rendering them more suitable for preclinical investigation. Our bac probes enable the targeted use of biomolecules in fluorescence imaging and Cerenkov luminescence for guided intraoperative imaging. Bacs' capacity for chelation provides opportunities for use in non-invasive positron emission tomography/computed tomography. Herein, we report the labeling of bacs with Hs1a, a (NaV1.7)-sodium-channel-binding peptide derived from the Chinese tarantula to yield Bac-Hs1a and radiolabeled Hs1a, which shuttles our bac sensor(s) to mouse nerves. In vivo, the bac sensor allowed us to observe high signal-to-background ratios in the nerves of animals injected with fluorescent Bac-Hs1a and radiolabeled Hs1a in all imaging modes. This study demonstrates that Bac-Hs1a and [Cu]Cu-Bac-Hs1a accumulate in peripheral nerves, providing contrast and utility in the preclinical space. For the chemistry and bio-imaging fields, this study represents an exciting starting point for the modular manipulation of bacs, their development and use as probes for diagnosis, and their deployment as formidable multiplex nerve-imaging agents for use in routine imaging experiments.
Topics: Animals; Mice; Porphyrins
PubMed: 37339504
DOI: 10.1021/jacs.3c02520 -
Cell Communication and Signaling : CCS Jan 2024Red blood cells (RBCs) transfusion is related to perioperative neurocognitive disorders. The toxic effect of free heme has been identified in many pathologies. However,...
BACKGROUND
Red blood cells (RBCs) transfusion is related to perioperative neurocognitive disorders. The toxic effect of free heme has been identified in many pathologies. However, the underlying mechanisms of RBCs transfusion or free heme in cognitive impairment have not been clearly explored. Therefore, this research was conducted to determine the mechanism of free heme-induced neuroinflammation and cognitive impairment.
METHODS
Rats were received intraperitoneal injection of hemin alone or combined with intracerebroventricular injection of Hemopexin (HPX), and MWM test was conducted to measure cognitive function. The amount of heme-HPX complexes was evaluated by flow cytometry for CD91 + cells. The microglial inflammatory response in rat brain was observed by immunofluorescence staining of Iba-1, and the inflammatory factors of TNF-α, IL-1β and IL-6 in rat brain and BV2 cells were detected by ELISA analysis. Furthermore, neuronal apoptosis in HT22 cells alone and in HT22 + BV2 coculture system was detected by flow cytometry and immunofluorescence staining. Finally, western blot was conducted to detect TLR4/MyD88/NF-κB proteins in rat brain and BV2 cells treated with hemin or combined with pathway inhibitors. Additionally, the M1 surface marker CD86 was observed in BV2 cells to further confirm neuroinflammation.
RESULTS
Intraperitoneal injection of hemin induced cognitive impairment, increase of CD91 + cells, up-regulation of TNF-α and IL-1β, down-regulation of IL-6, activation of microglia, and activation of the TLR4/MyD88/NF-κB signaling pathway in rat brain. Significantly, intracerebroventricular injection of HPX reduced the above effects. Hemin induced boost of TNF-α, IL-1β and IL-6 in BV2 cells, as well as apoptosis in HT22 cells. Notably, when HT22 cells were cocultured with BV2 cells, apoptosis was significantly increased. Hemin also induced activation of the TLR4/MyD88/NF-κB signaling pathway and increased the M1 surface marker CD86 in BV2 cells, and inhibiting this pathway reduced the inflammatory responses.
CONCLUSIONS
Free heme induces cognitive impairment, and the underlying mechanism may involve neuronal apoptosis and microglial inflammation via the TLR4/MyD88/NF-κB signaling pathway. HPX may have potential therapeutic effects. Video Abstract.
Topics: Animals; Rats; NF-kappa B; Heme; Microglia; Myeloid Differentiation Factor 88; Hemin; Neuroinflammatory Diseases; Interleukin-6; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Adaptor Proteins, Signal Transducing; Cognitive Dysfunction; Signal Transduction
PubMed: 38183122
DOI: 10.1186/s12964-023-01387-8 -
Redox Biology Nov 2023We recently reported a previously unknown salutary role for xanthine oxidoreductase (XOR) in intravascular heme overload whereby hepatocellular export of XOR to the...
We recently reported a previously unknown salutary role for xanthine oxidoreductase (XOR) in intravascular heme overload whereby hepatocellular export of XOR to the circulation was identified as a seminal step in affording protection. However, the cellular signaling and export mechanisms underpinning this process were not identified. Here, we present novel data showing hepatocytes upregulate XOR expression/protein abundance and actively release it to the extracellular compartment following exposure to hemopexin-bound hemin, hemin or free iron. For example, murine (AML-12 cells) hepatocytes treated with hemin (10 μM) exported XOR to the medium in the absence of cell death or loss of membrane integrity (2.0 ± 1.0 vs 16 ± 9 μU/mL p < 0.0001). The path of exocytosis was found to be noncanonical as pretreatment of the hepatocytes with Vaculin-1, a lysosomal trafficking inhibitor, and not Brefeldin A inhibited XOR release and promoted intracellular XOR accumulation (84 ± 17 vs 24 ± 8 hemin vs 5 ± 3 control μU/mg). Interestingly, free iron (Fe and Fe) induced similar upregulation and release of XOR compared to hemin. Conversely, concomitant treatment with hemin and the classic transition metal chelator DTPA (20 μM) or uric acid completely blocked XOR release (p < 0.01). Our previously published time course showed XOR release from hepatocytes likely required transcriptional upregulation. As such, we determined that both Sp1 and NF-kB were acutely activated by hemin treatment (∼2-fold > controls for both, p < 0.05) and that silencing either or TLR4 with siRNA prevented hemin-induced XOR upregulation (p < 0.01). Finally, to confirm direct action of these transcription factors on the Xdh gene, chromatin immunoprecipitation was performed indicating that hemin significantly enriched (∼5-fold) both Sp1 and NF-kB near the transcription start site. In summary, our study identified a previously unknown pathway by which XOR is upregulated via SP1/NF-kB and subsequently exported to the extracellular environment. This is, to our knowledge, the very first study to demonstrate mechanistically that XOR can be specifically targeted for export as the seminal step in a compensatory response to heme/Fe overload.
