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FASEB Journal : Official Publication of... May 2024Heme is a prosthetic group of proteins involved in vital physiological processes. It participates, for example, in redox reactions crucial for cell metabolism due to the...
Heme is a prosthetic group of proteins involved in vital physiological processes. It participates, for example, in redox reactions crucial for cell metabolism due to the variable oxidation state of its central iron atom. However, excessive heme can be cytotoxic due to its prooxidant properties. Therefore, the control of intracellular heme levels ensures the survival of organisms, especially those that deal with high concentrations of heme during their lives, such as hematophagous insects. The export of heme initially attributed to the feline leukemia virus C receptor (FLVCR) has recently been called into question, following the discovery of choline uptake by the same receptor in mammals. Here, we found that RpFLVCR is a heme exporter in the midgut of the hematophagous insect Rhodnius prolixus, a vector for Chagas disease. Silencing RpFLVCR decreased hemolymphatic heme levels and increased the levels of intracellular dicysteinyl-biliverdin, indicating heme retention inside midgut cells. FLVCR silencing led to increased expression of heme oxygenase (HO), ferritin, and mitoferrin mRNAs while downregulating the iron importers Malvolio 1 and 2. In contrast, HO gene silencing increased FLVCR and Malvolio expression and downregulated ferritin, revealing crosstalk between heme degradation/export and iron transport/storage pathways. Furthermore, RpFLVCR silencing strongly increased oxidant production and lipid peroxidation, reduced cytochrome c oxidase activity, and activated mitochondrial biogenesis, effects not observed in RpHO-silenced insects. These data support FLVCR function as a heme exporter, playing a pivotal role in heme/iron metabolism and maintenance of redox balance, especially in an organism adapted to face extremely high concentrations of heme.
Topics: Animals; Heme; Rhodnius; Oxidation-Reduction; Mitochondria; Receptors, Virus; Leukemia Virus, Feline; Insect Proteins
PubMed: 38780525
DOI: 10.1096/fj.202301671RR -
Infection and Immunity Jun 2024causes the genital ulcer disease chancroid and painful cutaneous ulcers in children who live in the tropics. To acquire heme from the host, expresses a TonB-dependent...
causes the genital ulcer disease chancroid and painful cutaneous ulcers in children who live in the tropics. To acquire heme from the host, expresses a TonB-dependent hemoglobin receptor, HgbA, which is necessary and sufficient for to progress to the pustular stage of disease in a controlled human infection model. HgbA transports hemoglobin across the outer membrane; how heme is transported across the cytoplasmic membrane is unclear. In previous studies, transcripts encoding the YfeABCD heme transporter were upregulated in experimental lesions caused by in human volunteers, suggesting the latter may have a role in virulence. Here we constructed a double deletion mutant, 35000HPΔΔ, which exhibited growth defects relative to its parent 35000HP in media containing human hemoglobin as an iron source. Five human volunteers were inoculated at three sites on the skin overlying the deltoid with each strain. The results of the trial showed that papules formed at 100% (95% CI, 71.5, 100) at both 35000HP and 35000HPΔΔ-inoculated sites ( = 1.0). Pustules formed at 60% (95% CI, 25.9, 94.1) at parent-inoculated sites and 53% (95% CI, 18.3, 88.4) at mutant-inoculated sites ( = 0.79). Thus, the ABC transporter encoded by and was dispensable for virulence in humans. In the absence of YfeABCD, likely utilizes other periplasmic binding proteins and ABC-transporters such as HbpA, SapABCDF, and DppBCDF to shuttle heme from the periplasm into the cytoplasm, underscoring the importance of redundancy of such systems in gram-negative pathogens.
Topics: Haemophilus ducreyi; Humans; Chancroid; Bacterial Proteins; Virulence; Iron; Male; Adult; Heme
PubMed: 38780215
DOI: 10.1128/iai.00058-24 -
Inorganic Chemistry Jun 2024Groups 10-12 metalloporphyrins have been recognized for their numerous properties essential for the development of new sensing materials. In this work, accurate...
