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International Journal of Molecular... Sep 2023Sigma receptors are non-opiate/non-phencyclidine receptors that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma... (Review)
Review
Sigma receptors are non-opiate/non-phencyclidine receptors that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma membrane and in the membranes of the endoplasmic reticulum, mitochondria, and nucleus. Until recently, the biology/pharmacology of these proteins focused primarily on their role in neuronal functions in the brain/retina. However, there have been recent developments in the field with the discovery of unexpected roles for these proteins in iron/heme homeostasis. Sigma receptor 1 (S1R) regulates the oxidative stress-related transcription factor NRF2 and protects against ferroptosis, an iron-induced cell death process. Sigma receptor 2 (S2R), which is structurally unrelated to S1R, complexes with progesterone receptor membrane components PGRMC1 and PGRMC2. S2R, PGRMC1, and PGRMC2, either independently or as protein-protein complexes, elicit a multitude of effects with a profound influence on iron/heme homeostasis. This includes the regulation of the secretion of the iron-regulatory hormone hepcidin, the modulation of the activity of mitochondrial ferrochelatase, which catalyzes iron incorporation into protoporphyrin IX to form heme, chaperoning heme to specific hemoproteins thereby influencing their biological activity and stability, and protection against ferroptosis. Consequently, S1R, S2R, PGRMC1, and PGRMC2 potentiate disease progression in hemochromatosis and cancer. These new discoveries usher this intriguing group of non-traditional progesterone receptors into an unchartered territory in biology and medicine.
Topics: Ferroptosis; Receptors, sigma; Heme; Receptors, Progesterone; Iron; Homeostasis
PubMed: 37834119
DOI: 10.3390/ijms241914672 -
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 -
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 -
The Journal of Clinical Investigation Dec 2023Microscopic hemorrhage is a common aspect of cancers, yet its potential role as an independent factor influencing both cancer progression and therapeutic response is...
Microscopic hemorrhage is a common aspect of cancers, yet its potential role as an independent factor influencing both cancer progression and therapeutic response is largely ignored. Recognizing the essential function of macrophages in red blood cell disposal, we explored a pathway that connects intratumoral hemorrhage with the formation of cancer-promoting tumor-associated macrophages (TAMs). Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs tend to cluster in perinecrotic hemorrhagic tumor regions. These cells resembled antiinflammatory erythrophagocytic macrophages. We identified heme, a red blood cell metabolite, as a pivotal microenvironmental factor steering macrophages toward protumorigenic activities. Single-cell RNA-Seq and functional assays of TAMs in 3D cell culture spheroids revealed how elevated intracellular heme signals via the transcription factor NRF2 to induce cancer-promoting TAMs. These TAMs stabilized epithelial-mesenchymal transition, enhancing cancer invasiveness and metastatic potential. Additionally, NRF2-activated macrophages exhibited resistance to reprogramming by IFN-γ and anti-CD40 antibodies, reducing their tumoricidal capacity. Furthermore, MC38 colon adenocarcinoma-bearing mice with NRF2 constitutively activated in leukocytes were resistant to anti-CD40 immunotherapy. Overall, our findings emphasize hemorrhage-activated NRF2 in TAMs as a driver of cancer progression, suggesting that targeting this pathway could offer new strategies to enhance cancer immunity and overcome therapy resistance.
Topics: Animals; Mice; NF-E2-Related Factor 2; Tumor-Associated Macrophages; Adenocarcinoma; Colonic Neoplasms; Immunotherapy; Heme; Tumor Microenvironment
PubMed: 38060331
DOI: 10.1172/JCI174528 -
Nature Communications Oct 2023Two-dimensional materials have unusual properties and promise applications in nanoelectronics, spintronics, photonics, (electro)catalysis, separations, and elsewhere....
Two-dimensional materials have unusual properties and promise applications in nanoelectronics, spintronics, photonics, (electro)catalysis, separations, and elsewhere. Most are inorganic and their properties are difficult to tune. Here we report the preparation of Zn porphene, a member of the previously only hypothetical organic metalloporphene family. Similar to graphene, these also are fully conjugated two-dimensional polymers, but are composed of fused metalloporphyrin rings. Zn porphene is synthesized on water surface by two-dimensional oxidative polymerization of a Langmuir layer of Zn porphyrin with KIrCl, reminiscent of known one-dimensional polymerization of pyrroles. It is transferable to other substrates and bridges μm-sized pits. Contrary to previous theoretical predictions of metallic conductivity, it is a p-type semiconductor due to a predicted Peierls distortion of its unit cell from square to rectangular, analogous to the appearance of bond-length alternation in antiaromatic molecules. The observed reversible insertion of various metal ions, possibly carrying a fifth or sixth ligand, promises tunability and even patterning of circuits on an atomic canvas without removing any π centers from conjugation.