Topics: Animals; Mice; Xanthine Dehydrogenase; Hemin; Iron; NF-kappa B; Heme; Hepatocytes
PubMed: 37703667
DOI: 10.1016/j.redox.2023.102866 -
Nano Letters Jul 2023Therapy-induced DNA damage is the most common strategy to inhibit tumor cell proliferation, but the therapeutic efficacy is limited by DNA repair machinery. Carrier-free...
Therapy-induced DNA damage is the most common strategy to inhibit tumor cell proliferation, but the therapeutic efficacy is limited by DNA repair machinery. Carrier-free nanoproteolysis targeting chimeras (PROTACs), designed as SDNpros, have been developed to enhance photodynamic therapy (PDT) by blocking the DNA damage repair pathway through BRD4 degradation. Specifically, SDNpros are constructed through noncovalent interactions between the photosensitizer of chlorine e6 (Ce6) and PROTACs of BRD4 degrader (dBET57) via self-assembly. SDNpro has favorable dispersibility and a uniform nanosize distribution without drug excipients. Upon light irradiation, SDNpro produces abundant reactive oxygen species (ROS) to induce DNA oxidative damage. Meanwhile, the DNA repair pathway would be interrupted by the concurrent degradation of BRD4, which could intensify the oxidative DNA damage and elevate PDT efficiency. Beneficially, SDNpro suppresses tumor growth and avoids systemic side effects, providing a promising strategy to promote the clinical translation of PROTACs for tumor treatment.
Topics: Nuclear Proteins; Excipients; Cell Line, Tumor; Transcription Factors; Photosensitizing Agents; Photochemotherapy; DNA Damage; Porphyrins; Nanoparticles
PubMed: 37387510
DOI: 10.1021/acs.nanolett.3c01812 -
Acta Biomaterialia Sep 2023After spinal cord injury (SCI), endogenous neural stem cells (NSCs) near the damaged site are activated, but few NSCs migrate to the injury epicenter and differentiate...
After spinal cord injury (SCI), endogenous neural stem cells (NSCs) near the damaged site are activated, but few NSCs migrate to the injury epicenter and differentiate into neurons because of the harsh microenvironment. It has demonstrated that implantation of hydrogel scaffold loaded with multiple cues can enhance the function of endogenous NSCs. However, programming different cues on request remains a great challenge. Herein, a time-programmed linear hierarchical structure scaffold is developed for spinal cord injury recovery. The scaffold is obtained through coaxial 3D printing by encapsulating a dual-network hydrogel (composed of hyaluronic acid derivatives and N-cadherin modified sodium alginate, inner layer) into a temperature responsive gelatin/cellulose nanofiber hydrogel (Gel/CNF, outer layer). The reactive species scavenger, metalloporphyrin, loaded in the outer layer is released rapidly by the degradation of Gel/CNF, inhibiting the initial oxidative stress at lesion site to protect endogenous NSCs; while the inner hydrogel with appropriate mechanical support, linear topology structure and bioactive cues facilitates the migration and neuronal differentiation of NSCs at the later stage of SCI treatment, thereby promoting motor functional restorations in SCI rats. This study offers an innovative strategy for fabrication of multifunctional nerve regeneration scaffold, which has potential for clinical treatment of SCI. STATEMENT OF SIGNIFICANCE: Two major challenges facing the recovery from spinal cord injury (SCI) are the low viability of endogenous neural stem cells (NSCs) within the damaged microenvironment, as well as the difficulty of neuronal regeneration at the injured site. To address these issues, a spinal cord-like coaxial scaffold was fabricated with free radical scavenging agent metalloporphyrin Mn (III) tetrakis (4-benzoic acid) porphyrin and chemokine N-cadherin. The scaffold was constructed by 3D bioprinting for time-programmed protection and modulation of NSCs to effectively repair SCI. This 3D coaxially bioprinted biomimetic construct enables multi-factor on-demand repair and may be a promising therapeutic strategy for SCI.
Topics: Rats; Animals; Cell Differentiation; Hydrogels; Metalloporphyrins; Tissue Scaffolds; Collagen; Spinal Cord Injuries; Spinal Cord; Cadherins; Spinal Cord Regeneration
PubMed: 37479156
DOI: 10.1016/j.actbio.2023.07.020