Groups 10-12 metalloporphyrins have been recognized for their numerous properties essential for the development of new sensing materials. In this work, accurate gas-phase enthalpies of formation, Δ(g,298.15), are predicted for the series of Ni, Cu, Zn, Pd, Ag, and Cd tetraphenylporphyrins (MTPPs) on the basis of the reaction-based Feller-Peterson-Dixon approach and high-level ab initio DLPNO-CCSD(T) calculations. Our recently developed automatic generator of the balanced chemical reactions was employed to reduce the bias of the theoretical Δ(g,298.15) toward a particular reaction. Theoretical Δ(g,298.15) for ZnTPP (227.0 ± 3.4 kcal mol) does not support the previously reported experimental value of 132 ± 2 kcal mol. The origin of the discrepancy probably lies in the experimental solid-state Δ(ZnTPP, cr,298.15) as it stems from our theoretical evaluations of the Δ(cr,298.15) values for the entire set of transition metal TPP complexes. The large discrepancy between experiment and theory also holds when different DFT functionals (ωB97M-V, PBE0-D4, and B3LYP-D4) paired with quadruple-ζ quality basis sets are used for the theoretical calculations. Experimental revisiting of the solid-state enthalpy of formation of ZnTPP and analogue measurements for other transition metal TPPs are needed to resolve the observed discrepancy. Based on the predicted enthalpies of formation of MTPPs, the relative energies of the metal-ligand bonding are evaluated and the trends are compared to those for the complexes of the unsubstituted porphyrin with the same set of metals derived in [, , , 1063]. According to both studies, Pd complexes exhibit the strongest bonding, while the Cd species are the least stable metallocomplexes within the considered series.
PubMed: 38780084
DOI: 10.1021/acs.inorgchem.4c00662 -
ACS Sensors Jun 2024Nitric oxide (NO) is an inorganic signaling molecule that plays a crucial role in the regulation of numerous physiological functions. An oxidation product of the...
Nitric oxide (NO) is an inorganic signaling molecule that plays a crucial role in the regulation of numerous physiological functions. An oxidation product of the cytoprotective NO is cytotoxic peroxynitrite (ONOO). In biological systems, the concentrations of NO and ONOO are typically transient, ranging from nanomolar to micromolar, and these increases are normally followed by a swift return to their basal levels due to their short life spans. To understand the vital physiological role of NO and ONOO and , sensitive and selective methods are necessary for direct and continuous NO and ONOO measurements in real time. Because electrochemical methods can be adjusted for selectivity, sensitivity, and biocompatibility in demanding biological environments, they are suitable for real-time monitoring of NO and ONOO release. Metalloporphyrin nanosensors, described here, have been designed to measure the concentration of NO and ONOO produced by a single human neural progenitor cell (hNPC) in real time. These nanosensors (200-300 nm in diameter) can be positioned accurately in the proximity of 4-5 ± 1 μm from an hNPC membrane. The response time of the sensors is better than a millisecond, while detection limits for NO and ONOO are 1 × 10 and 3 × 10 mol/L, respectively, with a linear concentration response of up to about 1 μM. The application of these metalloporphyrin nanosensors for the efficient measurement of the concentrations of NO and ONOO in hNPCs is demonstrated, providing an opportunity to observe in real time the molecular changes of the two signaling molecules .
Topics: Peroxynitrous Acid; Humans; Nitric Oxide; Neural Stem Cells; Metalloporphyrins; Biosensing Techniques; Electrochemical Techniques; Nanotechnology
PubMed: 38773722
DOI: 10.1021/acssensors.4c00234 -
ACS Applied Bio Materials Jun 2024The management of multibacterial infections remains clinically challenging in the care and treatment of chronic diabetic wounds. Photodynamic therapy (PDT) offers a...
The management of multibacterial infections remains clinically challenging in the care and treatment of chronic diabetic wounds. Photodynamic therapy (PDT) offers a promising approach to addressing bacterial infections. However, the limited target specificity and internalization properties of traditional photosensitizers (PSs) toward Gram-negative bacteria pose significant challenges to their antibacterial efficacy. In this study, we designed an iron heme-mimetic PS (MnO@Fe-TCPP(Zn)) based on the iron dependence of bacteria that can be assimilated by bacteria and retained in different bacteria strains (, , and methicillin-resistant ) and which shows high PDT antibacterial efficacy. For accelerated wound healing after antibacterial treatment, MnO@Fe-TCPP(Zn) was loaded into a zwitterionic hydrogel with biocompatibility and antifouling properties to form a nanocomposite antibacterial hydrogel (PSB-MnO@Fe-TCPP(Zn)). In the multibacterial infectious diabetic mouse wound model, the PSB-MnO@Fe-TCPP(Zn) hydrogel dressing rapidly promoted skin regeneration by effectively inhibiting bacterial infections, eliminating inflammation, and promoting angiogenesis. This study provides an avenue for developing broad-spectrum antibacterial nanomaterials for combating the antibiotic resistance crisis and promoting the healing of complex bacterially infected wounds.