PubMed: 37813887
DOI: 10.1038/s41467-023-41461-w -
Scientific Reports Sep 2023Intracerebral hemorrhage (ICH) is a disastrous disease without effective treatment. An extensive body of evidence indicate that neuronal ferroptosis is a key contributor...
Intracerebral hemorrhage (ICH) is a disastrous disease without effective treatment. An extensive body of evidence indicate that neuronal ferroptosis is a key contributor to neurological disfunctions after ICH. Omarigliptin, also known as MK3102, is an anti-diabetic drug that inhibits dipeptidyl peptidase (DPP4). Recently, MK3102 is reported to exhibit anti-ferroptosis and anti-oxidative effects in different pathological conditions. However, the anti-ferroptosis ability of MK3102 in ICH injury is unknown. Hemin was administrated to model ICH injury in cultured primary cortical neurons, and collagenase VII was used to induce ICH in C57BL/6 mice. MK3102 was administered after ICH. Cell Counting Kit-8 (CCK-8) was applied to detect cell viability. Neurological functions were assessed through the Focal deficits neurological scores and corner test. HE and TUNEL staining was applied to evaluate brain damage areas and cell death, respectively. Ferroptosis was evaluated in cultured neurons by fluorescent probe DCFH-DA, FerroOrange, Liperfluo and immunofluorescence of GPX4, AIFM2 and FACL4. Perls staining was performed to visualize Fe deposition. Ferroptosis-related proteins in mouse brain were measured by immunohistochemistry and western blotting. MK3102 reduced the neurotoxicity of hemin in cultured primary cortical neurons. It improved neurological functions associated with a decrease in the number of dead neurons and the area of brain damage after ICH in mice. Moreover, MK3102 prominently upregulated glucagon-like peptide-1 receptor (GLP-1R) levels after ICH. In addition, the elevation of iron content, lipid peroxidation and FACL4 after ICH; and reduction of GPX4 and AIFM2; were mitigated by MK3102 in vitro and in vivo. The neuroprotective effect of MK3102 may be related to anti-ferroptosis by regulating GLP-1R after ICH injury.
Topics: Animals; Mice; Mice, Inbred C57BL; Hemin; Cerebral Hemorrhage; Brain Injuries; Brain
PubMed: 37658227
DOI: 10.1038/s41598-023-41635-y -
The Journal of Physical Chemistry. A Sep 2023Two porphyrinoid nanorings have been studied computationally. They were built by linking 40 Zn-porphyrin units with butadiyne bridges. The molecular structures belonging...
Two porphyrinoid nanorings have been studied computationally. They were built by linking 40 Zn-porphyrin units with butadiyne bridges. The molecular structures belonging to the point group were fully optimized with the Turbomole program at the density functional theory (DFT) level using the B3LYP functional and the def2-SVP basis sets. The aromatic character was studied at the DFT level by calculating the magnetically induced current-density (MICD) susceptibility using the GIMIC program. The neutral molecules are globally non-aromatic with aromatic Zn-porphyrin units. Charged nanorings could not be studied because almost degenerate frontier orbitals led to vanishing optical gaps for the cations. Since DFT calculations of the MICD are computationally expensive, we also calculated the MICD using three pseudo-π models. Appropriate pseudo-π models were constructed by removing the outer hydrogen atoms and replacing all carbon and nitrogen atoms with hydrogen atoms. The central Zn atom was either replaced with a beryllium atom or with two inner hydrogen atoms. Calculations with the computationally inexpensive pseudo-π models yielded qualitatively the same magnetic response as obtained in the all-electron calculations.
PubMed: 37665662
DOI: 10.1021/acs.jpca.3c03564 -
Biotechnology Advances 2023Dye-decolorizing Peroxidases (DyPs) are heme-containing enzymes in fungi and bacteria that catalyze the reduction of hydrogen peroxide to water with concomitant... (Review)
Review
Dye-decolorizing Peroxidases (DyPs) are heme-containing enzymes in fungi and bacteria that catalyze the reduction of hydrogen peroxide to water with concomitant oxidation of various substrates, including anthraquinone dyes, lignin-related phenolic and non-phenolic compounds, and metal ions. Investigation of DyPs has shed new light on peroxidases, one of the most extensively studied families of oxidoreductases; still, details of their microbial physiological role and catalytic mechanisms remain to be fully disclosed. They display a distinctive ferredoxin-like fold encompassing anti-parallel β-sheets and α-helices, and long conserved loops surround the heme pocket with a role in catalysis and stability. A tunnel routes HO to the heme pocket, whereas binding sites for the reducing substrates are in cavities near the heme or close to distal aromatic residues at the surface. Variations in reactions, the role of catalytic residues, and mechanisms were observed among different classes of DyP. They were hypothetically related to the presence or absence of distal HO molecules in the heme pocket. The engineering of DyPs for improved properties directed their biotechnological applications, primarily centered on treating textile effluents and degradation of other hazardous pollutants, to fields such as biosensors and valorization of lignin, the most abundant renewable aromatic polymer. In this review, we track recent research contributions that furthered our understanding of the activity, stability, and structural properties of DyPs and their biotechnological applications. Overall, the study of DyP-type peroxidases has significant implications for environmental sustainability and the development of new bio-based products and materials with improved end-of-life options via biodegradation and chemical recyclability, fostering the transition to a sustainable bio-based industry in the circular economy realm.