Topics: Wound Healing; Animals; Mice; Anti-Bacterial Agents; Photochemotherapy; Photosensitizing Agents; Biocompatible Materials; Microbial Sensitivity Tests; Heme; Materials Testing; Iron; Escherichia coli; Particle Size; Diabetes Mellitus, Experimental; Methicillin-Resistant Staphylococcus aureus; Staphylococcus aureus; Manganese Compounds
PubMed: 38772009
DOI: 10.1021/acsabm.4c00427 -
Inorganic Chemistry Jun 2024Relativistic restricted active space (RAS) second-order multireference perturbation theory (MRPT2) methods, incorporating spin-orbit (SO) coupling perturbatively via...
Relativistic restricted active space (RAS) second-order multireference perturbation theory (MRPT2) methods, incorporating spin-orbit (SO) coupling perturbatively via state interaction (SO-MRPT2/RASSCF), were used to reproduce the absorption spectra of parent metalloporphyrins containing the Mg, Zn, Co, Ni, Cu, or FeCl ions in the 12,500-40,000 cm region. Particular attention was paid to the interaction between the porphyrin ring and the metal 3 electrons in states of different multiplicities (we used metal 3 and double -shell or 3' orbitals). For this class of compounds, the -electron valence state perturbation theory (NEVPT2) method is superior to the complete active space perturbation theory (CASPT2) and successfully reproduces the energies of all four characteristic transitions (, , , and ) of closed-shell metalloporphyrins. Inclusion of SO coupling was found to have very little effect on excitation energies and oscillator strengths. For FeCl porphyrin, we treated ligand-to-metal charge-transfer (LMCT; π), metal ligand field (), and metal-to-ligand charge-transfer (MLCT; ,π*) transitions within the same framework. The broad and intense spectral features associated with its (Soret) band are attributed to multiconfigurational LMCT (,π*) bands involving strong metal-ligand orbital mixing.
PubMed: 38770816
DOI: 10.1021/acs.inorgchem.3c04460 -
The Journal of Physical Chemistry... May 2024The strong coupling of light and matter within electromagnetic resonators leads to the formation of cavity polaritons whose hybrid nature may help certain ground and...
The strong coupling of light and matter within electromagnetic resonators leads to the formation of cavity polaritons whose hybrid nature may help certain ground and excited state chemical processes. To help enable the development of polariton chemistry, we have developed and applied a spectroscopic technique to leverage the relatively larger spatial coherence of polaritons to assess the determinants of relaxation in hybrid light-matter states. By exciting the lower polariton (LP) state in cavity samples filled with different metalloporphyrin chromophores, we measured and modeled angle-resolved photoluminescence excitation spectra. Our results suggest that the shortest lived constituent of the LP state characterized by specific Hopfield coefficients limits the light absorption of the intracavity molecules, which we equate with the effective polariton lifetime. Our results suggest that researchers need to consider the lifetimes of both photons and excitons participating in strong light-matter coupling when designing polaritonic systems and the methods they can use to assess the relaxation of polaritonic states.
PubMed: 38768370
DOI: 10.1021/acs.jpclett.4c01120 -
American Journal of Physiology. Cell... Jul 2024The blood-brain barrier (BBB) plays a critical role in the development and outcome of subarachnoid hemorrhage (SAH). This study focuses on the potential mechanism by...
The blood-brain barrier (BBB) plays a critical role in the development and outcome of subarachnoid hemorrhage (SAH). This study focuses on the potential mechanism by which G-protein-coupled estrogen receptor 30 (GPR30) affects the BBB after SAH. A rat SAH model was established using an intravascular perforation approach. G1 (GPR30 agonist) was administered to investigate the mechanism of BBB damage after SAH. Brain water content, Western blotting, Evans blue leakage, and immunofluorescence staining were performed. Brain microvascular endothelial cells were induced by hemin to establish SAH model in vitro. By adding LY294002 [a phosphatidylinositol 3-kinase (PI3K) blocker] and zinc protoporphyrin IX (ZnPP IX) [a heme oxygenase 1 (HO-1) antagonist], the mechanism of improving BBB integrity through the activation of GPR30 was studied. In vivo, GPR30 activation improved BBB disruption, as evidenced by decreased cerebral edema, downregulated albumin expression, and reduced extravasation of Evans blue and IgG after G1 administration in SAH rats. Moreover, SAH downregulated the levels of tight junction (TJ) proteins, whereas treatment with G1 reversed the effect of SAH. The protective effect of G1 on BBB integrity in vitro was consistent with that in vivo, as evidenced by G1 reducing the impact of hemin on transendothelial electrical resistance (TEER) value, dextran diffusivity, and TJ protein levels in brain microvascular endothelial cells. In addition, G1 activated the PI3K/ protein kinase B (Akt) and nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 pathways both in vivo and in vitro. Furthermore, the administration of LY294002 and ZnPP IX partially reversed the protective effect of G1 on BBB integrity in hemin-stimulated cells. We demonstrated that the activation of GPR30, at least partly through the PI3K/Akt and Nrf2/HO-1 pathways, alleviated BBB damage both in vivo and in vitro. This study introduced a novel therapeutic approach for protecting the BBB after SAH. The PI3K/Akt and Nrf2/HO-1 pathways might be potential mechanisms by which GPR30 protected the integrity of the BBB in SAH models. Therefore, treatment of SAH with GPR30 activator might be a promising therapeutic strategy.