Topics: Peroxidases; Biocatalysis; Lignin; Hydrogen Peroxide; Heme; Coloring Agents
PubMed: 37044267
DOI: 10.1016/j.biotechadv.2023.108153 -
Biochimie Jan 2024Overexpression of recombinant Bacillus cereus TSPO (BcTSPO) in E. coli bacteria leads to its recovery with a bound hemin both in bacterial membrane (MB) and inclusion...
Overexpression of recombinant Bacillus cereus TSPO (BcTSPO) in E. coli bacteria leads to its recovery with a bound hemin both in bacterial membrane (MB) and inclusion bodies (IB). Unlike mouse TSPO, BcTSPO purified in SDS detergent from IB is well structured and can bind various ligands such as high-affinity PK 11195, protoporphyrin IX (PPIX) and δ-aminolevulinic acid (ALA). For each of the three ligands, H-N HSQC titration NMR experiments suggest that different amino acids of BcTSPO binding cavity are involved in the interaction. PPIX, an intermediate of heme biosynthesis, binds to the cavity of BcTSPO and its fluorescence can be significantly reduced in the presence of light and oxygen. The light irradiation leads to two products that have been isolated and characterized as photoporphyrins. They result from the addition of singlet oxygen to the two vinyl groups hence leading to the formation of hydroxyaldehydes. The involvement of water molecules, recently observed along with the binding of heme in Rhodobacter sphaeroides (RsTSPO) is highly probable. Altogether, these results raise the question of the role of TSPO in heme biosynthesis regulation as a possible scavenger of reactive intermediates.
PubMed: 38280504
DOI: 10.1016/j.biochi.2024.01.011 -
MSystems Aug 2023Periodontal disease is a chronic inflammatory disease in which the oral pathogen plays an important role. expresses virulence determinants in response to higher hemin...
Periodontal disease is a chronic inflammatory disease in which the oral pathogen plays an important role. expresses virulence determinants in response to higher hemin concentrations, but the underlying regulatory processes remain unclear. Bacterial DNA methylation has the potential to fulfil this mechanistic role. We characterized the methylome of , and compared its variation to transcriptome changes in response to hemin availability. W50 was grown in chemostat continuous culture with excess or limited hemin, prior to whole-methylome and transcriptome profiling using Nanopore and Illumina RNA-Seq. DNA methylation was quantified for Dam/Dcm motifs and all-context N6-methyladenine (6mA) and 5-methylcytosine (5mC). Of all 1,992 genes analyzed, 161 and 268 were respectively over- and under-expressed with excess hemin. Notably, we detected differential DNA methylation signatures for the Dam "GATC" motif and both all-context 6mA and 5mC in response to hemin availability. Joint analyses identified a subset of coordinated changes in gene expression, 6mA, and 5mC methylation that target genes involved in lactate utilization and ABC transporters. The results identify altered methylation and expression responses to hemin availability in , with insights into mechanisms regulating its virulence in periodontal disease. IMPORTANCE DNA methylation has important roles in bacteria, including in the regulation of transcription. , an oral pathogen in periodontitis, exhibits well-established gene expression changes in response to hemin availability. However, the regulatory processes underlying these effects remain unknown. We profiled the novel epigenome, and assessed epigenetic and transcriptome variation under limited and excess hemin conditions. As expected, multiple gene expression changes were detected in response to limited and excess hemin that reflect health and disease, respectively. Notably, we also detected differential DNA methylation signatures for the Dam "GATC" motif and both all-context 6mA and 5mC in response to hemin. Joint analyses identified coordinated changes in gene expression, 6mA, and 5mC methylation that target genes involved in lactate utilization and ABC transporters. The results identify novel regulatory processes underlying the mechanism of hemin regulated gene expression in with phenotypic impacts on its virulence in periodontal disease.
Topics: Humans; Hemin; Porphyromonas gingivalis; DNA Methylation; Periodontal Diseases; ATP-Binding Cassette Transporters; Gene Expression
PubMed: 37436062
DOI: 10.1128/msystems.01193-22