Topics: Animals; NF-E2-Related Factor 2; Blood-Brain Barrier; Proto-Oncogene Proteins c-akt; Receptors, G-Protein-Coupled; Subarachnoid Hemorrhage; Male; Rats, Sprague-Dawley; Signal Transduction; Rats; Phosphatidylinositol 3-Kinases; Endothelial Cells; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Disease Models, Animal; Phosphatidylinositol 3-Kinase; Hemin
PubMed: 38766766
DOI: 10.1152/ajpcell.00035.2024 -
Chemistry & Biodiversity May 2024The cytochrome P450 is a superfamily of hemoproteins mainly present in the liver and are versatile biocatalysts. They participate in the primary metabolism and...
The cytochrome P450 is a superfamily of hemoproteins mainly present in the liver and are versatile biocatalysts. They participate in the primary metabolism and biosynthesis of various secondary metabolites. Chemical catalysts are utilized to replicate the activities of enzymes. Metalloporphyrins and Salen complexes can contribute to the products' characterization and elucidate biotransformation processes, which are investigated during pre-clinical trials. These catalysts also help discover biologically active compounds and get better yields of products of industrial interest. This review aims to investigate which natural product classes are being investigated by biomimetic chemical models and the functionalities applied in the use of these catalysts. A limited number of studies were observed, with terpenes and alkaloids being the most investigated natural product classes. The research also revealed that Metalloporphyrins are still the most popular in the studies, and the identity and yield of the products obtained depend on the reaction system conditions.
PubMed: 38763894
DOI: 10.1002/cbdv.202400668 -
Redox Biology Jul 2024Activation of inflammation is tightly associated with metabolic reprogramming in macrophages. The iron-containing tetrapyrrole heme can induce pro-oxidant and...
Activation of inflammation is tightly associated with metabolic reprogramming in macrophages. The iron-containing tetrapyrrole heme can induce pro-oxidant and pro-inflammatory effects in murine macrophages, but has been associated with polarization towards an anti-inflammatory phenotype in human macrophages. In the current study, we compared the regulatory responses to heme and the prototypical Toll-like receptor (TLR)4 ligand lipopolysaccharide (LPS) in human and mouse macrophages with a particular focus on alterations of cellular bioenergetics. In human macrophages, bulk RNA-sequencing analysis indicated that heme led to an anti-inflammatory transcriptional profile, whereas LPS induced a classical pro-inflammatory gene response. Co-stimulation of heme with LPS caused opposing regulatory patterns of inflammatory activation and cellular bioenergetics in human and mouse macrophages. Specifically, in LPS-stimulated murine, but not human macrophages, heme led to a marked suppression of oxidative phosphorylation and an up-regulation of glycolysis. The species-specific alterations in cellular bioenergetics and inflammatory responses to heme were critically dependent on the availability of nitric oxide (NO) that is generated in inflammatory mouse, but not human macrophages. Accordingly, studies with an inducible nitric oxide synthase (iNOS) inhibitor in mouse, and a pharmacological NO donor in human macrophages, reveal that NO is responsible for the opposing effects of heme in these cells. Taken together, the current findings indicate that NO is critical for the immunomodulatory role of heme in macrophages.
Topics: Humans; Heme; Animals; Nitric Oxide; Mice; Macrophages; Lipopolysaccharides; Inflammation; Nitric Oxide Synthase Type II; Oxidative Phosphorylation; Energy Metabolism; Glycolysis
PubMed: 38762951
DOI: 10.1016/j.redox.2024.103191